Author Report for: Liu JContact information:Liu JunjunHuazhong University of Science and Technology; Pharmaceutical Science; 13 Hangkong Rd.; Wuhan; 430030ChinaPhone : +8615527455184 Fax : Send E-Mail to Liu Junjun The 11th International Meeting on Cholinesterases (Kazan, Russia) The 13th International Meeting on Cholinesterases 7th Conference on Paraoxonase (Hradec Králové Czech Republic) The 14th International Symposium on Cholinergic Mechanisms (Hangzhou, China)
Chang X, Ding X, Wang J, Cai Q, Wang G, Liu J Ref: Ann Med, 55:2226910, 2023 : PubMed ESTHER: Chang_2023_Ann.Med_55_2226910 PubMedSearch: Chang 2023 Ann.Med 55 2226910 PubMedID: 37350750 Abstract OBJECTIVE: Graves' disease (GD) is an organ-specific autoimmune disease. The production of anti-thyrotropin receptor antibodies (TRAb) is associated with a loss of immune tolerance. Dipeptidyl peptidase-4 (DPP-4) is expressed on multiple immune cells. This study aimed to investigate the relationship between serum concentration/activity of DPP4 and the severity of hyperthyroidism in GD patients. METHODS: A total of 82 newly diagnosed drug-naive patients with GD hyperthyroidism, 20 patients with non-autoimmune thyrotoxicosis and 122 age- and sex- matched healthy controls were enrolled. The clinical parameters and serum concentration and activity of DPP4 were measured. RESULTS: The GD group had increased serum concentration and activity of DPP4 than the healthy controls and patients with non-autoimmune thyrotoxicosis, while no significant difference was observed in the latter two groups. Multivariate linear regression indicated that the serum concentration/activity of DPP4 were positively associated with FT3, FT4 and TRAb levels in the GD patients. And the positive association between serum concentration/activity of DPP4 and TRAb was remained even after adjustment for confounding factors (all p < 0.05). CONCLUSIONS: The GD patients had significantly increased serum concentration/activity of DPP4. And the serum concentration/activity of DPP4 was positively associated with the severity of hyperthyroidism in GD patients.Key messagesThe activity and concentration of DPP4 in patients with Graves' disease were higher than those in healthy controls.There was a significant positive correlation between serum DPP4 concentration and TRAb levels in patients with Graves' disease.In patients with Graves 'disease, serum DPP4 activity was positively correlated with TRAb levels. Title: Visual and Rapid Detection of Nerve Agent Mimics in Gas and Solution Phase by a Simple Fluorescent Probe Chen Q, Liu J, Liu S, Zhang J, He L, Liu R, Jiang H, Han X, Zhang K Ref: Analytical Chemistry, :, 2023 : PubMed ESTHER: Chen_2023_Anal.Chem__ PubMedSearch: Chen 2023 Anal.Chem PubMedID: 36802493 Abstract Chemical nerve agents are highly toxic organophosphorus compounds that are easy to obtain and can be utilized by terrorists to threaten homeland security and human safety. Those organophosphorus nerve agents contain nucleophilic ability that can react with acetylcholinesterase leading to muscular paralysis and human death. Therefore, there is great importance to explore a reliable and simple method to detect chemical nerve agents. Herein, the o-phenylenediamine-linked dansyl chloride as a colorimetric and fluorescent probe has been prepared to detect specific chemical nerve agent stimulants in the solution and vapor phase. The o-phenylenediamine unit serves as a detection site that can react with diethyl chlorophosphate (DCP) in a rapid response within 2 min. A satisfied relationship line was obtained between fluorescent intensity and the concentration of DCP in the range of 0-90 microM. In the optimized conditions, we conducted the fluorescent titration to measure the limits of detection (0.082 microM) with the fluorescent enhancement up to 18-fold. Fluorescence titration and NMR studies were also conducted to explore the detection mechanism, indicating that the formation of phosphate ester causes the intensity of fluorescent change during the PET process. Finally, probe 1 coated with the paper test is utilized to detect DCP vapor and solution by the naked eye. We expect that this probe may give some admiration to design the small molecule organic probe and applied in the selectivity detection of chemical nerve agents. Title: Novel N(1) or N(9) modified alpha-carboline analogues as potential ligands in Alzheimer's disease therapy: Synthesis and neurobiological activity evaluation Dan W, Cao Y, Sun Y, Zhang J, Liu J, Gao J, Han R, Dai J Ref: Bioorg Chem, 133:106378, 2023 : PubMed ESTHER: Dan_2023_Bioorg.Chem_133_106378 PubMedSearch: Dan 2023 Bioorg.Chem 133 106378 PubMedID: 36736035 Abstract A series of new alpha-carboline analogues modified at N(1) or N(9) positions by alkyl, benzyl and phenyl were synthesized and characterized as potential ligands for AD therapy. These compounds exhibited multifunctional neurobiological activities including anti-neuroinflammatory, neuroprotective and cholinesterase inhibition. Among them, compound 5d with good drug-like properties and no cytotoxicity, showed potent inhibitory activity against NO production (IC(50) = 1.45 microM), which could suppress the expression levels of iNOS and COX-2 in a dose-dependent manner. Further mechanism exploration indicated that compound 5d could regulate the NF-kappaB signaling pathway by decreasing the phosphorylation of IkappaB-alpha and p65. Notably, compound 5d could effectively decrease the LPS-induced aberrations in zebrafish. Compounds 3b, 4f, 5c, 5g, 5m and 6i exhibited potential neuroprotective activity (cell viability > 70 %) in the H(2)O(2)-induced PC-12 neuronal death model and rescued the SOD activity. In particular, compounds 3b, 4f, and 5g activated the Nrf2 signaling pathway, and improved the expressions of antioxidant proteins NQO-1 and HO-1, which alleviated the head cell apoptosis in zebrafish. Additionally, compound 6i exhibited potential inhibitory activity against BuChE with IC(50) of 0.77 microM. Overall, this work provided some lead compounds based on alpha-carboline used for AD therapy. Title: Steroids and dihydroisocoumarin glycosides from Xylaria sp. by the one strain many compounds strategy and their bioactivities Gan D, Li C, Shu Y, Wang J, Wang C, Zhu L, Yang Y, Liu J, He B and Ding Z <1 more author(s)> Gan D, Li C, Shu Y, Wang J, Wang C, Zhu L, Yang Y, Liu J, He B, Cai L, Ding Z (- 1) Ref: Chin J Nat Med, 21:154, 2023 : PubMed ESTHER: Gan_2023_Chin.J.Nat.Med_21_154 PubMedSearch: Gan 2023 Chin.J.Nat.Med 21 154 PubMedID: 36871983 Abstract The fungus Xylaria sp. KYJ-15 was isolated from Illigera celebica. Based on the one strain many compounds (OSMAC) strategy, the strain was fermented on potato and rice solid media, respectively. As a result, two novel steroids, xylarsteroids A (1) and B (2), which are the first examples of C(28)-steroid with an unusual beta- and gamma-lactone ring, respectively, along with two new dihydroisocoumarin glycosides, xylarglycosides A (3) and B (4), were identified. Their structures were elucidated by spectroscopic methods, X-ray diffraction and electronic circular dichroism (ECD) experiments. All isolated compounds were evaluated for cytotoxicity, DPPH radical scavenging activity, acetylcholinesterase inhibitory and antimicrobial effect. Compound 1 exhibited potent AChE inhibitory activity with an IC(50) value of 2.61 +/- 0.05 micromol.L(-1). The beta-lactone ring unit of 1 is critical for its AChE inhibitory activity. The finding was further confirmed through exploring the interaction of 1 with AChE by molecular docking. In addition, both compounds 1 and 2 exhibited obvious antibacterial activity against Bacillus subtilis with a minimum inhibitory concentration (MIC) of 2 microg.mL(-1). Compounds 3 and 4 exhibited antibacterial activities against Staphylococcus aureus with MICs of 4 and 2 microg.mL(-1), respectively, which also exhibited DPPH radical scavenging activity comparable to the positive control with IC(50) values of 9.2 +/- 0.03 and 13.3 +/- 0.01 micromol.L(-1), respectively. Title: Inhibition of Th17 cells by donepezil ameliorates experimental lung fibrosis and pulmonary hypertension Guo Y, He Z, Chen Z, Chen F, Wang C, Zhou W, Liu J, Liu H, Shi R Ref: Theranostics, 13:1826, 2023 : PubMed ESTHER: Guo_2023_Theranostics_13_1826 PubMedSearch: Guo 2023 Theranostics 13 1826 PubMedID: 37064881 Abstract Rationale: Pulmonary hypertension (PH) secondary to lung fibrosis belongs to WHO Group III, one of the most common subgroups of PH; however, it lacks effective treatment options. Cholinesterase inhibitor donepezil (DON) has been shown to effectively improve Group I PH. However, its effects on Group III PH are unknown. Methods: A lung fibrosis-induced PH mouse model was constructed using a single intratracheal instillation of bleomycin (BLM), after which DON was administered daily. Pulmonary artery and right ventricle (RV) remodeling were evaluated at the end of the study. Lung tissue in each group was analyzed using RNA sequencing, and the results were further verified with datasets from patients with PH. The mechanisms underlying DON-induced effects on PH were verified both in vivo and in vitro. Results: DON effectively improved pulmonary artery and RV remodeling in the BLM-induced mouse model. Transcriptomic profiles of lung tissue indicated that the expression of inflammatory and fibrotic genes was significantly changed in this process. In the animal model and patients with PH, T helper 17 lymphocytes (Th17) were the most common inflammatory cells infiltrating the lung tissue. DON significantly inhibited lung fibroblast activation; thus, preventing lung fibrosis and reducing the inflammatory response and Th17 cell infiltration in the BLM-induced lung tissue. In addition, Th17 cells could activate lung fibroblasts by secreting IL17A, and DON-mediated inhibition of Th17 cell differentiation was found to depend on the alpha7nAchR-JAK2-STAT3 pathway. Conclusion: DON can alleviate lung fibrosis and PH in an experimental mouse model. It inhibited pro-inflammatory Th17 cell differentiation, which is dependent on a cholinergic receptor pathway, thereby regulating fibroblast activation. Title: Molluscicidal activity of Nicotiana tabacum extracts on the invasive snail Pomacea canaliculata Guo J, Zhang S, Zeng J, Chen Y, Guo Y, Liu J, He A Ref: Sci Rep, 13:11597, 2023 : PubMed ESTHER: Guo_2023_Sci.Rep_13_11597 PubMedSearch: Guo 2023 Sci.Rep 13 11597 PubMedID: 37463929 Abstract Botanical molluscicides for controlling the invasive snail Pomacea canaliculata have attracted worldwide attention because of their cost and environmental friendliness. Aqueous extracts from discarded tobacco leaf (Nicotiana tobacum) were evaluated for molluscicidal activity against different-sized P. canaliculata under laboratory conditions. The results showed that over 90% of the snails died in 1 g/L tobacco extract within 4 days, and the survival of P. canaliculata was inversely proportional to the snail size, tobacco extract concentration and length of exposure time. Adult males were more susceptible to tobacco extract than females. The snails had few chances to feed or mate in 0.5 g/L tobacco extract, and reproduction was greatly limited in 0.2 g/L. The growth of juvenile snails was inhibited in 0.2 g/L tobacco extract, but adults were unaffected. The antioxidant capacity of P. canaliculata in response to tobacco extract can be size- and sex-dependent, and the activities of superoxide dismutase, catalase, and acetylcholinesterase and the contents of glutathione and malondialdehyde were increased in adult males. These results suggest that discarded tobacco leaves can be useful as a molluscicide for controlling the invasive snail P. canaliculata based on its effects on survival, behaviour, food intake, growth performance and antioxidant capacity. Title: Sphk1 deficiency induces apoptosis and developmental defects and premature death in zebrafish Huang L, Han F, Huang Y, Liu J, Liao X, Cao Z, Li W Ref: Fish Physiol Biochem, :, 2023 : PubMed ESTHER: Huang_2023_Fish.Physiol.Biochem__ PubMedSearch: Huang 2023 Fish.Physiol.Biochem PubMedID: 37464180 Abstract The sphk1 gene plays a crucial role in cell growth and signal transduction. However, the developmental functions of the sphk1 gene during early vertebrate zebrafish embryo remain not completely understood. In this study, we constructed zebrafish sphk1 mutants through CRISPR/Cas9 to investigate its role in zebrafish embryonic development. Knockout of the sphk1 gene was found to cause abnormal development in zebrafish embryos, such as darkening and atrophy of the head, trunk deformities, pericardial edema, retarded yolk sac development, reduced heart rate, and premature death. The acetylcholinesterase activity was significantly increased after the knockout of sphk1, and some of the neurodevelopmental genes and neurotransmission system-related genes were expressed abnormally. The deletion of sphk1 led to abnormal expression of immune genes, as well as a significant decrease in the number of hematopoietic stem cells and neutrophils. The mRNA levels of cardiac development-related genes were significantly decreased. In addition, cell apoptosis increases in the sphk1 mutants, and the proliferation of head cells decreases. Therefore, our study has shown that the sphk1 is a key gene for zebrafish embryonic survival and regulation of organ development. It deepened our understanding of its physiological function. Our study lays the foundation for investigating the mechanism of the sphk1 gene in early zebrafish embryonic development. Title: Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function Lee H, Chofflet N, Liu J, Fan S, Lu Z, Rojas M, Penndorf P, Bailey A, Russell W and Rudenko G <3 more author(s)> Lee H, Chofflet N, Liu J, Fan S, Lu Z, Rojas M, Penndorf P, Bailey A, Russell W, Machius M, Ren G, Takahashi H, Rudenko G (- 3) Ref: Journal of Biological Chemistry, :104586, 2023 : PubMed ESTHER: Lee_2023_J.Biol.Chem__104586 PubMedSearch: Lee 2023 J.Biol.Chem 104586 PubMedID: 36889589 Abstract MDGAs (MAM domain-containing glycosylphosphatidylinositol anchors) are synaptic cell surface molecules that regulate the formation of trans-synaptic bridges between neurexins (NRXNs) and neuroligins (NLGNs) which promote synaptic development. Mutations in MDGAs are implicated in various neuropsychiatric diseases. MDGAs bind NLGNs in cis on the postsynaptic membrane and physically block NLGNs from binding to NRXNs. In crystal structures, the six immunoglobulin (Ig) and single fibronectin III (FN3) domains of MDGA1 reveal a striking compact, triangular shape, both alone and in complex with NLGNs. Whether this unusual domain arrangement is required for biological function or other arrangements occur with different functional outcomes is unknown. Here, we show that wild-type MDGA1 can adopt both compact and extended 3D conformations that bind NLGN2. Designer mutants targeting strategic molecular elbows in MDGA1 alter the distribution of 3D conformations while leaving the binding affinity between soluble ectodomains of MDGA1 and NLGN2 intact. In contrast, in a cellular context, these mutants result in unique combinations of functional consequences, including altered binding to NLGN2, decreased capacity to conceal NLGN2 from NRXN1beta, and/or suppressed NLGN2-mediated inhibitory presynaptic differentiation, despite the mutations being located far from the MDGA1:NLGN2 interaction site. Thus, the 3D conformation of the entire MDGA1 ectodomain appears critical for its function, and its NLGN-binding site on Ig1-Ig2 is not independent of the rest of the molecule. As a result, global 3D conformational changes to the MDGA1 ectodomain via strategic elbows may form a molecular mechanism to regulate MDGA1 action within the synaptic cleft. Title: Dual functional antioxidant and butyrylcholinesterase inhibitors for the treatment of Alzheimer's disease: Design, synthesis and evaluation of novel melatonin-alkylbenzylamine hybrids Liu P, Cheng M, Guo J, Cao D, Luo J, Wan Y, Fang Y, Jin Y, Xie SS, Liu J Ref: Bioorganic & Medicinal Chemistry, 78:117146, 2023 : PubMed ESTHER: Liu_2023_Bioorg.Med.Chem_78_117146 PubMedSearch: Liu 2023 Bioorg.Med.Chem 78 117146 PubMedID: 36580744 Inhibitor(s) related to this paper: Melatonin-alkylbenzylamine-Cpd5 Abstract Here, we have designed and synthesized a series of melatonin-alkylbenzylamine hybrids as multitarget agents for the treatment of Alzheimer's disease (AD). Most of them exhibited a potent multifunctional profile involving cholinesterase inhibition and antioxidant effects. Among these compounds, compound 5 was most the potent antioxidant (ORAC =5.13) and also an excellent selective inhibitor of BuChE (huBuChE IC(50)=1.20 microM, huAChE IC(50) = 177.49 microM, SIs= 147.91). Moreover, kinetic study indicated compound 5 was a mixed-type inhibitor for huBuChE. Furthermore, it could induce expression of the Nrf2 as well as its downstream markers at the protein level in cells. More importantly, compound 5 display no acute toxicity in mice at doses up to 2500 mg/kg. And we found compound 5 could improve memory function of scopolamine-induced amnesia mice. These results highlighted compound 5 as a possible hit molecule for further investigation of new anti-AD drugs. Title: Genome wide identification of GDSL gene family explores a novel GhirGDSL26 gene enhancing drought stress tolerance in cotton Liu J, Wang H, Khan A, Xu Y, Hou Y, Wang Y, Zhou Z, Zheng J, Liu F, Cai X Ref: BMC Plant Biol, 23:14, 2023 : PubMed ESTHER: Liu_2023_BMC.Plant.Biol_23_14 PubMedSearch: Liu 2023 BMC.Plant.Biol 23 14 PubMedID: 36609252 Abstract BACKGROUND: Current climate change scenarios are posing greater threats to the growth and development of plants. Thus, significant efforts are required that can mitigate the negative effects of drought on the cotton plant. GDSL esterase/lipases can offer an imperative role in plant development and stress tolerance. However, thesystematic and functional roles of the GDSL gene family, particularly in cotton under water deficit conditions have not yet been explored. RESULTS: In this study, 103, 103, 99, 198, 203, 239, 249, and 215 GDSL proteins were identified in eight cotton genomes i.e., Gossypium herbaceum (A1), Gossypium arboretum (A2), Gossypium raimondii (D5), Gossypium hirsutum (AD1), Gossypium barbadense (AD2), Gossypium tomentosum (AD3), Gossypium mustelinum (AD4), Gossypium darwinii (AD5), respectively. A total of 198 GDSL genes of Gossypium hirsutum were divided into eleven clades using phylogenetic analysis, and the number of GhirGDSL varied among different clades. The cis-elements analysis showed that GhirGDSL gene expression was mainly related to light, plant hormones, and variable tense environments. Combining the results of transcriptome and RT-qPCR, GhirGDSL26 (Gh_A01G1774), a highly up-regulated gene, was selected for further elucidating its tole in drought stress tolerance via estimating physiological and biochemical parameters. Heterologous expression of the GhirGDSL26 gene in Arabidopsis thaliana resulted in a higher germination and survival rates, longer root lengths, lower ion leakage and induced stress-responsive genes expression under drought stress. This further highlighted that overexpressed plants had a better drought tolerance as compared to the wildtype plants. Moreover, 3, 3'-diaminobenzidine (DAB) and Trypan staining results indicated reduced oxidative damage, less cell membrane damage, and lower ion leakage in overexpressed plants as compared to wild type. Silencing of GhirGDSL26 in cotton via VIGS resulting in a susceptible phenotype, higher MDA and H(2)O(2) contents, lower SOD activity, and proline content. CONCLUSION: Our results demonstrated that GhirGDSL26 plays a critical role in cotton drought stress tolerance. Current findings enrich our knowledge of GDSL genes in cotton and provide theoretical guidance and excellent gene resources for improving drought tolerance in cotton. Title: Design and construction of Carboxylesterase 2c Gene knockout Rats by CRISPR/Cas9 Liu J, Shang X, Yao B, Zhang Y, Huang S, Guo Y, Wang X Ref: Curr Drug Metab, :, 2023 : PubMed ESTHER: Liu_2023_Curr.Drug.Metab__ PubMedSearch: Liu 2023 Curr.Drug.Metab PubMedID: 36694315 Gene_locus related to this paper: ratno-pbcxe Abstract BACKGROUND: Carboxylesterase 2 (CES2) is mainly distributed in the human liver and gut, and plays an active role in the metabolic activation of many prodrugs and lipid metabolism. Although CES2 is of great significance, there are still few animal models related to CES2. OBJECTIVES: This research aims to construct Ces2c gene knockout (KO) rats and further study the function of CES2. METHODS: CRISPR/Cas9 gene editing technology was used to target and cleave the rat Ces2c gene. Compensatory effects of major CES subtypes both in the liver and small intestine of KO rats were detected at mRNA levels. Meanwhile, diltiazem and aspirin were used as substrates to test the metabolic capacity of Ces2c in KO rats. RESULTS: This Ces2c KO rat model showed normal growth and breeding without off-target effects. The metabolic function of Ces2c KO rats was verified by the metabolic study of CES2 substrates in vitro. The results showed that the metabolic capacity of diltiazem in KO rats was weakened, while the metabolic ability of aspirin did not change significantly. In addition, the serum physiological indexes showed that the Ces2c deletion did not affect the liver function of rats. CONCLUSION: The Ces2c KO rat model was successfully constructed by CRISPR/Cas9 system. This rat model can not only be used as an important tool to study the drug metabolism mediated by Ces2, but also as an important animal model to study the physiological function of Ces2. Title: Detection of target site mutations in the acetylcholinesterase and voltage-gated sodium channel in field populations of Culex quinquefasciatus and Cx. tritaeniorhynchus from southern Sichuan region of China Liu J, Wang Y, Liu P, Yu X, Tan AI, Zeng J, Li L, Qiu X Ref: J Am Mosq Control Assoc, :, 2023 : PubMed ESTHER: Liu_2023_J.Am.Mosq.Control.Assoc__ PubMedSearch: Liu 2023 J.Am.Mosq.Control.Assoc PubMedID: 36752737 Abstract Culex quinquefasciatus and Cx. tritaeniorhynchus are 2 dominant disease vectors in Neijiang City, Sichuan Province, China. Although there is evidence of confirmed resistance against insecticides in mosquito vectors, nothing is known about the existing insecticide resistance-conferring mutations in Cx. quinquefasciatus and Cx. tritaeniorhynchu in this region so far. In this study, the G119S mutation in the acetylcholinesterase (AChE) was detected in Cx. quinquefasciatus at a very low frequency (0.9%) with no resistant homozygotes being observed. Two resistance mutations in the voltage-gated sodium channel (VGSC) (L1014F and L1014S) were found in Cx. quinquefasciatus with frequencies of 88.7% and 8.3%, respectively. By contrast, the AChE F455W mutation was found to be fixed (with a frequency of 100%) in 3 of the 5 studied populations, with an overall frequency being 98.1%. In addition, 1 resistance-conferring VGSC mutation (L1014F) was detected with an overall frequency of 15.2% in Cx. tritaeniorhynchus. These results indicate that the well-recognized insecticide resistance-conferring mutations in both AChE and VGSC are present in the 2 Culex species in Neijiang. The contrasting patterns in the frequency of resistance alleles indicate that species-customized strategies of insecticide resistance management should be considered for the 2 species. Title: Do 'Newly Born' orphan proteins resemble 'Never Born' proteins? A study using three deep learning algorithms Liu J, Yuan R, Shao W, Wang J, Silman I, Sussman JL Ref: Proteins, :, 2023 : PubMed ESTHER: Liu_2023_Proteins__ PubMedSearch: Liu 2023 Proteins PubMedID: 37092778 Abstract "Newly Born" proteins, devoid of detectable homology to any other proteins, known as orphan proteins, occur in a single species or within a taxonomically restricted gene family. They are generated by the expression of novel open reading frames, and appear throughout evolution. We were curious if three recently developed programs for predicting protein structures, namely, AlphaFold2, RoseTTAFold, and ESMFold, might be of value for comparison of such "Newly Born" proteins to random polypeptides with amino acid content similar to that of native proteins, which have been called "Never Born" proteins. The programs were used to compare the structures of two sets of "Never Born" proteins that had been expressed-Group 1, which had been shown experimentally to possess substantial secondary structure, and Group 3, which had been shown to be intrinsically disordered. Overall, although the models generated were scored as being of low quality, they nevertheless revealed some general principles. Specifically, all four members of Group 1 were predicted to be compact by all three algorithms, in agreement with the experimental data, whereas the members of Group 3 were predicted to be very extended, as would be expected for intrinsically disordered proteins, again consistent with the experimental data. These predicted differences were shown to be statistically significant by comparing their accessible surface areas. The three programs were then used to predict the structures of three orphan proteins whose crystal structures had been solved, two of which display novel folds. Surprisingly, only for the protein which did not have a novel fold, and was taxonomically restricted, rather than being a true orphan, did all three algorithms predict very similar, high-quality structures, closely resembling the crystal structure. Finally, they were used to predict the structures of seven orphan proteins with well-identified biological functions, whose 3D structures are not known. Two proteins, which were predicted to be disordered based on their sequences, are predicted by all three structure algorithms to be extended structures. The other five were predicted to be compact structures with only two exceptions in the case of AlphaFold2. All three prediction algorithms make remarkably similar and high-quality predictions for one large protein, HCO_11565, from a nematode. It is conjectured that this is due to many homologs in the taxonomically restricted family of which it is a member, and to the fact that the Dali server revealed several nonrelated proteins with similar folds. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:Proteins:3. Title: Neuropathy target esterase activity predicts retinopathy among PNPLA6 disorders Liu J, He Y, Lwin C, Han M, Guan B, Naik A, Bender C, Moore N, Huryn LA and Hufnagel RB <35 more author(s)> Liu J, He Y, Lwin C, Han M, Guan B, Naik A, Bender C, Moore N, Huryn LA, Sergeev Y, Qian H, Zeng Y, Dong L, Liu P, Lei J, Haugen CJ, Prasov L, Shi R, Dollfus H, Aristodemou P, Laich Y, Nemeth AH, Taylor J, Downes S, Krawczynski M, Meunier I, Strassberg M, Tenney J, Gao J, Shear MA, Moore AT, Duncan JL, Menendez B, Hull S, Vincent A, Siskind CE, Traboulsi EI, Blackstone C, Sisk R, Utz V, Webster AR, Michaelides M, Arno G, Synofzik M, Hufnagel RB (- 35) Ref: Biorxiv, :, 2023 : PubMed ESTHER: Liu_2023_bioRxiv__ PubMedSearch: Liu 2023 bioRxiv PubMedID: 37333224 Abstract Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. PNPLA6 encodes Neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a clinical meta-analysis of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6 -associated clinical diagnoses unambiguously reclassified 10 variants as likely pathogenic and 36 variants as pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship and the generation of a preclinical animal model pave the way for therapeutic trials, using NTE as a biomarker. Title: Serum cholinesterase as a new nutritional indicator for predicting weaning failure in patients Liu J, Shao T, Chen H, Ma C, Lu X, Yang X, Song K, Wang L, Lei S, Wang D Ref: Front Med (Lausanne), 10:1175089, 2023 : PubMed ESTHER: Liu_2023_Front.Med.(Lausanne)_10_1175089 PubMedSearch: Liu 2023 Front.Med.(Lausanne) 10 1175089 PubMedID: 37502364 Abstract AIM: The objective of this study is to examine the correlation between patient serum cholinesterase (SCHE) concentration and weaning failure in the context of invasive mechanical ventilation (IMV), as well as to identify predictors of ventilator weaning failure. Additionally, this study investigates the potential relationship between SCHE and nutritional risk for developing more effective weaning strategies. METHOD: A retrospective observational study was conducted. The sample was collected from 227 patients with IMV over 48h who underwent SBT before weaning. Relevant experimental samples and data collection were analyzed at the time of patient admission and before the initiation of the SBT. The correlation between SCHE and weaning failure was determined by multifactorial logistic regression and propensity matching scores. RESULTS: Weaning was successful in 127 patients and failed in 100 patients. Depending on the difficulty of weaning, 55 of these patients had difficulty in weaning and 45 had long-term weaning. In the crude cohort, experimental data collected on the day of SBT showed that SCHE concentrations were higher in patients with successful weaning than in those with failed weaning (4,514 u/l vs. 3,190 u/l p<0.01). The critical value for predicting weaning failure was SCHE 3,228 u/l (p<0.01). Ventilator weaning failure was predicted by multifactorial logistic regression analysis of SCHE, heart rate, and PaO(2) before SBT, with SCHE predicting ventilator weaning failure (AUC 0.714; 95% CI 0.647-0.782) better than heart rate (AUC 0.618; 95% CI 0.545-0.690), PaO(2) (AUC 0.59; 95% CI 0.515-0.664). After propensity-matched scores, SCHE remained an independent predictor of weaning failure (p=0.05). And the SCHE concentration was strongly correlated with the patient's weaning difficulties (p<0.01). The Nutrition Risk in Critically Ill (NUTRIC) score was also significantly correlated with SCHE according to Spearman's correlation analysis (p<0.01). CONCLUSION: Our study revealed that the patients who experienced weaning failure exhibited lower SCHE values compared to those who successfully underwent weaning. Before spontaneous breathing trial (SBT), SCHE, heart rate, and PaO(2) were identified as independent predictors of weaning failure. Following propensity score matching (PSM), SCHE and heart rate remained independent predictors. Patients with SCHE levels below 3,228 u/l should undergo careful evaluation before weaning. Our findings suggest that malnutrition may be a contributing factor to weaning failure in patients. Title: Acute toxicity of tire wear particles and leachate to Daphnia magna Liu J, Feng Q, Yang H, Fan X, Jiang Y, Wu T Ref: Comparative Biochemistry & Physiology C Toxicol Pharmacol, :109713, 2023 : PubMed ESTHER: Liu_2023_Comp.Biochem.Physiol.C.Toxicol.Pharmacol__109713 PubMedSearch: Liu 2023 Comp.Biochem.Physiol.C.Toxicol.Pharmacol 109713 PubMedID: 37544637 Abstract Tire wear particles (TWP) are a new pollutant widely present in the environment, and have been identified as microplastics (MPs), which are receiving increasing attention due to their toxic effects on aquatic organisms. In this study, D. magna was used as test organism, and the leachate from TWP was prepared by hot water extraction for 30 (30-E) and 120 min (120-E). The acute toxic effects of particles and leachate on D. magna were studied under different exposure concentrations. The results showed that zinc and pyrene were the highest detected contaminants in the leachate. The 48 h-LC(50) values for particles and leachate were determined to be 56.99, 461.30 (30-E), and 153.00 mg/L (120-E), respectively. Following a 48 h exposure period, the immobilization of D. magna exposed to the particles and their leachate were increased with the concentration increase. The physical damage of the gut was found to be a possible mechanism for particle-induced biotoxicity. The compounds leached from TWP were responsible for the acute toxicity of leachate. Particles usually demonstrated a greater degree of toxicity in comparison to their leachate, especially at environmentally relevant concentrations. Exposure to particles and leachate resulted in the inhibition of swimming speed, swimming acceleration, filtration rate, and ingestion rate in D. magna. Furthermore, thoracic limb activity was observed to be inhibited. The heart rate of D. magna was significantly increased by the presence of particles at a concentration of 200 mg/L and leachate at concentrations of 400 and 800 mg/L (120-E). The observed alterations in behavior and physiological endpoints may be related to oxidative stress and neurotoxicity in the organism. Reduced superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) activities indicated that D. magna may suffer from excessive oxidative stress, whereas the increase of acetylcholinesterase (AChE) activity may serve as a biomarker of susceptibility to evaluate the environmental risks of TWP and corresponding leachates as potential aquatic pollutants.. Therefore, a more comprehensive risk assessment of TWP in the environment is necessary. Title: The effects of carvacrol on development and gene expression profiles in Spodoptera frugiperda Liu J, Lin Y, Huang Y, Liu L, Cai X, Lin J, Shu B Ref: Pestic Biochem Physiol, 195:105539, 2023 : PubMed ESTHER: Liu_2023_Pestic.Biochem.Physiol_195_105539 PubMedSearch: Liu 2023 Pestic.Biochem.Physiol 195 105539 PubMedID: 37666589 Abstract The fall armyworm, Spodoptera frugiperda, is a highly polyphagous agricultural pest that is widely distributed around the world and causes severe crop yield loss. Carvacrol showed adverse effects on many pests, such as larval death and growth inhibition. While the effects of carvacrol on S. frugiperda larvae are not yet known. In this study, the effects of carvacrol on S. frugiperda, including larval growth inhibition and mortality induction, were observed. The detoxification and digestive enzyme activities of larvae with 1.0 and 2.0 g/kg carvacrol treatments were analyzed. Carvacrol boosted the enzyme activities of carboxylesterase (CarE) and glutathione S-transferase (GST) while decreasing the activities of alpha-amylase (AMS), lipase (LIP), and trypsin. A total of 3422 differentially expressed genes were identified in the larvae treated with 2.0 g/kg carvacrol, of which the DEGs involved in xenobiotic detoxification, food digestion, and insecticidal targets were further examined. These results suggest that carvacrol could regulate growth and development by affecting the process of food digestion, and exert its toxicity on the larvae through interaction with a variety of insecticidal targets. While the altered expressions of detoxification enzymes might be related to the detoxification and metabolism of carvacrol. Our findings offer a theoretical foundation for the use of carvacrol for S. frugiperda control in the field. Title: PNPLA6 disorders: what's in a name? Liu J, Hufnagel RB Ref: Ophthalmic Genet, :1, 2023 : PubMed ESTHER: Liu_2023_Ophthalmic.Genet__1 PubMedSearch: Liu 2023 Ophthalmic.Genet 1 PubMedID: 37732399 Abstract BACKGROUND: Variants in the patatin-like phospholipase domain containing 6 (PNPLA6) gene cause a broad spectrum of neurological disorders characterized by gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. This review examines the clinical, cellular, and biochemical features found across the five PNPLA6-related diseases, with a focus on future questions to be addressed. MATERIALS AND METHODS: A literature review was performed on published clinical reports on patients with PNPLA6 variants. Additionally, in vitro and in vivo models used to study the encoded protein, Neuropathy Target Esterase (NTE), are summarized to lend mechanistic perspective to human diseases. RESULTS: Biallelic pathogenic PNPLA6 variants cause five systemic neurological disorders: spastic paraplegia type 39, Gordon-Holmes, Boucher-Neuhuser, Laurence-Moon, and Oliver-McFarlane syndromes. PNPLA6 encodes NTE, an enzyme involved in maintaining phospholipid homeostasis and trafficking in the nervous system. Retinal disease presents with a unique chorioretinal dystrophy that is phenotypically similar to choroideremia and Leber congenital amaurosis. Animal and cellular models support a loss-of-function mechanism. CONCLUSIONS: Clinicians should be aware of choroideremia-like ocular presentation in patients who also experience growth defects, motor dysfunction, and/or hair anomalies. Although NTE biochemistry is well characterized, further research on the relationship between genotype and the presence or absence of retinopathy should be explored to improve diagnosis and prognosis. Title: Emodin derivatives as promising multi-aspect intervention agents for amyloid aggregation: molecular docking/dynamics simulation, bioactivities evaluation, and cytoprotection Shen Y, Duan H, Yuan L, Asikaer A, Liu Y, Zhang R, Wang Y, Lin Z, Shen R and Kou X <4 more author(s)> Shen Y, Duan H, Yuan L, Asikaer A, Liu Y, Zhang R, Wang Y, Lin Z, Shen R, Zhao W, Li X, Liu J, Yang A, Kou X (- 4) Ref: Mol Divers, :, 2023 : PubMed ESTHER: Shen_2023_Mol.Divers__ PubMedSearch: Shen 2023 Mol.Divers PubMedID: 37523101 37737959 Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disease with complex pathogenesis. Despite the pathogenesis is unknown, the misfolding and accumulation of beta-amyloid (Abeta) peptide play the important role in the occurrence and development of AD. Hence, multi-aspect intervention of the misfolded Abeta peptides aggregation is a promising therapy for AD. In previous work, we obtained the emodin derivatives (a-d) with multifunctional anti-AD activities, including metal ions chelation, cholinesterase inhibition, and hydroxyl/superoxide anion radical elimination. In this work, we predicted the interaction of emodin derivatives (a-d) with Abeta by combining molecular docking simulation and molecular dynamics simulation, and evaluated the ability to intervene with the self-, Cu(2+)- and AChE-induced Abeta aggregation via in vitro methods. The results indicated that a-d could act as the potent multi-aspect intervention agents for Abeta aggregation. In addition, a-d could effectively eliminate peroxyl radical, had virtually no neurotoxicity, and protect cells from oxidative and Abeta-induced damage. The prediction results of ADMET properties showed that a-d had suitable pharmacokinetic characteristics. It suggested that a-d could act as the promising multi-targeted directed ligands (MTDLs) for AD. These results may provide meaningful information for the development of the potential MTDLs for AD which are modified from natural-origin scaffolds. Title: Engineering lipase at the molecular scale for cleaner biodiesel production - A review Tan Z, Chen G, Chen S, Zhang J, Liu J, Ma X, Liao H, Hu Z, Ge F and Bilal M <2 more author(s)> Tan Z, Chen G, Chen S, Zhang J, Liu J, Ma X, Liao H, Hu Z, Ge F, Ju F, Shi H, Bilal M (- 2) Ref: Molecular Catalysis, 546:113271, : PubMed ESTHER: Tan_2023_Mol.Catal_546_113271 PubMedSearch: Tan 2023 Mol.Catal 546 113271 Abstract Increasing environmental concerns and significant demand for industrial fuels necessitate the development of alternate and sustainable energy sources. Biodiesel is a renewable and environmentally friendly fuel produced by trans-esterifying a variety of feedstocks. Lipases are robust triacylglycerol ester hydrolases that catalyze hydrolysis, esterification, interesterification, transesterification, acylation, acidolysis, alcoholysis, aminolysis, and resolution of racemates. Although the lipase-assisted greener biosynthesis of biodiesel has numerous advantages over the traditional alkali-based process, low catalytic efficiency, marginal stability, and high cost of lipase enzymes limit its widespread industrial processability. Protein engineering methodologies such as directed evolution, semi-rational design, and rational design can effectively tailor or improve the biocatalytic characteristics of lipase enzymes used in biodiesel generation, such as thermostability, solvent tolerance, activity, and substrate specificity. These innovative techniques improved our ability to predict structure-function relationships, engineering qualities, computational tools for designing new biocatalysts, and functional screening to manipulate enzyme traits for application in prevalent industrial bioprocesses. Many recent studies have demonstrated improved lipase performance, such as activity, stability, and specificity via protein engineering. This review spotlights a current overview of lipase engineering at the molecular scale with robust biocatalytic properties for biodiesel synthesis. Title: Construction of a ratiometric fluorescent sensing platform based on near-infrared carbon dots for organophosphorus pesticides detection Xie W, Liu J, Qu Y, Du F Ref: Anal Sci, :, 2023 : PubMed ESTHER: Xie_2023_Anal.Sci__ PubMedSearch: Xie 2023 Anal.Sci PubMedID: 36944823 Abstract In this work, a convenient ratiometric fluorescent platform was designed to measure organophosphorus pesticides (OPs) based on acetylcholinesterase (AChE), acetylthiocholine (ATCh), manganese dioxide nanosheets (MnO(2)), near-infrared carbon dots (RCDs) and o-phenylenediamine (OPD). In this platform, a direct oxidation of OPD by MnO(2) generated the luminescent product 2,3-diaminophenolazine (DAP) through intrinsic oxidase activity, while RCDs served as a fluorescent reference indicator. In the presence of AChE and ATCh, the enzymatic hydrolysate thiocholine (TCh) would reduce MnO(2) nanosheets to Mn(2+), leading to the quenching of DAP fluorescence. On the other hand, OPs can inhibit the catabolism of ATCh by AChE thus acting as a recognizer of OPs. According to these reactions, OPs were quantitatively analyzed by the intensity ratio of fluorescence emitted from RCDs and DAP (F(560)/F(676)). The constructed platform can detect OPs with the range of 0.2-0.6 microM with a detection limit of 4.3 nM. Figure A ratiometric fluorescent probe based on carbon dots was obtained and using it to determine the concentration of organophosphorus pesticides. Title: Neurodevelopmental toxicity of bisphenol AF in zebrafish larvae and the protective effects of curcumin Yang Q, Liu J, Ding J Ref: J Appl Toxicol, :, 2023 : PubMed ESTHER: Yang_2023_J.Appl.Toxicol__ PubMedSearch: Yang 2023 J.Appl.Toxicol PubMedID: 37423901 Abstract Bisphenol AF (BPAF) is one of the most commonly used alternatives of bisphenol A in the plastics industry. The effects of BPAF on nervous development are unclear. Curcumin (CUR) has been determined to be an anti-inflammatory and antioxidant agent. In this study, the effects of BPAF on neurotoxicity of zebrafish embryos/larvae and whether CUR could reverse effects induced by BPAF were investigated. The results showed that BPAF treatment induced deficits in locomotor behavior, altered the larval brain development, caused aberrant expression of neurogenesis related genes (elavl3, zn5, alpha-tubulin, syn2a, and gap43), decreased acetylcholinesterase (AChE) activity, and induced oxidative stress, cell apoptosis, and neuroinflammation in zebrafish larvae. CUR addition could block the adverse effects of BPAF on nervous development by attenuated oxidative stress and cell apoptosis induced by BPAF in zebrafish, enhanced the activity of AChE, and increased the expression of genes involved in the pro-inflammatory cytokines (IL-6, IL-1beta, TNF-alpha, and IL-8). The results of this study indicate that BPAF could induce aberrant development on nervous system. However, CUR exerts neuroprotective effects on BPAF-induced neurotoxicity in zebrafish larvae. Title: Strigolactones positively regulate Verticillium wilt resistance in cotton via crosstalk with other hormones Yi F, An G, Song A, Cheng K, Liu J, Wang C, Wu S, Wang P, Zhu J and Cai Y <11 more author(s)> Yi F, An G, Song A, Cheng K, Liu J, Wang C, Wu S, Wang P, Zhu J, Liang Z, Chang Y, Chu Z, Cai C, Zhang X, Chen A, Xu J, Burritt DJ, Herrera-Estrella L, Tran LP, Li W, Cai Y (- 11) Ref: Plant Physiol, :, 2023 : PubMed ESTHER: Yi_2023_Plant.Physiol__ PubMedSearch: Yi 2023 Plant.Physiol PubMedID: 36718522 Abstract Verticillium wilt caused by Verticillium dahliae is a serious vascular disease in cotton (Gossypium spp.). V. dahliae induces the expression of the CAROTENOID CLEAVAGE DIOXYGENASE 7 (GauCCD7) gene involved in strigolactone (SL) biosynthesis in Gossypium australe, suggesting a role for SLs in Verticillium wilt resistance. We found that the SL analog rac-GR24 enhanced while the SL biosynthesis inhibitor TIS108 decreased cotton resistance to Verticillium wilt. Knock-down of GbCCD7 and GbCCD8b genes in island cotton (Gossypium barbadense) decreased resistance, whereas overexpression of GbCCD8b in upland cotton (Gossypium hirsutum) increased resistance to Verticillium wilt. Additionally, Arabidopsis (Arabidopsis thaliana) SL mutants defective in CCD7 and CCD8 putative orthologs were susceptible, whereas both Arabidopsis GbCCD7- and GbCCD8b-overexpressing plants were more resistant to Verticillium wilt than wild-type (WT) plants. Transcriptome analyses showed that several genes related to the jasmonic acid (JA)- and abscisic acid (ABA)-signaling pathways, such as MYELOCYTOMATOSIS 2 (GbMYC2) and ABA-INSENSITIVE 5, respectively, were up-regulated in the roots of WT cotton plants in responses to rac-GR24 and V. dahliae infection but down-regulated in the roots of both GbCCD7- and GbCCD8b-silenced cotton plants. Furthermore, GbMYC2 suppressed the expression of GbCCD7 and GbCCD8b by binding to their promoters, which might regulate the homeostasis of SLs in cotton through a negative feedback loop. We also found that GbCCD7- and GbCCD8b-silenced cotton plants were impaired in V. dahliae-induced reactive oxygen species (ROS) accumulation. Taken together, our results suggest that SLs positively regulate cotton resistance to Verticillium wilt through crosstalk with the JA and ABA-signaling pathways and by inducing ROS accumulation. Title: Pyridostigmine ameliorates pristane-induced arthritis symptoms in Dark Agouti rats Zeng M, Issotina Zibrila A, Li X, Liu X, Wang X, Zeng Z, Wang Z, He Y, Meng L, Liu J Ref: Scand J Rheumatol, :1, 2023 : PubMed ESTHER: Zeng_2023_Scand.J.Rheumatol__1 PubMedSearch: Zeng 2023 Scand.J.Rheumatol 1 PubMedID: 37339380 Abstract OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disorder. Pyridostigmine (PYR), an acetylcholinesterase (AChE) inhibitor, has been shown to reduce inflammation and oxidative stress in several animal models for inflammation-associated conditions. The present study aimed to investigate the effects of PYR on pristane-induced (PIA) in Dark Agouti (DA) rats. METHOD: DA rats were intradermally infused with pristane to establish the PIA model, which was treated with PYR (10 mg/kg/day) for 27 days. The effects of PYR on synovial inflammation, oxidative stress, and gut microbiota were evaluated by determining arthritis scores, H&E staining, quantitative polymerase chain reaction, and biochemical assays, as well as 16S rDNA sequencing. RESULTS: Pristane induced arthritis, with swollen paws and body weight loss, increased arthritis scores, synovium hyperplasia, and bone or cartilage erosion. The expression of pro-inflammatory cytokines in synovium was higher in the PIA group than in the control group. PIA rats also displayed elevated levels of malondialdehyde, nitric oxide, superoxide dismutase, and catalase in plasma. Moreover, sequencing results showed that the richness, diversity, and composition of the gut microbiota dramatically changed in PIA rats. PYR abolished pristane-induced inflammation and oxidative stress, and corrected the gut microbiota dysbiosis. CONCLUSION: The results of this study support the protective role of PYR in PIA in DA rats, associated with the attenuation of inflammation and correction of gut microbiota dysbiosis. These findings open new perspectives for pharmacological interventions in animal models of RA. Title: Construction of a Label-Free Ratiometric Biosensor Based on Target Recycling Amplification and Hg-ZnSe QDs for Assay of BChE and OPs Zhang J, Wang M, Liu J, Lv Y, Su X Ref: Journal of Agricultural and Food Chemistry, 71:11884, 2023 : PubMed ESTHER: Zhang_2023_J.Agric.Food.Chem_71_11884 PubMedSearch: Zhang 2023 J.Agric.Food.Chem 71 11884 PubMedID: 37554068 Abstract Herein, we constructed a label-free ratiometric fluorescence biosensing strategy for the determination of butyrylcholinesterase (BChE) activity and organophosphorus (OPs) concentration. BChE promoted the hydrolysis of iodized s-butyrylthiocholine (BTCh) into a reducing substance thiocholine, which can decompose CoOOH nanosheets (CoOOH NSs) to Co(2+). Subsequently, the single-stranded DNA (ssDNA) on the surface of CoOOH NSs was released. Then, ssDNA hybridized with hairpin DNA (h-DNA) and triggered the target recycling amplification process, producing large amounts of G-quadruplex. After adding thioflavin T (ThT), the target BChE was converted into activatable G-quadruplex/ThT with an amplified yellow fluorescence signal. The addition of OPs could significantly inhibit the hydrolysis of BTCh by BChE and thus unable to produce the yellow fluorescence G-quadruplex/ThT complex. Throughout the entire process, the fluorescence intensity of Hg-ZnSe QDs as a reference signal remained unchanged at 630 nm. Furthermore, this work provided an effective approach for detecting the BChE activity in serum samples and OPs in fruits and vegetables. Title: Penetrating the Blood-Brain Barrier for Targeted Treatment of Neurotoxicant Poisoning by Nanosustained-Released 2-PAM@VB1-MIL-101-NH(2)(Fe) Zhao D, Liu J, Zhou Y, Zhang L, Zhong Y, Yang Y, Zhao B, Yang M, Wang Y Ref: ACS Appl Mater Interfaces, :, 2023 : PubMed ESTHER: Zhao_2023_ACS.Appl.Mater.Interfaces__ PubMedSearch: Zhao 2023 ACS.Appl.Mater.Interfaces PubMedID: 36867458 Abstract It is very important to establish a sustained-release pralidoxime chloride (2-PAM) drug system with brain targeting function for the treatment of neurotoxicant poisoning. Herein, Vitamin B1 (VB1), also known as thiamine, which can specifically bind to the thiamine transporter on the surface of the blood-brain barrier, was incorporated onto the surface of MIL-101-NH(2)(Fe) nanoparticles with a size of -100 nm. Pralidoxime chloride was further loaded within the interior of the above resulted composite by soaking, and a resulting composite drug (denoted as 2-PAM@VB1-MIL-101-NH(2)(Fe)) with a loading capacity of 14.8% (wt) was obtained. The results showed that the drug release rate of the composite drug was increased in PBS solution with the increase of pH (2-7.4) and a maximum drug release rate of 77.5% at pH 4. Experiments on the treatment of poisoning by gavage with the nerve agent sarin in mice combined with atropine revealed that sustained release of 2-PAM from the composite drug was achieved for more than 72 h. Sustained and stable reactivation of poisoned acetylcholinesterase (AChE) was observed with an enzyme reactivation rate of 42.7% in the ocular blood samples at 72 h. By using both zebrafish brain and mouse brain as models, we found that the composite drug could effectively cross the blood-brain barrier and restore the AChE activity in the brain of poisoned mice. The composite drug is expected to be a stable therapeutic drug with brain targeting and prolonged drug release properties for nerve agent intoxication in the middle and late stages of treatment. Title: The Cell-Cell Communication Signal Indole Controls the Physiology and Interspecies Communication of Acinetobacter baumannii Cui B, Chen X, Guo Q, Song S, Wang M, Liu J, Deng Y Ref: Microbiol Spectr, :e0102722, 2022 : PubMed ESTHER: Cui_2022_Microbiol.Spectr__e0102722 PubMedSearch: Cui 2022 Microbiol.Spectr e0102722 PubMedID: 35862954 Gene_locus related to this paper: acicp-AbiS Abstract Many bacteria utilize quorum sensing (QS) to control group behavior in a cell density-dependent manner. Previous studies have demonstrated that Acinetobacter baumannii employs an N-acyl-L-homoserine lactone (AHL)-based QS system to control biological functions and virulence. Here, we report that indole controls biological functions, virulence and AHL signal production in A. baumannii. The biosynthesis of indole is performed by A1S_3160 (AbiS, Acinetobacter baumannii indole synthase), which is a novel indole synthase annotated as an alpha/beta hydrolase in A. baumannii. Heterologous expression of AbiS in an Escherichia coli indole-deficient mutant also rescued the production of indole by using a distinct biosynthetic pathway from the tryptophanase TnaA, which produces indole directly from tryptophan in E. coli. Moreover, we revealed that indole from A. baumannii reduced the competitive fitness of Pseudomonas aeruginosa by inhibiting its QS systems and type III secretion system (T3SS). As A. baumannii and P. aeruginosa usually coexist in human lungs, our results suggest the crucial roles of indole in both the bacterial physiology and interspecies communication. IMPORTANCE Acinetobacter baumannii is an important human opportunistic pathogen that usually causes high morbidity and mortality. It employs the N-acyl-L-homoserine lactone (AHL)-type quorum sensing (QS) system, AbaI/AbaR, to regulate biological functions and virulence. In this study, we found that A. baumannii utilizes another QS signal, indole, to modulate biological functions and virulence. It was further revealed that indole positively controls the production of AHL signals by regulating abaI expression at the transcriptional levels. Furthermore, indole represses the QS systems and type III secretion system (T3SS) of P. aeruginosa and enhances the competitive ability of A. baumannii. Together, our work describes a QS signaling network where a pathogen uses to control the bacterial physiology and pathogenesis, and the competitive ability in microbial community. Title: Leveraging a Fluorescent Fatty Acid Probe to Discover Cell-Permeable Inhibitors of Plasmodium falciparum Glycerolipid Biosynthesis Dapper C, Liu J, Klemba M Ref: Microbiol Spectr, :e0245622, 2022 : PubMed ESTHER: Dapper_2022_Microbiol.Spectr__e0245622 PubMedSearch: Dapper 2022 Microbiol.Spectr e0245622 PubMedID: 36314974 Abstract A sensitive and quantitative fluorescence-based approach is presented for characterizing fatty acid acquisition and lipid biosynthesis by asexually replicating, intraerythrocytic Plasmodium falciparum. We show that a BODIPY-containing, green-fluorescent fatty acid analog is efficiently and rapidly incorporated into parasite neutral lipids and phospholipids. Prelabeling with a red-fluorescent ceramide analog permits normalization and enables reliable quantitation of glycerolipid labeling. Inhibition of lipid labeling by competition with natural fatty acids and by acyl-coenzyme A synthetase and diacylglycerol acyltransferase inhibitors demonstrates that the fluorescent fatty acid probe is acquired, activated, and transferred to lipids through physiologically-relevant pathways. To assess its utility in discovering small molecules that block parasite lipid biosynthesis, the lipid labeling assay was used to screen a panel of mammalian lipase inhibitors and a selection of compounds from the "Malaria Box" anti-malarial collection. Several compounds were identified that inhibited the incorporation of the fluorescent fatty acid probe into lipids in cultured parasites at low micromolar concentrations. Two contrasting profiles of suppression of neutral lipid and phospholipid synthesis were observed, which implies the inhibition of distinct pathways. IMPORTANCE The human malaria parasite Plasmodium falciparum relies on fatty acid scavenging to supply this essential precursor of lipid synthesis during its asexual replication cycle in human erythrocytes. This dependence on host fatty acids represents a potential vulnerability that can be exploited to develop new anti-malarial therapies. The quantitative experimental approach described here provides a platform for simultaneously interrogating multiple facets of lipid metabolism- fatty acid uptake, fatty acyl-CoA synthesis, and neutral lipid and phospholipid biosynthesis- and of identifying cell-permeable inhibitors that are active in situ. Title: The suppression of pancreatic lipase-related protein 2 ameliorates experimental hepatic fibrosis in mice Ding Z, Cheng R, Liu J, Zhao Y, Ge W, Yang Y, Xu X, Wang S, Zhang J Ref: Biochimica & Biophysica Acta Molecular & Cellular Biology Lipids, 1867:159102, 2022 : PubMed ESTHER: Ding_2022_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids_1867_159102 PubMedSearch: Ding 2022 Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids 1867 159102 PubMedID: 34995790 Gene_locus related to this paper: mouse-LIPR2 Abstract Quiescent hepatic stellate cells (HSCs) store vitamin A as lipid droplets in the cytoplasm. When activated, these cells lose vitamin A and exhibit an increased capacity for proliferation, mobility, contractility, and the synthesis of collagen and other components of the extracellular matrix. Our previous work demonstrated that the lipid hydrolytic gene pancreatic lipase-related protein 2 (mPlrp2) is involved in the hydrolysis of retinyl esters (REs) in the liver. Here, we showed that bile duct ligation (BDL)-induced liver injury triggered the conditional expression of mPlrp2 in livers and describe evidence of a strong relationship between the expression of mPlrp2 and Acta-2, a marker for activated HSCs. RNA interference targeting mPlrp2 inhibited HSC activation and ameliorated hepatic fibrosis induced by BDL in mice. Liver BDL markedly reduced the adenosine level and increased the ratio between S-adenosyl-L-methionine (SAM) and S-adenosyl-L-homocysteine (SAH). Chromatin immunoprecipitation (ChIP) analysis demonstrated an increase in trimethylated histone H3K4 at the mPlrp2 promoter in BDL mice, which was associated with the conditional expression of mPlrp2 in the liver. SAM, a well-known hepatoprotective substance, inhibited mPlrp2 expression and reduced RE hydrolysis in mice with hepatic fibrosis induced by chronic CCl(4) treatment. Liver fibrosis induced by CCl(4) or BDL was improved in Plrp2(-/-) mice. Our results reveal that mPlrp2 suppression is a potential approach for treating hepatic fibrosis. Title: Tissue-specific accumulation, depuration, and effects of perfluorooctanoic acid on fish: Influences of aqueous pH and sex Dong H, Lu G, Wang X, Zhang P, Yang H, Yan Z, Liu J, Jiang R Ref: Sci Total Environ, :160567, 2022 : PubMed ESTHER: Dong_2022_Sci.Total.Environ__160567 PubMedSearch: Dong 2022 Sci.Total.Environ 160567 PubMedID: 36455738 Abstract Perfluorooctanoic acid (PFOA) is widely distributed in nature, particularly in aquatic environments. Its bioaccumulation and toxicity in aquatic organisms can be affected by both the chemical status of PFOA in water and the physiology of the organism. However, research on the patterns of these effects is scarce. In this study, we investigated the influence of aqueous pH (pH 6, acidic; pH 7.5, neutral; pH 9, basic) and fish sex on PFOA uptake, clearance, and biochemical effects in crucian carp (C. auratus) using flow-through exposure. In the 17-d kinetic experiment, PFOA bioaccumulation adhered to a uniform first-order model in which PFOA uptake rates from water to blood and liver in acidic conditions were faster than those in other conditions, indicating possible acidic pH influence on PFOA uptake. PFOA clearance rates in these compartments of males were slower than in females, which was attributed to the notably stronger expression of Oat2 (organic anion transporter 2, responsible for reabsorption) in the kidneys of males. Similar responses were observed for peroxisome proliferation-related biomarkers at different pH levels and in different sexes. These biochemical responses were driven by the internal concentrations of PFOA. The inhibition acetylcholinesterase activity in the fish brain was closely linked to changes in P-glycoprotein content, demonstrating a protective relationship. Collectively, an aqueous pH lower than 7.5 might affect the uptake of PFOA by fish. The clearance discrepancies between the sexes highlight the importance of anion carriers for ionizable organic compounds in aquatic organisms. Title: FASN promotes lymph node metastasis in cervical cancer via cholesterol reprogramming and lymphangiogenesis Du Q, Liu P, Zhang C, Liu T, Wang W, Shang C, Wu J, Liao Y, Chen Y and Yao S <5 more author(s)> Du Q, Liu P, Zhang C, Liu T, Wang W, Shang C, Wu J, Liao Y, Chen Y, Huang J, Tan H, Zhao Y, Xia M, Liu J, Yao S (- 5) Ref: Cell Death Dis, 13:488, 2022 : PubMed ESTHER: Du_2022_Cell.Death.Dis_13_488 PubMedSearch: Du 2022 Cell.Death.Dis 13 488 PubMedID: 35597782 Abstract Cervical cancer (CC) patients with lymph node metastasis (LNM) have a poor prognosis. Clarification of the detailed mechanisms underlying LNM may provide potential clinical therapeutic targets for CC patients with LNM. However, the molecular mechanism of LNM in CC is unclear. In the present study, we demonstrated that fatty acid synthase (FASN), one of the key enzymes in lipid metabolism, had upregulated expression in the CC samples and was correlated with LNM. Moreover, multivariate Cox proportional hazards analysis identified FASN as an independent prognostic factor of CC patients. Furthermore, gain-of-function and loss-of-function approaches showed that FASN promoted CC cell migration, invasion, and lymphangiogenesis. Mechanistically, on the one hand, FASN could regulate cholesterol reprogramming and then activate the lipid raft-related c-Src/AKT/FAK signaling pathway, leading to enhanced cell migration and invasion. On the other hand, FASN induced lymphangiogenesis by secreting PDGF-AA/IGFBP3. More importantly, knockdown of FASN with FASN shRNA or the inhibitors C75 and Cerulenin dramatically diminished LNM in vivo, suggesting that FASN plays an essential role in LNM of CC and the clinical application potential of FASN inhibitors. Taken together, our findings uncover a novel molecular mechanism in LNM of CC and identify FASN as a novel prognostic factor and potential therapeutic target for LNM in CC. Title: Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1H)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease Guo J, Xu A, Cheng M, Wan Y, Wang R, Fang Y, Jin Y, Xie SS, Liu J Ref: Drug Des Devel Ther, 16:1495, 2022 : PubMed ESTHER: Guo_2022_Drug.Des.Devel.Ther_16_1495 PubMedSearch: Guo 2022 Drug.Des.Devel.Ther 16 1495 PubMedID: 35611357 Abstract BACKGROUND: Alzheimer's disease (AD) belongs to neurodegenerative disease, and the increasing number of AD patients has placed a heavy burden on society, which needs to be addressed urgently. ChEs/MAOs dual-target inhibitor has potential to treat AD according to reports. PURPOSE: To obtain effective multi-targeted agents for the treatment of AD, a novel series of hybrid compounds were designed and synthesized by fusing the pharmacophoric features of 3,4-dihydro-2 (1H)-quinolinone and dithiocarbamate. METHODS: All compounds were evaluated for their inhibitory abilities of ChEs and MAOs. Then, further biological activities of the most promising candidate 3e were determined, including the ability to cross the blood-brain barrier (BBB), kinetics and molecular model analysis, cytotoxicity in vitro and acute toxicity studies in vivo. RESULTS: Most compounds showed potent and clear inhibition to AChE and MAOs. Among them, compound 3e was considered to be the most effective and balanced inhibitor to both AChE and MAOs (IC(50)=0.28 microM to eeAChE; IC(50)=0.34 microM to hAChE; IC(50)=2.81 microM to hMAO-B; IC(50)=0.91 microM to hMAO-A). In addition, 3e showed mixed inhibition of hAChE and competitive inhibition of hMAO-B in the enzyme kinetic studies. Further studies indicated that 3e could penetrate the BBB and showed no toxicity on PC12 cells and HT-22 cells when the concentration of 3e was lower than 12.5 microM. More importantly, 3e lacked acute toxicity in mice even at high dose (2500 mg/kg, P.O.). CONCLUSION: This work indicated that compound 3e with a six-carbon atom linker and a piperidine moiety at terminal position was a promising candidate and was worthy of further study. Title: A multi-target directed ligands strategy for the treatment of Alzheimer's disease: Dimethyl fumarate plus Tranilast modified Dithiocarbate as AChE inhibitor and Nrf2 activator Guo J, Cheng M, Liu P, Cao D, Luo J, Wan Y, Fang Y, Jin Y, Xie SS, Liu J Ref: Eur Journal of Medicinal Chemistry, 242:114630, 2022 : PubMed ESTHER: Guo_2022_Eur.J.Med.Chem_242_114630 PubMedSearch: Guo 2022 Eur.J.Med.Chem 242 114630 PubMedID: 35987018 Inhibitor(s) related to this paper: 4c2-AChE-IN-24 Abstract Alzheimer's disease (AD) possessed intricate pathogenesis. Currently, multi-targeted drugs were considered to have the potential to against AD by simultaneously triggering molecules in functionally complementary pathways. Hence, a series of molecules based on the pharmacophoric features of Dimethyl fumarate, Tranilast, and Dithiocarbate were designed and synthesized. These compounds showed significant AChE inhibitory activity in vitro. Among them, compound 4c(2) displayed the mighty inhibitory activity to hAChE (IC(50) = 0.053 microM) and held the ability to cross the BBB. Kinetic study and molecular docking pointed out that 4c(2) bound well into the active sites of hAChE, forming steady and sturdy interactions with key residues in hAChE. Additionally, 4c(2) as an Nrf2 activator could promote the nuclear translocation of Nrf2 protein and induce the expressions of Nrf2-dependent enzymes HO-1, NQO1, and GPX4. Moreover, 4c(2) rescued BV-2 cells from H(2)O(2)-induced injury and inhibited ROS accumulation. For the anti-neuroinflammatory potential of 4c(2), we observed that 4c(2) could lower the levels of pro-inflammatory cytokines (NO, IL-6 and TNF-alpha) and suppressed the expressions of iNOS and COX-2. In particular, 4c(2) was well tolerated in mice (2500 mg/kg, p.o.) and efficaciously recovered the memory impairment in a Scopolamine-induced mouse model. Overall, these results highlighted that 4c(2) was a promising multi-targeted agent for treating AD. Title: Protective effect of Monarda didymaL. essential oil and its main component thymol on learning and memory impairment in aging mice Guo Y, Qu Y, Li W, Shen H, Cui J, Liu J, Li J, Wu D Ref: Front Pharmacol, 13:992269, 2022 : PubMed ESTHER: Guo_2022_Front.Pharmacol_13_992269 PubMedSearch: Guo 2022 Front.Pharmacol 13 992269 PubMedID: 36105199 Abstract The aging process of human beings is accompanied by the decline of learning and memory ability and progressive decline of brain function, which induces Alzheimer's Disease (AD) in serious cases and seriously affects the quality of patient's life. In recent years, more and more studies have found that natural plant antioxidants can help to improve the learning and memory impairment, reduce oxidative stress injury and aging lesions in tissues. This study aimed to investigate the effect of Monarda didymaL. essential oil and its main component thymol on learning and memory impairment in D-galactose-induced aging mice and its molecular mechanism. The composition of Monarda didymaL. essential oil was analyzed by Gas Chromatography-Mass Spectrometer (GC-MS). A mouse aging model was established by the subcutaneous injection of D-galactose in mice. The behavior changes of the mice were observed by feeding the model mice with essential oil, thymol and donepezil, and the histopathological changes of the hippocampus were observed by HE staining. And the changes of acetylcholinesterase (AchE), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities, and the content of malondialdehyde (MDA) in hippocampal tissues were detected by corresponding kits. The expression of mitogen activated protein kinase (MAPK) and nuclear factor E2 related factor 2 (Nrf2) pathways related proteins were detected by western blot. Animal experimental results showed that compared with model group, the above indexes in Monarda didymaL. essential oil and thymol groups improved significantly in a dose-dependent manner. Monarda didymaL. essential oil and its main active component thymol can improve the learning and memory impairment of aging mice to some extent, and Nrf2 and MAPK pathways may be involved in its action process. Title: Transcriptome-wide association study reveals cholesterol metabolism gene Lpl is a key regulator of cognitive dysfunction Hu W, Liu J, Hu Y, Xu Q, Deng T, Wei M, Lu L, Mi J, Bergquist J and Tian G <1 more author(s)> Hu W, Liu J, Hu Y, Xu Q, Deng T, Wei M, Lu L, Mi J, Bergquist J, Xu F, Tian G (- 1) Ref: Front Mol Neurosci, 15:1044022, 2022 : PubMed ESTHER: Hu_2022_Front.Mol.Neurosci_15_1044022 PubMedSearch: Hu 2022 Front.Mol.Neurosci 15 1044022 PubMedID: 36590920 Abstract Cholesterol metabolism in the brain plays a crucial role in normal physiological function, and its aberrations are associated with cognitive dysfunction. The present study aimed to determine which cholesterol-related genes play a vital role in cognitive dysfunction and to dissect its underlying molecular mechanisms using a systems genetics approach in the BXD mice family. We first systematically analyzed the association of expression of 280 hippocampal genes related to cholesterol metabolism with cognition-related traits and identified lipoprotein lipase (Lpl) as a critical regulator. This was further confirmed by phenome-wide association studies that indicate Lpl associated with hippocampus volume residuals and anxiety-related traits. By performing expression quantitative trait locus mapping, we demonstrate that Lpl is strongly cis-regulated in the BXD hippocampus. We also identified -3,300 genes significantly (p < 0.05) correlated with the Lpl expression. Those genes are mainly involved in the regulation of neuron-related traits through the MAPK signaling pathway, axon guidance, synaptic vesicle cycle, and NF-kappa B signaling pathway. Furthermore, a protein-protein interaction network analysis identified several direct interactors of Lpl, including Rab3a, Akt1, Igf1, Crp, and Lrp1, which indicates that Lpl involves in the regulation of cognitive dysfunction through Rab3a-mediated synaptic vesicle cycle and Akt1/Igf1/Crp/Lrp1-mediated MAPK signaling pathway. Our findings demonstrate the importance of the Lpl, among the cholesterol-related genes, in regulating cognitive dysfunction and highlighting the potential signaling pathways, which may serve as novel therapeutic targets for the treatment of cognitive dysfunction. Title: Two-Stage SN38 Release from a Core-Shell Nanoparticle Enhances Tumor Deposition and Antitumor Efficacy for Synergistic Combination with Immune Checkpoint Blockade Jiang X, Lee M, Xia J, Luo T, Liu J, Rodriguez M, Lin W Ref: ACS Nano, :, 2022 : PubMed ESTHER: Jiang_2022_ACS.Nano__ PubMedSearch: Jiang 2022 ACS.Nano PubMedID: 36382721 Abstract Long-circulating nanomedicines efficiently deliver chemotherapies to tumors to reduce general toxicity. However, extended blood circulation of nanomedicines can increase drug exposure to leukocytes and lead to hematological toxicity. Here, we report a two-stage release strategy to enhance the drug deposition and antitumor efficacy of OxPt/SN38 core-shell nanoparticles with a hydrophilic oxaliplatin (OxPt) prodrug coordination polymer core and a lipid shell containing a hydrophobic cholesterol-conjugated SN38 prodrug (Chol-SN38). By conjugating cholesterol to the phenol group of SN38 via an acetal linkage and protecting the 20-hydroxy position with a trimethylsilyl (TMS) group, Chol-SN38 releases SN38 in two stages via esterase-catalyzed cleavage of the acetal linkage in the liver followed by acid-mediated hydrolysis of the TMS group to preferentially release SN38 in tumors. Compared to irinotecan, OxPt/SN38 reduces SN38 blood exposure by 9.0 times and increases SN38 tumor exposure by 4.7 times. As a result, OxPt/SN38 inhibits tumor growth on subcutaneous, spontaneous, and metastatic tumor models by causing apoptotic and immunogenic cell death. OxPt/SN38 exhibits strong synergy with the immune checkpoint blockade to regress subcutaneous colorectal and pancreatic tumors with 33-50% cure rates and greatly inhibits tumor growth and invasion in a spontaneous prostate cancer model and a liver metastasis model of colorectal cancer without causing side effects. Mechanistic studies revealed important roles of enhanced immunogenic cell death and upregulated PD-L1 expression by OxPt/SN38 in activating the tumor immune microenvironment to elicit potent antitumor immunity. This work highlights the potential of combining innovative prodrug design and nanomedicine formulation to address unmet needs in cancer therapy. Title: Characterization of pectin methylesterase gene family and its possible role in juice sac granulation in navel orange (Citrus sinensis Osbeck) Li Z, Wu L, Wang C, Wang Y, He L, Wang Z, Ma X, Bai F, Feng G and Song F <2 more author(s)> Li Z, Wu L, Wang C, Wang Y, He L, Wang Z, Ma X, Bai F, Feng G, Liu J, Jiang Y, Song F (- 2) Ref: BMC Genomics, 23:185, 2022 : PubMed ESTHER: Li_2022_BMC.Genomics_23_185 PubMedSearch: Li 2022 BMC.Genomics 23 185 PubMedID: 35249536 Abstract BACKGROUND: Citrus is one of the most important fresh fruit crops worldwide. Juice sac granulation is a physiological disorder, which leads to a reduction in soluble solid concentration, total sugar, and titratable acidity of citrus fruits. Pectin methylesterase (PME) catalyzes the de-methylesterification of homogalacturonans and plays crucial roles in cell wall modification during plant development and fruit ripening. Although PME family has been well investigated in various model plants, little is known regarding the evolutionary property and biological function of PME family genes in citrus. RESULTS: In this study, 53 non-redundant PME genes were identified from Citrus sinensis genome, and these PME genes were divided into four clades based on the phylogenetic relationship. Subsequently, bioinformatics analyses of gene structure, conserved domain, chromosome localization, gene duplication, and collinearity were performed on CsPME genes, providing important clues for further research on the functions of CsPME genes. The expression profiles of CsPME genes in response to juice sac granulation and low-temperature stress revealed that CsPME genes were involved in the low temperature-induced juice sac granulation in navel orange fruits. Subcellular localization analysis suggested that CsPME genes were localized on the apoplast, endoplasmic reticulum, plasma membrane, and vacuole membrane. Moreover, yeast one-hybrid screening and dual luciferase activity assay revealed that the transcription factor CsRVE1 directly bound to the promoter of CsPME3 and activated its activity. CONCLUSION: In summary, this study conducts a comprehensive analysis of the PME gene family in citrus, and provides a novel insight into the biological functions and regulation patterns of CsPME genes during juice sac granulation of citrus. Title: Biological activities and gene expression of detoxifying enzymes in Tribolium castaneum induced by Moutan cortex essential oil Li X, Xu Y, Liu J, Yu X, Zhang W, You C Ref: J Toxicol Environ Health A, :1, 2022 : PubMed ESTHER: Li_2022_J.Toxicol.Environ.Health.A__1 PubMedSearch: Li 2022 J.Toxicol.Environ.Health.A 1 PubMedID: 35435144 Abstract Tribolium castaneum is one of the most harmful storage pests in the world. The aim of this study was to determine the chemical composition, repellent, and contact activities of Moutan cortex essential oil against this insect pest. In addition, the effects of Moutan cortex were examined on the expressions of three major detoxifying enzyme genes in T. castaneum. Four components were identified in this essential oil by gas chromatography-mass spectrometry (GC-MS), which was predominantly paeonol (99.13%). Paeonol exerted significant repellent activity against T. castaneum, which was more potent than the positive control N.N-diethyl-meta-toluamide (DEET). The most significant contact toxicity was observed at 24 h after exposure to paeonol. Further, quantitative real-time PCR (qRT-PCR) was used to assess expression changes in three detoxification enzyme genes in T. castaneum, including carboxylesterase (CarE), glutathione S-transferase (Gst) and cytochrome P4506BQ8 (Cyp6bq8). Among these, Gst was most highly up-regulated after treatment with paeonol with the highest expression level of 4.9-fold (Rps18 as internal reference gene) greater than control at 24 h following treatment. Data indicated that Gst might play a critical role in metabolic detoxification of toxic xenobiotics. Taken together, our findings might lay a foundation for development of paeonol as a potential natural repellent or pesticide to control storage pests. Title: Novel and Potent Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease from Natural (+/-)-7,8-Dihydroxy-3-methyl-isochroman-4-one Li X, Jia Y, Li J, Zhang P, Li T, Lu L, Yao H, Liu J, Zhu Z, Xu J Ref: Molecules, 27:3090, 2022 : PubMed ESTHER: Li_2022_Molecules_27_3090 PubMedSearch: Li 2022 Molecules 27 3090 PubMedID: 35630563 Abstract Alzheimer's disease (AD) is a neurodegenerative disease that causes memory and cognitive decline as well as behavioral problems. It is a progressive and well recognized complex disease; therefore, it is very urgent to develop novel and effective anti-AD drugs. In this study, a series of novel isochroman-4-one derivatives from natural (+/-)-7,8-dihydroxy-3-methyl-isochroman-4-one [(+/-)-XJP] were designed and synthesized, and their anti-AD potential was evaluated. Among them, compound 10a [(Z)-3-acetyl-1-benzyl-4-((6,7-dimethoxy-4-oxoisochroman-3-ylidene)methyl)pyridin-1-ium bromide] possessed potent anti-acetylcholinesterase (AChE) activity as well as modest antioxidant activity. Further molecular modeling and kinetic investigations revealed that compound 10a was a dual-binding inhibitor that binds to both catalytic anionic site (CAS) and peripheral anionic site (PAS) of the enzyme AChE. In addition, compound 10a exhibited low cytotoxicity and moderate anti-Abeta aggregation efficacy. Moreover, the in silico screening suggested that these compounds could pass across the blood-brain barrier with high penetration. These findings show that compound 10a was a promising lead from a natural product with potent AChE inhibitory activity and deserves to be further developed for the prevention and treatment of AD. Title: Hollow urchin-shaped manganese dioxide microspheres immobilized acetylcholinesterase for rapid screening inhibitors from traditional herbal medicines Liu J, Ha W, Zhang HX, Shi YP Ref: Journal of Chromatography A, 1665:462824, 2022 : PubMed ESTHER: Liu_2022_J.Chromatogr.A_1665_462824 PubMedSearch: Liu 2022 J.Chromatogr.A 1665 462824 PubMedID: 35051752 Abstract Acetylcholinesterase (AChE) is generally considered to be a valuable therapeutic target for Alzheimer's disease (AD). To rapidly screen novel AChE inhibitors from Traditional Chinese medicines (TCMs), polydopamine (PDA) coated hollow urchin-shaped manganese dioxide microspheres (h-MnO(2)@PDA) were fabricated in this work. AChE was immobilized onto the surface of h-MnO(2)@PDA for the first time, and the prepared h-MnO(2)@PDA immobilized AChE coupled with capillary electrophoresis (CE) was applied to AChE inhibitor screening. The enzyme catalytic activity and kinetic performances of the immobilized AChE were determined by measuring the peak areas of 5-thio-2-nitrobenzoic acid (TNB), which was produced by the reaction of thiocholine (TCh) with 5,5-dithiobis-(2-nitrobenzoic acid) (DTNB). Inhibition kinetics for the immobilized AChE was performed by employing huperzine A as model inhibitor, and its inhibition constant and IC(50) were determined. The constructed AChE immobilized h-MnO(2)@PDA presented outstanding pH, thermal and storage stability. Ultimately, the constructed strategy was applied to screen AChE inhibitors from 7 TCMs and Schisandrae Chinensis Fructus was screened out for its superior AChE inhibitory activity. Therefore, our work not only established a platform for efficiently screening novel AChE inhibitors from TCMs, but also provided inspiration for further exploration of Schisandrae Chinensis Fructus as a potential drug for AD. Title: Novel inhibitors of AChE and Abeta aggregation with neuroprotective properties as lead compounds for the treatment of Alzheimer's disease Liu Y, Uras G, Onuwaje I, Li W, Yao H, Xu S, Li X, Phillips J, Allen S and Xu J <4 more author(s)> Liu Y, Uras G, Onuwaje I, Li W, Yao H, Xu S, Li X, Phillips J, Allen S, Gong Q, Zhang H, Zhu Z, Liu J, Xu J (- 4) Ref: Eur Journal of Medicinal Chemistry, 235:114305, 2022 : PubMed ESTHER: Liu_2022_Eur.J.Med.Chem_235_114305 PubMedSearch: Liu 2022 Eur.J.Med.Chem 235 114305 PubMedID: 35339839 Inhibitor(s) related to this paper: Fluoropezil Abstract A series of sulfone analogs of donepezil were designed and synthesized as novel acetylcholinesterase (AChE) inhibitors with the potent inhibiting Abeta aggregation and providing neuroprotective effects as potential modalities for Alzheimer's disease (AD). Most of the target compounds displayed effective inhibition of AChE, especially compound 24r which displayed powerful inhibitory activity (IC(50) = 2.4 nM). Kinetic and docking studies indicated that compound 24r was a mixed-type inhibitor. Furthermore, in glyceraldehyde (GA)-exposed SH-SY5Y differentiated neuronal cells, compound 24r could potently inhibit AChE, reduce tau phosphorylation at S396 residue, provide neuroprotection by rescuing neuronal morphology and increasing cell viability. It was also found to reduce amyloid aggregation in the presence of AChE. In addition, compound 24r showed evident protections from mitochondrial membrane dysfunction and oxidative stress in okadaic acid-induced pharmacological models. Moreover, compound 24r exhibited more effective treatment prospects in vivo than donepezil, including a moderate blood-brain barrier permeability, a more potent AChE inhibitory activity and behavioral improvement in scopolamine-induced cognition-impaired mice model at a much lower dose. Collectively, compound 24r is a promising lead compound for further investigation to discovery and development of new anti-AD agents. Title: Highly Selective Detection of Paraoxon in Food Based on the Platform of Cu Nanocluster/MnO(2) Nanosheets Liu S, Zhang P, Miao Y, Li C, Shi YE, Liu J, Lv YK, Wang Z Ref: Nanomaterials (Basel), 12:, 2022 : PubMed ESTHER: Liu_2022_Nanomaterials.(Basel)_12_ PubMedSearch: Liu 2022 Nanomaterials.(Basel) 12 PubMedID: 35564138 Abstract Selective and sensitive identification of paraoxon residue in agricultural products is greatly significant for food safety but remains a challenging task. Herein, a detection platform was developed by integrating Cu nanoclusters (Cu NCs) with MnO(2) nanosheets, where the fluorescence of Cu NCs was effectively quenched. Upon introducing butyrylcholinesterase and butyrylcholine into the system, their hydrolysate, thiocholine, leads to the decomposition of the platform through a reaction between the MnO(2) nanosheets and thiol groups on thiocholine. The electron-rich groups on thiocholine can further promote the fluorescence intensity of Cu NCs through host-guest interactions. Adding paraoxon results in the failure of fluorescence recovery and further promotion, which could be utilized for the quantitative detection of paraoxon, and a limit of detection as low as 0.22 ng/mL can be achieved. The detection platform shows strong tolerance to common interference species, which endows its applications for the detection of paraoxon in vegetables and fruit. These presented results not only open a new door for the functionalization of metal nanoclusters but also offer an inspiring strategy for analytic techniques in nanomedicine and environmental science. Title: BCHE as a Prognostic Biomarker in Endometrial Cancer and Its Correlation with Immunity Liu J, Tian T, Liu X, Cui Z Ref: J Immunol Res, 2022:6051092, 2022 : PubMed ESTHER: Liu_2022_J.Immunol.Res_2022_6051092 PubMedSearch: Liu 2022 J.Immunol.Res 2022 6051092 PubMedID: 35915658 Abstract BACKGROUND: In developed countries, the most common gynecologic malignancy is endometrial carcinoma (EC), making the identification of EC biomarkers extremely essential. As a natural enzyme, butyrylcholinesterase (BCHE) is found in hepatocytes and plasma. There is a strong correlation between BCHE gene mutations and cancers and other diseases. The aim of this study was to analyze the role of BCHE in patients with EC. METHODS: A variety of analyses were conducted on The Cancer Genome Atlas (TCGA) data, including differential expression analysis, enrichment analysis, immunity, clinicopathology, and survival analysis. The Gene Expression Omnibus (GEO) database was used to validate outcomes. Using R tools, Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) analyses revealed the potential mechanisms of BCHE in EC. Sangerbox tools were used to delve into the relations between BCHE expression and tumor microenvironment, including microsatellite instability (MSI), tumor neoantigen count (TNC), and tumor mutation burden (TMB). BCHE's genetic alteration analysis was conducted by cBioPortal. In addition, the Human Protein Atlas (HPA) was used to validate the outcomes by immunohistochemistry, and an analysis of the protein-protein interaction network (PPI) was performed with the help of the STRING database. RESULTS: Based on our results, BCHE was a significant independent prognostic factor for patients with EC. The prognosis with EC was affected by age, stage, grade, histological type, and BCHE. GSEA showed that BCHE was closely related to pathways regulating immune response, including transforming growth factor-beta (TGF-beta) signaling pathways and cancer immunotherapy through PD1 blockade pathways. The immune analysis revealed that CD4+ regulatory T cells (Tregs) were negatively correlated with BCHE expression and the immune checkpoint molecules CD28, ADORA2A, BTNL2, and TNFRSF18 were all significantly related to BCHE. BCHE expression was also associated with TMB by genetic alteration analysis. CONCLUSIONS: Identifying BCHE as a biomarker for EC might help predict its prognosis and could have important implications for immunotherapy. Title: Emerging role of carboxylesterases in nonalcoholic fatty liver disease Liu J, Yao B, Gao L, Zhang Y, Huang S, Wang X Ref: Biochemical Pharmacology, :115250, 2022 : PubMed ESTHER: Liu_2022_Biochem.Pharmacol__115250 PubMedSearch: Liu 2022 Biochem.Pharmacol 115250 PubMedID: 36130649 Abstract Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as a global public health problem. Carboxylesterases (CESs), as potential influencing factors of NAFLD, are very important to improve clinical outcomes. This review aims to deeply understand the role of CESs in the progression of NAFLD and proposes that CESs can be used as potential targets for NAFLD treatment. We first introduced CESs and analyzed the relationship between CESs and hepatic lipid metabolism and inflammation. Then, we further reviewed the regulation of nuclear receptors on CESs, including PXR, CAR, PPARalpha, HNF4alpha and FXR, which may influence the progression of NAFLD. Finally, we evaluated the advantages and disadvantages of existing NAFLD animal models and summarized the application of CES-related animal models in NAFLD research. In general, this review provides an overview of the relationship between CESs and NAFLD and discusses the role and potential value of CESs in the treatment and prevention of NAFLD. Title: Dwarf and High Tillering1 represses rice tillering through mediating the splicing of D14 pre-mRNA Liu T, Zhang X, Zhang H, Cheng Z, Liu J, Zhou C, Luo S, Luo W, Li S and Wan J <12 more author(s)> Liu T, Zhang X, Zhang H, Cheng Z, Liu J, Zhou C, Luo S, Luo W, Li S, Xing X, Chang Y, Shi C, Ren Y, Zhu S, Lei C, Guo X, Wang J, Zhao Z, Wang H, Zhai H, Lin Q, Wan J (- 12) Ref: Plant Cell, 34:3301, 2022 : PubMed ESTHER: Liu_2022_Plant.Cell_34_3301 PubMedSearch: Liu 2022 Plant.Cell 34 3301 PubMedID: 35670739 Abstract Strigolactones (SLs) constitute a class of plant hormones that regulate many aspects of plant development, including repressing tillering in rice (Oryza sativa). However, how SL pathways are regulated is still poorly understood. Here, we describe a rice mutant dwarf and high tillering1 (dht1), which exhibits pleiotropic phenotypes (such as dwarfism and increased tiller numbers) similar to those of mutants defective in SL signaling. We show that DHT1 encodes a monocotyledon-specific hnRNP-like protein that acts as a previously unrecognized intron splicing factor for many precursor mRNAs (pre-mRNAs), including for the SL receptor gene D14. We find that the dht1 (DHT1I232F) mutant protein is impaired in its stability and RNA binding activity, causing defective splicing of D14 pre-mRNA and reduced D14 expression, and consequently leading to the SL signaling-defective phenotypes. Overall, our findings deepen our understanding of the functional diversification of hnRNP-like proteins and establish a connection between posttranscriptional splicing and SL signaling in the regulation of plant development. Title: Inhibition of Dipeptidyl Peptidase-4 by Flavonoids: Structure-Activity Relationship, Kinetics and Interaction Mechanism Pan J, Zhang Q, Zhang C, Yang W, Liu H, Lv Z, Liu J, Jiao Z Ref: Front Nutr, 9:892426, 2022 : PubMed ESTHER: Pan_2022_Front.Nutr_9_892426 PubMedSearch: Pan 2022 Front.Nutr 9 892426 PubMedID: 35634373 Abstract With the aim to establish a structure-inhibitory activity relationship of flavonoids against dipeptidyl peptidase-4 (DPP-4) and elucidate the interaction mechanisms between them, a pannel of 70 structurally diverse flavonoids was used to evaluate their inhibitory activities against DPP-4, among which myricetin, hyperoside, narcissoside, cyanidin 3-O-glucoside, and isoliquiritigenin showed higher inhibitory activities in a concentration-dependent manner. Structure-activity relationship analysis revealed that introducing hydroxyl groups to C3', C4', and C6 of the flavonoid structure was beneficial to improving the inhibitory efficacy against DPP-4, whereas the hydroxylation at position 3 of ring C in the flavonoid structure was unfavorable for the inhibition. Besides, the methylation of the hydroxyl groups at C3', C4', and C7 of the flavonoid structure tended to lower the inhibitory activity against DPP-4, and the 2,3-double bond and 4-carbonyl group on ring C of the flavonoid structure was essential for the inhibition. Glycosylation affected the inhibitory activity diversely, depending on the structure of flavonoid aglycone, type of glycoside, as well as the position of substitution. Inhibition kinetic analysis suggested that myricetin reversibly inhibited DPP-4 in a non-competitive mode, whereas hyperoside, narcissoside, cyanidin 3-O-glucoside, and isoliquiritigenin all reversibly inhibited DPP-4 in a mixed type. Moreover, the fluorescence quenching analysis indicated that all the five flavonoid compounds could effectively quench the intrinsic fluorescence of DPP-4 by spontaneously binding with it to form an unstable complex. Hydrogen bonds and van der Waals were the predominant forces to maintain the complex of myricetin with DPP-4, and electrostatic forces might play an important role in stabilizing the complexes of the remaining four flavonoids with DPP-4. The binding of the tested flavonoids to DPP-4 could also induce the conformation change of DPP-4 and thus led to inhibition on the enzyme. Molecular docking simulation further ascertained the binding interactions between DPP-4 and the selected five flavonoids, among which hyperoside, narcissoside, cyaniding 3-O-glucoside, and isoliquiritigenin inserted into the active site cavity of DPP-4 and interacted with the key amino acid residues of the active site, whereas the binding site of myricetin was located in a minor cavity close to the active pockets of DPP-4. Title: Acquisition of T6SS Effector TseL Contributes to the Emerging of Novel Epidemic Strains of Pseudomonas aeruginosa Ren A, Jia M, Liu J, Zhou T, Wu L, Dong T, Cai Z, Qu J, Liu Y and Zhang Y <1 more author(s)> Ren A, Jia M, Liu J, Zhou T, Wu L, Dong T, Cai Z, Qu J, Liu Y, Yang L, Zhang Y (- 1) Ref: Microbiol Spectr, :e0330822, 2022 : PubMed ESTHER: Ren_2022_Microbiol.Spectr__e0330822 PubMedSearch: Ren 2022 Microbiol.Spectr e0330822 PubMedID: 36546869 Gene_locus related to this paper: pseae-T6SSTseL Abstract Pseudomonas aeruginosa is an opportunistic pathogen with multiple strategies to interact with other microbes and host cells, gaining fitness in complicated infection sites. The contact-dependent type VI secretion system (T6SS) is one critical secretion apparatus involved in both interbacterial competition and pathogenesis. To date, only limited numbers of T6SS-effectors have been clearly characterized in P. aeruginosa laboratory strains, and the importance of T6SS diversity in the evolution of clinical P. aeruginosa remains unclear. Recently, we characterized a P. aeruginosa clinical strain LYSZa7 from a COVID-19 patient, which adopted complex genetic adaptations toward chronic infections. Bioinformatic analysis has revealed a putative type VI secretion system (T6SS) dependent lipase effector in LYSZa7, which is a homologue of TseL in Vibrio cholerae and is widely distributed in pathogens. We experimentally validated that this TseL homologue belongs to the Tle2, a subfamily of T6SS-lipase effectors; thereby, we name this effector TseL (TseL(PA) in this work). Further, we showed the lipase-dependent bacterial toxicity of TseL(PA), which primarily targets bacterial periplasm. The toxicity of TseL(PA) can be neutralized by two immunity proteins, TsiP1 and TsiP2, which are encoded upstream of tseL. In addition, we proved this TseL(PA) contributes to bacterial pathogenesis by promoting bacterial internalization into host cells. Our study suggests that clinical bacterial strains employ a diversified group of T6SS effectors for interbacterial competition and might contribute to emerging of new epidemic clonal lineages. IMPORTANCE Pseudomonas aeruginosa is one predominant pathogen that causes hospital-acquired infections and is one of the commonest coinfecting bacteria in immunocompromised patients and chronic wounds. This bacterium harbors a diverse accessory genome with a high frequency of gene recombination, rendering its population highly heterogeneous. Numerous Pa lineages coexist in the biofilm, where successful epidemic clonal lineage or strain-specific type commonly acquires genes to increase its fitness over the other organisms. Current studies of Pa genomic diversity commonly focused on antibiotic resistant genes and novel phages, overlooking the contribution of type VI secretion system (T6SS). We characterized a Pa clinical strain LYSZa7 from a COVID-19 patient, which adopted complex genetic adaptations toward chronic infections. We report, in this study, a novel T6SS-lipase effector that is broadly distributed in Pa clinical isolates and other predominant pathogens. The study suggests that hospital transmission may raise the emergence of new epidemic clonal lineages with specified T6SS effectors. Title: Preparation, characterization and bioactivities of selenized polysaccharides from Lonicera caerulea L. fruits Shao C, Zhong J, Liu J, Yang Y, Li M, YangYu, Xu Y, Wang L Ref: Int J Biol Macromol, :, 2022 : PubMed ESTHER: Shao_2022_Int.J.Biol.Macromol__ PubMedSearch: Shao 2022 Int.J.Biol.Macromol PubMedID: 36403769 Abstract Native polysaccharide was obtained from Lonicera caerulea L. fruits (PLP). Two selenized polysaccharides (PSLP-1 and PSLP-2) were synthesized by the microwave-assisted HNO(3)-Na(2)SeO(3) method, where the selenium (Se) contents were 228 +/-24 and 353 +/- 36 microg/g, respectively. The molecular weights of PLP, PSLP-1, and PSLP-2 were 5.9 10(4), 5.6 10(4), and 5.1 10(4) kDa, respectively. PSLP-1 and PSLP-2 contained the same type of monosaccharides as PLP but with different molar ratios. The main chain structure of the native polysaccharide was not changed after selenization. PLP, PSLP-1, and PSLP-2 contained the same six types of glycosidic bonds. Bioactivity assays revealed that the two selenized polysaccharides possessed better antioxidant activities than PLP, but their bile acid-binding abilities and inhibitory activities on acetylcholinesterase (AChE) had weakened. In summary, PLP, PSLP-1, and PSLP-2 may be promising Se supplements in functional foods and inhibitors for the treatment of AChE. Title: A hemicyanine-based fluorescent probe for simultaneous imaging of Carboxylesterases and Histone deacetylases in hepatocellular carcinoma Shu Y, Huang C, Liu H, Hu F, Wen H, Liu J, Wang X, Shan C, Li W Ref: Spectrochim Acta A Mol Biomol Spectrosc, 281:121529, 2022 : PubMed ESTHER: Shu_2022_Spectrochim.Acta.A.Mol.Biomol.Spectrosc_281_121529 PubMedSearch: Shu 2022 Spectrochim.Acta.A.Mol.Biomol.Spectrosc 281 121529 PubMedID: 35797949 Abstract Carboxylesterases (CESs) and Histone deacetylases (HDACs) are regarded as important signaling enzymes highly associated with the development and progression of multiple cancers, including hepatocellular carcinoma (HCC). In this work, a near-infrared (NIR) fluorescent probe named Lys-HXPI was designed and synthesized, which linked a hemicyanine dye and 6-acetamidohexanoic acid via an ester bond. Lys-HXPI displayed a remarkable increase with a NIR emission at 720 nm, a low detection limit (<10 nM) for HDAC1, HDAC 6, CES1 and CES2, as well as a high selectivity for the target enzymes over other relevant analytes. Furthermore, Lys-HXPI was used to image endogenous target enzymes in living cells, tumor-bearing nude mice and tissue slices. The ability of Lys-HXPI to simultaneous image CESs and HDACs was demonstrated with RT-qPCR and the confocal imaging in Hep G2 and MDA-MB-231. Taking advantage of NIR emission, the probe was also successfully applied to imaging Hep G2 tumor mice and tissue slices. Lys-HXPI is expected to be useful for the effective detecting of CESs and HDACs in complex biosystems. Title: Design, synthesis and insecticidal activity and mechanism research of Chasmanthinine derivatives Song Z, Li X, Xu K, Sun G, Yang L, Huang L, Liu J, Yin P, Huang S and Chen L <2 more author(s)> Song Z, Li X, Xu K, Sun G, Yang L, Huang L, Liu J, Yin P, Huang S, Gao F, Zhou X, Chen L (- 2) Ref: Sci Rep, 12:15290, 2022 : PubMed ESTHER: Song_2022_Sci.Rep_12_15290 PubMedSearch: Song 2022 Sci.Rep 12 15290 PubMedID: 36088472 Abstract Unrestricted reproduction and spread of pest had caused great damage to the quality and yield of crops in recent years. Besides the use of traditional chemical pesticides, natural products also make a huge contribution against pests. Chasmanthinine, a diterpenoid alkaloid isolated from Aconitum franchetii var. villosulum, shown extremely antifeedant activity against Spodoptera exigua. Therefore, a series of novel Chasmanthinine derivatives were synthesized and their biological activity was studied in this work. Compound 33 showed the strongest antifeedant activity (EC(50) = 0.10 mg/cm(2)) among all the test compounds. The mechanism research of 33 revealed that its antifeedant effect was related to the inhibition of carboxylesterase (CES), and proved the thiophene acyl group could form a strong binding effect with CES by molecular docking. Moreover, compound 10 exhibited the strongest cytotoxicity (IC(50) = 12.87 microM) against Sf9 cell line and moderate contact toxicity. The mechanism research indicated that compound 10 could induce Sf9 cells apoptosis. In summary, the results lay a foundation for the application of diterpene alkaloids in plant protection. Title: The efficacy of Azotobacter chroococcum in altering maize plant-defense responses to armyworm at elevated CO(2) concentration Song Y, Liu J, Fu M, Liu H, Wang W, Wang S, Chen F Ref: Ecotoxicology & Environmental Safety, 248:114296, 2022 : PubMed ESTHER: Song_2022_Ecotoxicol.Environ.Saf_248_114296 PubMedSearch: Song 2022 Ecotoxicol.Environ.Saf 248 114296 PubMedID: 36399994 Abstract Elevated atmospheric carbon dioxide (eCO(2)) concentrations can alter the carbon:nitrogen ratio and palatability of host plants for herbivorous insects, but rhizobacteria likely mitigate the alteration and influence physiological adaptation of insects. In this study, we conducted transcriptomic analysis of maize (Zea mays) response to Azotobacter chroococcum (AC) inoculation under eCO(2) conditions in contrast to ambient CO(2) (aCO(2)), and studied the effects of plant-defense change of maize under eCO(2) on the oriental armyworm, Mythimna separata. Results showed that there were 16, 14, 16 and 135 differentially expressed genes that were associated with plant-defense response in maize leaves between aCO(2)-CK and aCO(2)-AC, eCO(2)-CK and eCO(2)-AC, aCO(2)-CK and eCO(2)-CK, aCO(2)-AC and eCO(2)-AC, respectively. Moreover, A. chroococcum inoculation and eCO(2) influenced plant hormone signal transduction of maize. Interestingly, A. chroococcum inoculation significantly decreased the contents of JA (jasmonic acid) and JA-Ile (isoleucine conjugate of JA) in leaves, but eCO(2) markedly increased contents of JA-Ile, JA and SA (salicylic acid). Compared to aCO(2), eCO(2) significantly decreased activity of protective enzyme (catalase), and increased activities of digestive (lipase and protease), protective (peroxidase) and detoxifying enzymes (carboxylesterase, Mixed-functional oxidase and glutathione s-transferase), prolonged developmental time, and decreased survival rate and body weight of larvae (P<0.05). A. chroococcum inoculation significantly increased the activity of protective enzyme (catalase), and decreased the activities of detoxifying enzymes (carboxylesterase, glutathione s-transferase and mixed-functional oxidase), thus increased the growth rate and body weight of larvae in comparison with no-inoculation of A. chroococcum (P<0.05). The indices of M. separata were significantly correlated with the foliar contents of JA, JA-Ile and SA (|r| = 0.44-0.85, P<0.05), indicating that A. chroococcum inoculation altered the physiological adaptation of M. separata under eCO(2) by disturbing defense substances in maize. Our results in understanding effects of A. chroococcum inoculation on maize resistance to herbivorous insects will be valuable for agricultural pest control in the future at eCO(2) conditions. Title: Saxagliptin alleviates erectile dysfunction through increasing SDF-1 in diabetes mellitus Sun T, Xu W, Wang J, Wang T, Wang S, Liu K, Liu J Ref: Andrology, :, 2022 : PubMed ESTHER: Sun_2022_Andrology__ PubMedSearch: Sun 2022 Andrology PubMedID: 36113503 Abstract BACKGROUND: Diabetes mellitus-induced erectile dysfunction (DMED) is one of the complications of diabetes and has a poor response to phosphodiesterase type 5 inhibitor, the first-line treatment for ED. Saxagliptin (Sax), a dipeptidyl peptidase-4 inhibitor (DPP-4i), has been officially used in the treatment of type 2 diabetes. Stromal cell-derived factor-1 (SDF-1) is one of the important substrates of DPP-4, and has been proven to be beneficial for several DM complications. However, it is unknown whether Sax contributes to the management of DMED. OBJECTIVES: To explore the effect and possible underlying mechanisms of Sax in the treatment of DMED. METHODS: The model of DM was established by intraperitoneal injection of streptozotocin. All rats were divided into 3 groups (n = 8 per group): control group, DMED group and DMED+Sax group. In cellular experiments, the corpus cavernosum smooth muscle cells (CCSMCs) were exposed to high glucose (HG), and treated with Sax and AMD3100 (SDF-1 receptor inhibitor). The penile tissue and CCSMCs were harvested for detection. RESULTS: We found erectile function was impaired in DMED rats compared with the control group, which was partially relieved by Sax. Decreased expression of DPP-4 and increased level of SDF-1 were also observed in DMED+Sax group, together with elevation of PI3K/AKT pathway and inhibition of endothelial dysfunction, oxidative stress and apoptosis in corpus cavernosum. Moreover, Sax could also regulate oxidative stress and apoptosis in CCSMCs under HG condition, which was blocked in part by AMD3100. CONCLUSION: Sax could alleviate DMED through increasing SDF-1 and PI3K/AKT pathway, in company with moderation of endothelial dysfunction, oxidative stress and apoptosis. Our findings indicated that DPP-4is may be beneficial to the management of DMED. This article is protected by copyright. All rights reserved. Title: Synthesis and biological evaluation of new series of benzamide derivatives containing urea moiety as sEH inhibitors Tian Y, Li S, Yang P, Su X, Liu J, Lv X, Dong K, Yang T, Duan M and Zhao Y <9 more author(s)> Tian Y, Li S, Yang P, Su X, Liu J, Lv X, Dong K, Yang T, Duan M, Hu G, Yue H, Sun Y, Zhang H, Du Z, Miao Z, Tong M, Hou Y, Gao Z, Zhao Y (- 9) Ref: Bioorganic & Medicinal Chemistry Lett, 70:128805, 2022 : PubMed ESTHER: Tian_2022_Bioorg.Med.Chem.Lett_70_128805 PubMedSearch: Tian 2022 Bioorg.Med.Chem.Lett 70 128805 PubMedID: 35598794 Abstract The pharmacological inhibition of soluble epoxide hydrolase (sEH) was shown to reduce inflammation and pain. Herein, we described a series of newly synthesized sEH inhibitors with the trident-shaped skeleton. Intensive structural modifications led to the identification of compound B15 as a potent sEH inhibitor with an IC(50) value of 0.03 +/- 0.01 nM. Furthermore, compound B15 showed satisfactory metabolic stability in human liver microsomes with a half-time of 197 min. In carrageenan-induced inflammatory pain rat model, compound B15 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib, which demonstrated the proof of potential as anti-inflammatory agents for pain relief. Title: Discovery of benzamide derivatives containing urea moiety as soluble epoxide hydrolase inhibitors Tian Y, Li S, Dong K, Su X, Fu S, Lv X, Duan M, Yang T, Han Y and Zhao Y <13 more author(s)> Tian Y, Li S, Dong K, Su X, Fu S, Lv X, Duan M, Yang T, Han Y, Hu G, Liu J, Sun Y, Yue H, Zhang H, Du Z, Miao Z, Tong M, Liu Y, Qin M, Gong P, Hou Y, Gao Z, Zhao Y (- 13) Ref: Bioorg Chem, 127:105898, 2022 : PubMed ESTHER: Tian_2022_Bioorg.Chem_127_105898 PubMedSearch: Tian 2022 Bioorg.Chem 127 105898 PubMedID: 35792317 Abstract The elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Herein, we reported the discovery of a series of benzamide derivatives containing urea moiety as sEH inhibitors. Intensive structural modifications led to the identification of compound A34 as a potent sEH inhibitor with good physicochemical properties. Molecular docking revealed an additional hydrogen-bonding interaction between the unique amide scaffold and Phe497, contributing to sEH inhibition potency enhancement. Compound A34 exhibited outstanding inhibitory activity against human sEH, with an IC(50) value of 0.04 +/- 0.01 nM and a K(i) value of 0.2 +/- 0.1 nM. It also showed moderate systemic drug exposure and oral bioavailability in vivo metabolism studies. In carrageenan-induced inflammatory pain rat model, compound A34 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib. Metabolism studies in vivo together with an inflammatory pain evaluation suggest that A34 may be a viable lead compound for the development of highly potent sEH inhibitors. Title: Characterization of the synergistic inhibitory effect of cyanidin-3-O-glucoside and catechin on pancreatic lipase Wang Y, Chen L, Liu H, Xie J, Yin W, Xu Z, Ma H, Wu W, Zheng M and Liu J <1 more author(s)> Wang Y, Chen L, Liu H, Xie J, Yin W, Xu Z, Ma H, Wu W, Zheng M, Liu M, Liu J (- 1) Ref: Food Chem, 404:134672, 2022 : PubMed ESTHER: Wang_2022_Food.Chem_404_134672 PubMedSearch: Wang 2022 Food.Chem 404 134672 PubMedID: 36323025 Abstract This study aimed to identify novel pancreatic lipase (PL) inhibitors using affinity ultrafiltration combined with spectroscopy and molecular docking. Cyanidin-3-O-glucoside (C3G; IC(50): 0.268 mg/mL) and catechin (IC(50): 0.280 mg/mL) were shown to be potent PL inhibitors extracted from black rice and adzuki bean coat extracts. Isobologram analysis revealed that the combined use of C3G and catechin at a ratio of 2:3 had a remarkable synergistic effect (IC(50) of the mixture: 0.201 mg/mL). The inhibitory mechanism of C3G-catechin mixture was of mixed type. The C3G-catechin mixture had a great impact on PL secondary structures. Molecular docking analysis further demonstrated that these polyphenols formed hydrophobic interactions and hydrogen bonds with amino acid residues in the binding pocket of PL. Collectively, C3G and catechin were shown to inhibit PL in a synergistic manner and can be potentially used for the development of food supplements for obesity prevention. Title: Polyketide Derivatives from the Endophytic Fungus Phaeosphaeria sp. LF5 Isolated from Huperzia serrata and Their Acetylcholinesterase Inhibitory Activities Xiao Y, Liang W, Zhang Z, Wang Y, Zhang S, Liu J, Chang J, Ji C, Zhu D Ref: J Fungi (Basel), 8:, 2022 : PubMed ESTHER: Xiao_2022_J.Fungi.(Basel)_8_ PubMedSearch: Xiao 2022 J.Fungi.(Basel) 8 PubMedID: 35330234 Abstract The secondary metabolites of Phaeosphaeria sp. LF5, an endophytic fungus with acetylcholinesterase (AChE) inhibitory activity isolated from Huperzia serrata, were investigated. Their structures and absolute configurations were elucidated by means of extensive spectroscopic data, including one- and two-dimensional nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) analyses, and calculations of electronic circular dichroism (ECD). A chemical study on the solid-cultured fungus LF5 resulted in 11 polyketide derivatives, which included three previously undescribed derivatives: aspilactonol I (4), 2-(1-hydroxyethyl)-6-methylisonicotinic acid (7), and 6,8-dihydroxy-3-(1'R, 2'R-dihydroxypropyl)-isocoumarin (9), and two new natural-source-derived aspilactonols (G, H) (2, 3). Moreover, the absolute configuration of de-O-methyldiaporthin (11) was identified for the first time. Compounds 4 and 11 exhibited inhibitory activity against AChE with half maximal inhibitory concentration (IC(50)) values of 6.26 and 21.18 microM, respectively. Aspilactonol I (4) is the first reported furanone AChE inhibitor (AChEI). The results indicated that Phaeosphaeria is a good source of polyketide derivatives. This study identified intriguing lead compounds for further research and development of new AChEIs. Title: Zeaxanthin remodels cytoplasmic lipid droplets via beta3-adrenergic receptor signaling and enhances perilipin 5-mediated lipid droplet-mitochondrion interactions in adipocytes Xie J, Liu H, Yin W, Ge S, Jin Z, Zheng M, Cai D, Liu M, Liu J Ref: Food Funct, :, 2022 : PubMed ESTHER: Xie_2022_Food.Funct__ PubMedSearch: Xie 2022 Food.Funct PubMedID: 35924967 Abstract Cytoplasmic lipid droplets (LDs), which are remarkably dynamic, neutral lipid storage organelles, play fundamental roles in lipid metabolism and energy homeostasis. Both the dynamic remodeling of LDs and LD-mitochondrion interactions in adipocytes are effective mechanisms to ameliorate obesity and related comorbidities. Zeaxanthin (ZEA) is a natural carotenoid and has beneficial effects on anti-obesity. However, the underlying mechanisms of ZEA on LD modulation are still unclear. In the present study, ZEA efficiently inhibited LD accumulation and attenuated adipocyte proliferation by arresting the cell cycle. ZEA drove transcriptional alterations to reprogram a lipid oxidative metabolism phenotype in mature 3T3-L1 adipocytes. ZEA significantly decreased the TAG and FA content and modulated the dynamic alterations of LDs by upregulating the expression of lipases and the LD-mitochondrion contact site protein, perilipin 5 (PLIN5), and downregulating the LD fusion protein, fat-specific protein 27 (FSP27). Mechanistically, ZEA stimulated LD remodeling and ameliorated mitochondrial defects caused by large and unilocular LD accumulation by activating beta3-adrenergic receptor (beta3-AR) signaling. Furthermore, the knockdown of PLIN5 impaired the LD-mitochondrion interactions, thereby disrupting the role of ZEA in promoting mitochondrial fatty acid oxidation and respiratory chain operation. Collectively, the present study demonstrates that ZEA induces LD structural and metabolic remodeling by activating beta3-AR signaling and enhances PLIN5-mediated LD-mitochondrion interactions in hypertrophic white adipocytes, thereby enhancing oxidative capacity, and has the potential as a nutritional intervention for the prevention and treatment of obesity and associated metabolic syndrome. Title: Microplastics induce neurotoxicity in aquatic animals at environmentally realistic concentrations: A meta-analysis Xiong F, Liu J, Xu K, Huang J, Wang D, Li F, Wang S, Zhang J, Pu Y, Sun R Ref: Environ Pollut, 318:120939, 2022 : PubMed ESTHER: Xiong_2022_Environ.Pollut_318_120939 PubMedSearch: Xiong 2022 Environ.Pollut 318 120939 PubMedID: 36581239 Abstract Microplastics (MPs) draw international attention owing to their widespread distribution in water ecosystems, but whether MPs cause neurotoxic effects in aquatic animals at environmentally realistic concentrations is still controversial. This meta-analysis recompiled 35 studies to determine whether MPs could change the levels of brain (in vivo) neurotransmitters in aquatic animals at environmentally realistic concentrations (>=1smg/L, median = 0.100 mg/L). Then, a group comparison was conducted to compare the effects of different factors on the effect size and to explore the significant factors affecting the neurotoxicity of MPs. The results demonstrated that MP exposure could considerably decrease the levels of acetylcholinesterase (AchE) in the brain of aquatic animals by 16.2%. However, the effects of MPs on cholinesterase (CHE), acetylcholine (ACh), dopamine (DA) and gamma-aminobutyric acid (GABA) were not statistically significant due to the small number of studies and samples. The neurotoxicity of MPs was closely linked with particle size and exposure time but independent of animal species, MP compositions, MP morphology and MP concentrations. Further literatures review indicated that MP-induced neurotoxicity and behavioral changes are related with multiple biological processes, including nerve damage, oxidative stress, intestinal flora disturbance and metabolic disorder. Furthermore, some factors influencing MP neurotoxicity in the real environment (e.g. the aging of MPs, the release of MP additives, and the co-exposure of MPs and pollutants) were discussed. Overall, this study preliminarily explored whether MPs induced changes in neurotoxicity-related indicators in aquatic animals through meta-analysis and provided scientific evidence for evaluating the health risks and neurotoxicity of MPs at the environmental level. Title: Application of a novel fluorogenic polyurethane analogue probe in polyester-degrading microorganisms screening by microfluidic droplet Xu A, Liu J, Cao S, Xu B, Guo C, Yu Z, Chen X, Zhou J, Dong W, Jiang M Ref: Microb Biotechnol, :, 2022 : PubMed ESTHER: Xu_2022_Microb.Biotechnol__ PubMedSearch: Xu 2022 Microb.Biotechnol PubMedID: 35881631 Abstract Application of polyester-degrading microorganisms or enzymes should be considered as an eco-friendly alternative to chemical recycling due to the huge plastic waste disposal nowadays. However, current impranil DLN-based screening of polyester-degrading microorganisms is time-consuming, labour-intensive and unable to distinguish polyesterases from other protease- or amidase-like enzymes. Herein, we present an approach that combined a novel synthetic fluorescent polyurethane analogue probe (FPAP), along with the droplet-based microfluidics to screen polyurethane-degrading microorganisms through fluorescence-activated droplet sorting (FADS) pipeline. The fluorescent probe FPAP exhibited a fluorescence enhancement effect once hydrolysed by polyesterases, along with a strong specificity in discriminating polyesterases from other non-active enzymes. Application of FPAP in a microfluidic droplet system demonstrated that this probe exhibited high sensitivity and efficiency in selecting positive droplets containing leaf-branch compost cutinase (LCC) enzymes. This novel fluorogenic probe, FPAP, combined with the droplet microfluidic system has the potential to be used in the exploitation of novel PUR-biocatalysts for biotechnological and environmental applications. Title: Cation-Exchangeable Pralidoxime Chloride@bio-MOF-1 as a Treatment for Nerve Agent Poisoning and Sulfur Mustard Skin Poisoning in Animals Yang Y, Liu J, Liu L, Zhou Y, Zhang L, Zhong Y, Zhao D, Wang Y Ref: ACS Omega, 7:30720, 2022 : PubMed ESTHER: Yang_2022_ACS.Omega_7_30720 PubMedSearch: Yang 2022 ACS.Omega 7 30720 PubMedID: 36092617 Abstract A 2-PAM@bio-MOF-1 composite was prepared by cationic exchange of counter N,N-dimethylammonium cations in the pores of the anionic, biocompatible metal-organic framework (bio-MOF-1) with pralidoxime chloride (2-PAM-Cl) by impregnation. In vitro drug release measurements revealed that the release rate of 2-PAM from 2-PAM@bio-MOF-1 in simulated body fluid (SBF) was more than four-fold higher than that in deionized water, indicating that the presence of endogenous cations in SBF triggered the release of 2-PAM through cation exchange. The release of 2-PAM was rapid within the first 10 h but was much slower over the period of 10-50 h. At room temperature, the maximum release rate of 2-PAM was 88.5% (15 mg of 2-PAM@bio-MOF-1 in 1 mL of SBF), indicating that the drug was efficiently released from the composite MOF in SBF. In simulated gastric fluid, 64.3% of 2-PAM was released from bio-MOF-1 into the simulated gastric fluid after 50h. This suggested that 2-PAM@bio-MOF-1 might be effective for enabling the slow release of 2-PAM in the human body. Indeed, the maximum reactivation rate of acetylcholinesterase in sarin-poisoned mice reached 82.5%. In addition, 2-PAM@bio-MOF-1 demonstrated the ability to adsorb and remove sulfur mustard (HD) in solution and from the skin of guinea pigs. Title: Phenolic and bisamide derivatives from Aglaia odorata and their biological activities Yang X, Yu Y, Wu P, Liu J, Li Y, Tao L, Tan R, Hao X, Yuan C, Yi P Ref: Nat Prod Res, :1, 2022 : PubMed ESTHER: Yang_2022_Nat.Prod.Res__1 PubMedSearch: Yang 2022 Nat.Prod.Res 1 PubMedID: 36580570 Abstract Three new compounds (1-3), including two bisamide derivatives (1 and 2) and a lignin (3), along with 15 known compounds were isolated from Aglaia odorata. Compound 2 was a pair of enantiomers and successfully resolved into the anticipated enantiomers. Their structures were elucidated by extensive spectroscopic analysis, electronic circular dichroism (ECD) calculations, and X-ray crystallography. Three compounds showed excellent inhibitory activities on alpha-glucosidase with IC(50) values ranging from 54.48 to 240.88 microM, better than that of the positive control (acarbose, IC(50) = 590.94 microM). Moreover, compounds 3, 13, and 15 presented moderate inhibitory activities against butyrylcholinesterase. Compound 17 exhibited potent PTP1B inhibitory activity with an IC(50) value of 179.45 microM. Representative active compounds were performed for the molecular docking study. Herein, we described the isolation, structure elucidation, the inhibitory effects on three enzymes, and molecular docking of the isolates from the title plant. Title: Development and validation of a LC-MS/MS method for simultaneous determination of remdesivir and its hydrolyzed metabolite and nucleoside, and its application in a pharmacokinetic study of normal and diabetic nephropathy mice Yuan M, Hu W, Feng Y, Tong Y, Wang X, Tan B, Xu H, Liu J Ref: Biomedical Chromatography, :e5380, 2022 : PubMed ESTHER: Yuan_2022_Biomed.Chromatogr__e5380 PubMedSearch: Yuan 2022 Biomed.Chromatogr e5380 PubMedID: 35373846 Abstract Remdesivir (RDV), a phosphoramidate prodrug, has broad-spectrum antiviral activity. It is the first antiviral drug approved by the US Food and Drug Administration (FDA) for the treatment of COVID-19. RDV is rapidly metabolized in the body to produce derivatives: alanine metabolite (RM-442) and RDV C-nucleoside (RN). Here, phosphatase inhibitor PhosSTOP and carboxylesterase inhibitor 5,5'-dithiobis-2-nitrobenzoic acid were used to improve stability of RDV in mouse blood. We developed a rapid and sensitive LC-MS/MS method to simultaneously quantify RDV, RM-442 and RN in mouse blood. Chromatographic separation was achieved by gradient elution on an ACQUITY HSS T(3) column. The run time was 3.2 min. The linearity ranges of the analytes were 0.5-1000 ng/mL for RDV, 5-10000 ng/mL for both RM-442 and RN, respectively. The method had an acceptable precision (RSD < 8.4% for RDV, RSD < 10.7% for RM-442, and RSD < 7.2% for RN) and accuracy (91.0%-106.3% for RDV, 92.5%-98.6% for RM-442, and 87.5%-98.4% for RN). This method was successfully applied to analyze RDV, RM-442 and RN in blood of normal and diabetic nephropathy DBA/2J mice after intravenous injection of RDV 20 mg/kg. The AUC(0-t) of RN between the normal and diabetic nephropathy mice had significant difference (P < 0.01). Title: Populus euphratica Phospholipase Ddelta Increases Salt Tolerance by Regulating K(+)/Na(+) and ROS Homeostasis in Arabidopsis Zhang Y, Yao J, Yin K, Liu Z, Deng C, Liu J, Hou S, Zhang H, Yu D and Chen S <2 more author(s)> Zhang Y, Yao J, Yin K, Liu Z, Deng C, Liu J, Hou S, Zhang H, Yu D, Zhao N, Zhao R, Chen S (- 2) Ref: Int J Mol Sci, 23:4911, 2022 : PubMed ESTHER: Zhang_2022_Int.J.Mol.Sci_23_4911 PubMedSearch: Zhang 2022 Int.J.Mol.Sci 23 4911 PubMedID: 35563299 Abstract Phospholipase Dalpha (PLDalpha), which produces signaling molecules phosphatidic acid (PA), has been shown to play a critical role in plants adapting to salt environments. However, it is unclear whether phospholipase Ddelta (PLDdelta) can mediate the salt response in higher plants. PePLDdelta was isolated from salt-resistant Populus euphratica and transferred to Arabidopsis thaliana to testify the salt tolerance of transgenic plants. The NaCl treatment (130 mM) reduced the root growth and whole-plant fresh weight of wild-type (WT) A. thaliana, vector controls (VC) and PePLDdelta-overexpressed lines, although a less pronounced effect was observed in transgenic plants. Under salt treatment, PePLDdelta-transgenic Arabidopsis exhibited lower electrolyte leakage, malondialdehyde content and H(2)O(2) levels than WT and VC, resulting from the activated antioxidant enzymes and upregulated transcripts of genes encoding superoxide dismutase, ascorbic acid peroxidase and peroxidase. In addition, PePLDdelta-overexpressed plants increased the transcription of genes encoding the plasma membrane Na(+)/H(+) antiporter (AtSOS1) and H(+)-ATPase (AtAHA2), which enabled transgenic plants to proceed with Na(+) extrusion and reduce K(+) loss under salinity. The capacity to regulate reactive oxygen species (ROS) and K(+)/Na(+) homeostasis was associated with the abundance of specific PA species in plants overexpressing PePLDdelta. PePLDdelta-transgenic plants retained a typically higher abundance of PA species, 34:2 (16:0-18:2), 34:3 (16:0-18:3), 36:4 (18:2-18:2), 36:5 (18:2-18:3) and 36:6 (18:3-18:3), under control and saline conditions. It is noteworthy that PA species 34:2 (16:0-18:2), 34:3 (16:0-18:3), 36:4 (18:2-18:2) and 36:5 (18:2-18:3) markedly increased in response to NaCl in transgenic plants. In conclusion, we suppose that PePLDdelta-derived PA enhanced the salinity tolerance by regulating ROS and K(+)/Na(+) homeostasis in Arabidopsis. Title: Role of epoxyeicosatrienoic acids in cardiovascular diseases and cardiotoxicity of drugs Zhang Y, Gao L, Yao B, Huang S, Liu J, Liu Z, Wang X Ref: Life Sciences, 310:121122, 2022 : PubMed ESTHER: Zhang_2022_Life.Sci_310_121122 PubMedSearch: Zhang 2022 Life.Sci 310 121122 PubMedID: 36309225 Abstract Epoxyeicosatrienoic acids (EETs) are important endogenous substances that affect heart function in human body. Animal models of cytochrome P450 (CYP) and soluble epoxide hydrolase (sEH) related cardiovascular diseases (CVD) have revealed the physiological effects of EETs, mainly including vascular function regulation, angiogenesis, myocardial fibrosis, myocardial hypertrophy, and cardiovascular inflammation. At the same time, clinical studies have found that most of the substrates and inhibitors of CYP2J2 affect the content of EETs, resulting in cardiotoxicity of drugs. Therefore, the regulation of CYP and sEH enzymes on EETs points out the direction for exploring EET-mediated cardiac protection. The metabolic pathway of EETs is not only an important target for the development of new drugs for CVD but also an important factor in preventing drug cardiotoxicity. The development and clinical application of sEH inhibitors and EETs analogues provide broad prospects for the treatment of CVD. Title: Novel AP2238-clorgiline hybrids as multi-target agents for the treatment of Alzheimer's disease: Design, synthesis, and biological evaluation Zhong G, Guo J, Pang C, Su D, Tang C, Jing L, Zhang F, He P, Yan Y and Jiang N <2 more author(s)> Zhong G, Guo J, Pang C, Su D, Tang C, Jing L, Zhang F, He P, Yan Y, Chen Z, Liu J, Jiang N (- 2) Ref: Bioorg Chem, 130:106224, 2022 : PubMed ESTHER: Zhong_2022_Bioorg.Chem_130_106224 PubMedSearch: Zhong 2022 Bioorg.Chem 130 106224 PubMedID: 36332315 Abstract Cholinesterase and monoamine oxidase are potential targets for the therapy of Alzheimer's disease. A series of novel AP2238-clorgiline hybrids as multi-target agents were designed, synthesized and investigated in vitro for their inhibition of cholinesterases and monoamine oxidases. Many compounds displayed balanced and good inhibitory activity against AChE, BuChE and MAO-B with an obvious selective inhibitory effect on MAO-B. Among them, Compound 5l showed the most balanced potency to inhibit ChEs (eeAChE: IC(50) = 4.03 +/- 0.03 microM, eqBuChE: IC(50) = 5.64 +/- 0.53 microM; hAChE: IC(50) = 8.30 +/- 0.04 microM, hBuChE: IC(50) = 1.91 +/- 0.06 microM) and hMAO-B (IC(50) = 3.29 +/- 0.09 microM). Molecular modeling and kinetic studies showed that 5l was a mixed inhibitor for both AChE and BuChE, and a competitive MAO-B inhibitor. Compound 5l exhibited no toxicity to PC12 and BV-2 cells at 12.5 microM and no acute toxicity at a dosage of 2500 mg/kg. Moreover, 5l can improve the memory function of mice with scopolamine-induced memory impairment and have an excellent ability to cross the blood-brain barrier. Overall, these findings suggested that compound 5l could be deemed as a promising, balanced multi-target drug candidate against Alzheimer's disease. Title: Pancreatic Cancer Cell-Derived Exosomes Promote Lymphangiogenesis by Downregulating ABHD11-AS1 Expression Zhou X, Zhong F, Yan Y, Wu S, Wang H, Liu J, Li F, Cui D, Xu M Ref: Cancers (Basel), 14:, 2022 : PubMed ESTHER: Zhou_2022_Cancers.(Basel)_14_ PubMedSearch: Zhou 2022 Cancers.(Basel) 14 PubMedID: 36230535 Gene_locus related to this paper: human-ABHD11 Abstract Research on pancreatic cancer microbiomes has attracted attention in recent years. The current view is that enriched microbial communities in pancreatic cancer tissues may affect pancreatic cancer metastasis, including lymph node (LN) metastasis. Similar to carriers of genetic information between cells, such as DNA, mRNA, protein, and non-coding RNA, exosomes are of great importance in early LN metastasis in tumors, including pancreatic cancer. Our previous study showed that the long non-coding RNA ABHD11-AS1 was highly expressed in tissues of patients with pancreatic cancer, and was correlated with patient survival time. However, the role of ABHD11-AS1 in pancreatic cancer LN metastasis has rarely been studied. Hence, in this paper we confirmed that exosomes derived from pancreatic cancer cells could promote lymphangiogenesis in vitro and in vivo, and that the mechanism was related to the downregulation of ABHD11-AS1 expression in lymphatic endothelial cells, and to the enhancement of their ability to proliferate, migrate, and form tubes. These findings preliminarily show a new mechanism by which pancreatic cancer cells regulate peripheral lymphangiogenesis, providing a new therapeutic strategy for inhibiting LN metastasis in pancreatic cancer. Title: Endophytic Fungal Community of Huperzia serrata: Diversity and Relevance to the Production of Huperzine A by the Plant Host Cui L, Noushahi HA, Zhang Y, Liu J, Cosoveanu A, Liu Y, Yan L, Zhang J, Shu S Ref: Molecules, 26:, 2021 : PubMed ESTHER: Cui_2021_Molecules_26_ PubMedSearch: Cui 2021 Molecules 26 PubMedID: 33567664 Abstract As the population ages globally, there seem to be more people with Alzheimer's disease. Unfortunately, there is currently no specific treatment for the disease. At present, Huperzine A (HupA) is one of the best drugs used for the treatment of Alzheimer's disease and has been used in clinical trials for several years in China. HupA was first separated from Huperzia serrata, a traditional medicinal herb that is used to cure fever, contusions, strains, hematuria, schizophrenia, and snakebite for several hundreds of years in China, and has been confirmed to have acetylcholinesterase inhibitory activity. With the very slow growth of H. serrata, resources are becoming too scarce to meet the need for clinical treatment. Some endophytic fungal strains that produce HupA were isolated from H. serrate in previous studies. In this article, the diversity of the endophytic fungal community within H. serrata was observed and the relevance to the production of HupA by the host plant was further analyzed. A total of 1167 strains were obtained from the leaves of H. serrata followed by the stems (1045) and roots (824). The richness as well as diversity of endophytic fungi within the leaf and stem were higher than in the root. The endophytic fungal community was similar within stems as well as in leaves at all taxonomic levels. The 11 genera (Derxomyces, Lophiostoma, Cyphellophora, Devriesia, Serendipita, Kurtzmanomyces, Mycosphaerella, Conoideocrella, Brevicellicium, Piskurozyma, and Trichomerium) were positively correlated with HupA content. The correlation index of Derxomyces with HupA contents displayed the highest value (CI = 0.92), whereas Trichomerium showed the lowest value (CI = 0.02). Through electrospray ionization mass spectrometry (ESI-MS), it was confirmed that the HS7-1 strain could produce HupA and the total alkaloid concentration was 3.7 ug/g. This study will enable us to screen and isolate the strain that can produce HupA and to figure out the correlation between endophytic fungal diversity with HupA content in different plant organs. This can provide new insights into the screening of strains that can produce HupA more effectively. Title: A Roadmap to the Structure-Related Metabolism Pathways of Per- and Polyfluoroalkyl Substances in the Early Life Stages of Zebrafish (Danio rerio) Han J, Gu W, Barrett H, Yang D, Tang S, Sun J, Liu J, Krause HM, Houck KA, Peng H Ref: Environmental Health Perspectives, 129:77004, 2021 : PubMed ESTHER: Han_2021_Environ.Health.Perspect_129_77004 PubMedSearch: Han 2021 Environ.Health.Perspect 129 77004 PubMedID: 34288731 Abstract BACKGROUND: Thousands of per- and polyfluoroalkyl substances (PFAS) with diverse structures have been detected in the ambient environment. Apart from a few well-studied PFAS, the structure-related toxicokinetics of a broader set of PFAS remain unclear. OBJECTIVES: To understand the toxicokinetics of PFAS, we attempted to characterize the metabolism pathways of 74 structurally diverse PFAS samples from the U.S. Environmental Protection Agency's PFAS screening library. METHODS: Using the early life stages of zebrafish (Danio rerio) as a model, we determined the bioconcentration factors and phenotypic toxicities of 74 PFAS. Then, we applied high-resolution mass spectrometry-based nontargeted analysis to identify metabolites of PFAS in zebrafish larvae after 5 d of exposure by incorporating retention time and mass spectra. In vitro enzymatic activity experiments with human recombinant liver carboxylesterase (hCES1) were employed to validate the structure-related hydrolysis of 11 selected PFAS. RESULTS: Our findings identified five structural categories of PFAS prone to metabolism. The metabolism pathways of PFAS were highly related to their structures as exemplified by fluorotelomer alcohols that the predominance of beta-oxidation or taurine conjugation pathways were primarily determined by the number of hydrocarbons. Hydrolysis was identified as a major metabolism pathway for diverse PFAS, and perfluoroalkyl carboxamides showed the highest in vivo hydrolysis rates, followed by carboxyesters and sulfonamides. The hydrolysis of PFAS was verified with recombinant hCES1, with strong substrate preferences toward perfluoroalkyl carboxamides. CONCLUSIONS: We suggest that the roadmap of the structure-related metabolism pathways of PFAS established in this study would provide a starting point to inform the potential health risks of other PFAS. https://doi.org/10.1289/EHP7169. Title: Mitochondrial homeostasis and redox status in cardiovascular diseases: Protective role of the vagal system He X, Liu J, Zang WJ Ref: Free Radic Biol Med, 178:369, 2021 : PubMed ESTHER: He_2021_Free.Radic.Biol.Med_178_369 PubMedSearch: He 2021 Free.Radic.Biol.Med 178 369 PubMedID: 34906725 Abstract Mitochondria participate in essential cellular functions, including energy production, metabolism, redox homeostasis regulation, intracellular Ca(2+) handling, apoptosis, and cell fate determination. Disruption of mitochondrial homeostasis under pathological conditions results in mitochondrial reactive oxygen species (ROS) generation and energy insufficiency, which further disturb mitochondrial and cellular homeostasis in a deleterious loop. Mitochondrial redox status has therefore become a potential target for therapy against cardiovascular diseases. In this review, we highlight recent progress in determining the roles of mitochondrial processes in regulating mitochondrial redox status, including mitochondrial dynamics (fusion-fission pathways), mitochondrial cristae remodeling, mitophagy, biogenesis, and mitochondrion-organelle interactions (endoplasmic reticulum-mitochondrion interactions, nucleus-mitochondrion communication, and lipid droplet-mitochondrion interactions). The strategies that activate vagal system include direct vagal activation (electrical vagal stimulation and administration of vagal neurotransmitter acetylcholine) and pharmacological modulation (choline and cholinesterase inhibitors). The vagal system plays an important role in maintaining mitochondrial homeostasis and suppressing mitochondrial oxidative stress by promoting mitochondrial biogenesis and mitophagy, moderating mitochondrial fusion and fission, strengthening mitochondrial cristae stabilization, regulating mitochondrion-organelle interactions, and inhibiting mitochondrial Ca(2+) overload. Therefore, enhancement of vagal activity can maintain mitochondrial homeostasis and represents a promising therapeutic strategy for cardiovascular diseases. Title: Association of EPHX1 polymorphisms with plasma concentration of carbamazepine in epileptic patients: Systematic review and meta-analysis Hu T, Zeng X, Tian T, Liu J Ref: J Clin Neurosci, 91:159, 2021 : PubMed ESTHER: Hu_2021_J.Clin.Neurosci_91_159 PubMedSearch: Hu 2021 J.Clin.Neurosci 91 159 PubMedID: 34373022 Abstract BACKGROUND: Carbamazepine (CBZ) is a wildly used anti-epileptic drug (AED). Increasing evidence suggested that polymorphisms in Epoxide Hydrolase1 (EPHX1) gene are associated with the pharmacokinetics (PK) and pharmacodynamics (PD) of CBZ, albeit the results were inconsistent. METHODS: A literature search on PubMed, Embase, and Cochrane Library was conducted to identify eligible studies published between 1974 and 2020. A meta-analysis was performed and the standardized mean difference (SMD) and 95% confidence interval (95% CI) were estimated using a random-effects model. The heterogeneity and leave-one-study-out sensitivity analyses of each article and the publication bias were also performed. All the statistical analyses were performed using STATA 14.0. RESULTS: A total of 6 articles with 1746 subjects were included in this meta-analysis. A significant correlation was detected between EPHX1 rs1051740 T > C polymorphisms and decreased plasma concentration of CBZ (TT vs CC: SMD = 0.34, P < 0.001; TC vs CC: SMD = 0.35, P = 0.009). However, similar results were not detected in the comparison of TT vs. TC in the EPHX1 rs1051740 T > C variation (P = 0.637), while subgroup analyses showed an association with plasma CBZ concentration in the non-Asian group (P < 0.001, I(2) = 0.0%, Ph = 0.400). Although the association of EPHX1 rs2234922 A > G polymorphisms with plasma CBZ concentration was not detected (AA vs GG:SMD = 0.54, P = 0.102; AA vs AG:SMD = -0.05, P = 0.670; AG vs GG: SMD = 0.86, P = 0.107), subgroup analyses showed that the GG genotype EPHX1 rs2234922 was associated with increased plasma CBZ concentration in the Asian group (P = 0.005, I(2) = 48.6%, Ph = 0.143). CONCLUSION: EPHX1 rs1051740 T > C and rs2234922 A > G are important genetic variants associated with plasma CBZ concentration. The role of EPHX1 polymorphisms in the interindividual variability of plasma CBZ concentration varied significantly among different ethnic groups, which should be considered during clinical validation and in future studies. Title: Explainable machine learning model for predicting spontaneous bacterial peritonitis in cirrhotic patients with ascites Hu Y, Chen R, Gao H, Lin H, Wang J, Wang X, Liu J, Zeng Y Ref: Sci Rep, 11:21639, 2021 : PubMed ESTHER: Hu_2021_Sci.Rep_11_21639 PubMedSearch: Hu 2021 Sci.Rep 11 21639 PubMedID: 34737270 Abstract Spontaneous bacterial peritonitis (SBP) is a life-threatening complication in patients with cirrhosis. We aimed to develop an explainable machine learning model to achieve the early prediction and outcome interpretation of SBP. We used CatBoost algorithm to construct MODEL-1 with 46 variables. After dimensionality reduction, we constructed MODEL-2. We calculated and compared the sensitivity and negative predictive value (NPV) of MODEL-1 and MODEL-2. Finally, we used the SHAP (SHapley Additive exPlanations) method to provide insights into the model's outcome or prediction. MODEL-2 (AUROC: 0.822; 95% confidence interval [CI] 0.783-0.856), liked MODEL-1 (AUROC: 0.822; 95% CI 0.784-0.856), could well predict the risk of SBP in cirrhotic ascites patients. The 6 most influential predictive variables were total protein, C-reactive protein, prothrombin activity, cholinesterase, lymphocyte ratio and apolipoprotein A1. For binary classifier, the sensitivity and NPV of MODEL-1 were 0.894 and 0.885, respectively, while for MODEL-2 they were 0.927 and 0.904, respectively. We applied CatBoost algorithm to establish a practical and explainable prediction model for risk of SBP in cirrhotic patients with ascites. We also identified 6 important variables closely related to the occurrence of SBP. Title: Pyridostigmine ameliorates preeclamptic features in pregnant rats by inhibiting tumour necrosis factor-alpha synthetsis and antagonizing tumour necrosis factor-alpha-related effects Issotina Zibrila A, Wang Z, Ali MA, Osei JA, Sun Y, Zafar S, Liu K, Li C, Kang Y, Liu J Ref: J Hypertens, :, 2021 : PubMed ESTHER: Issotina_2021_J.Hypertens__ PubMedSearch: Issotina 2021 J.Hypertens PubMedID: 34232157 Abstract OBJECTIVE: Preeclampsia is a hypertensive disorder of pregnancy marked by an excessive inflammatory response. The anti-inflammatory effect of pyridostigmine (PYR) was previously reported; however, its role in hypertensive pregnancies remains unclear. We hypothesized that PYR could attenuate increased blood pressure and other pathological features in preeclampsia models. METHODS: The expression of tumour necrosis factor (TNF)-alpha was evaluated in normal and preeclampsia pregnant women. PYR (20mg/kg) was administered daily to reduced uterine perfusion pressure (RUPP) and TNF-alpha (150ng/day) infused rats from gestation day 14 to GD19. In a cell culture experiment, the effect of acetylcholine (ACh) on TNF-alpha-stimulated primary human umbilical endothelial cells (HUVEC) was assessed. RESULTS: Preeclampsia women had higher placental TNF-alpha expression than normal pregnant women. Mean arterial pressure (MAP) in the RUPP group was higher than in the Sham group. PYR inhibited serum and placental acetylcholinesterase activity in rats, and reduced MAP, placental oxidative stress, apoptosis and inflammation in the RUPP group but not in the Sham group. In addition, PYR significantly attenuated the TNF-alpha-induced increase in MAP, placental oxidative stress and apoptosis. Moreover, TNF-alpha decreased cell viability and increased the number of TUNEL-positive nuclei of HUVEC, which could largely be abolished by ACh treatment. CONCLUSION: Collectively, PYR ameliorated hypertension and other preeclampsia-like symptoms in rat models of preeclampsia not only by inhibiting the synthesis of TNF-alpha but also by acting against TNF-alpha-induced detrimental effects directly, which is worthy of further investigation and may be used as a potential agent for preeclampsia management. Title: Acetylcholinesterase inhibition with Pyridostigmine attenuates hypertension and neuroinflammation in the paraventricular nucleus in rat model for Preeclampsia Issotina Zibrila A, Li Y, Wang Z, Zhao G, Liu H, Leng J, Ahasan Ali M, Ampofo Osei J, Kang YM, Liu J Ref: Int Immunopharmacol, :108365, 2021 : PubMed ESTHER: Issotina_2021_Int.Immunopharmacol__108365 PubMedSearch: Issotina 2021 Int.Immunopharmacol 108365 PubMedID: 34815190 Abstract Preeclampsia (PE) is characterized by hypertension, autonomic imbalance and inflammation. The subfornical organ (SFO) reportedly relays peripheral inflammatory mediator's signals to the paraventricular nucleus (PVN), a brain autonomic center shown to mediate hypertension in hypertensive rat but not yet in PE rat models. Additionally, we previously showed that Pyridostigmine (PYR), an acetylcholinesterase inhibitor, attenuated placental inflammation and hypertension in PE models. In this study, we investigated the effect of PYR on the activities of these brain regions in PE model. PYR (20 mg/kg/day) was administered to reduced uterine perfusion pressure (RUPP) Sprague-Dawley rat from gestational day (GD) 14 to GD19. On GD19, the mean arterial pressure (MAP) was recorded and samples were collected for analysis. RUPP rats exhibited increased MAP (P = 0.0025), elevated circulating tumor necrosis factor-alpha (TNF-alpha, P = 0.0075), reduced baroreflex sensitivity (BRS), increased neuroinflammatory markers including TNF-alpha, interleukin-1beta (IL-1beta), microglial activation (P = 0.0039), oxidative stress and neuronal excitation within the PVN and the SFO. Changes in MAP, in molecular and cellular expression induced by RUPP intervention were improved by PYR. The ability of PYR to attenuate TNF-alpha mediated central effect was evaluated in TNF-alpha-infused pregnant rats. TNF-alpha infusion-promoted neuroinflammation in the PVN and SFO in dams was abolished by PYR. Collectively, our data suggest that PYR improves PE-like symptoms in rat by dampening placental ischemia and TNF-alpha-promoted inflammation and pro-hypertensive activity in the PVN. This broadens the therapeutical potential of PYR in PE. Title: Biogenetic cantharidin is a promising leading compound to manage insecticide resistance of Mythimna separata (Lepidoptera: Noctuidae) Li Y, Sun H, Yasoob H, Tian Z, Li R, Zheng S, Liu J, Zhang Y Ref: Pestic Biochem Physiol, 172:104769, 2021 : PubMed ESTHER: Li_2021_Pestic.Biochem.Physiol_172_104769 PubMedSearch: Li 2021 Pestic.Biochem.Physiol 172 104769 PubMedID: 33518040 Abstract Cantharidin (CTD) is a natural toxin with effective toxicity to lepidopteran pests. Nevertheless, little information is available on whether pests develop resistance to CTD. After being exposed to CTD (50 mg/L to 90 mg/L) or 10 generations, the resistance ratio of laboratory selected cantharidin-resistant Mythimna separata (Cantharidin-SEL) strain was only elevated 1.95-fold. Meanwhile, the developmental time for M. separata was prolonged (delayed1.65 in males and 1.84 days in females). The reported CTD target, the serine/threonine phosphatases (PSPs), have not been shown significant activity variation during the whole process of CTD-treatment. The activity of detoxification enzymes (cytochrome monooxygenase P450, glutathione-S-transferase (GST) and carboxylesterase) were affected by CTD selection, but this change was not mathematically significant. More importantly, no obvious cross-resistance with other commonly used insecticides was observed in the M. separata population treated with CTD for 10 generations (resistance ratios were all lower 2.5). Overall, M. separata is unlikely to produce target-site insensitivity resistance, metabolic resistance to CTD. Meanwhile, cantharidin-SEL is not prone to develop cross-resistance with other insecticides. These results indicate that CTD is a promising biogenetic lead compound which can be applied in the resistance management on M. separata. Title: Effects of perioperative interventions for preventing postoperative delirium: A protocol for systematic review and meta-analysis of randomized controlled trials Li X, Wang Y, Liu J, Xiong Y, Chen S, Han J, Xie W, Wu Q Ref: Medicine (Baltimore), 100:e26662, 2021 : PubMed ESTHER: Li_2021_Medicine.(Baltimore)_100_e26662 PubMedSearch: Li 2021 Medicine.(Baltimore) 100 e26662 PubMedID: 34398027 Abstract BACKGROUND: Postoperative delirium (POD) not only increases the medical burden but also adversely affects patient prognosis. Although some cases of delirium can be avoided by early intervention, there is no clear evidence indicating whether any of these measures can effectively prevent POD in specific patient groups. OBJECTIVE: The aim of this meta-analysis was to compare the efficacy and safety of the existing preventive measures for managing POD. METHODS: The PubMed, OVID (Embase and MEDLINE), Web of Science, and the Cochrane Library databases were searched for articles published before January 2020. The relevant randomized controlled trials (RCTs) were selected based on the inclusion and exclusion criteria. Data extraction and methodological quality assessment were performed according to a predesigned data extraction form and scoring system, respectively. The interventions were compared on the basis of the primary outcome like incidence of POD, and secondary outcomes like duration of delirium and the length of intensive care unit and hospital stay. RESULTS: Sixty-three RCTs were included in the study, covering interventions like surgery, anesthesia, analgesics, intraoperative blood glucose control, cholinesterase inhibitors, anticonvulsant drugs, antipsychotic drugs, sleep rhythmic regulation, and multi-modal nursing. The occurrence of POD was low in 4 trials that monitored the depth of anesthesia with bispectral index during the operation (P<.0001). Two studies showed that supplementary analgesia was useful for delirium prevention (P=.002). Seventeen studies showed that perioperative sedation with alpha2-adrenergic receptor agonists prevented POD (P=.0006). Six studies showed that both typical and atypical antipsychotic drugs can reduce the incidence of POD (P=.002). Multimodal nursing during the perioperative period effectively reduced POD in 6 studies (P<.00001). Furthermore, these preventive measures can reduce the duration of delirium, as well as the total and postoperative length of hospitalized stay for non-cardiac surgery patients. For patients undergoing cardiac surgery, effective prevention can only reduce the length of intensive care unit stay. CONCLUSION: Measures including intraoperative monitoring of bispectral index, supplemental analgesia, alpha2-adrenergic receptor agonists, antipsychotic drugs, and multimodal care are helpful to prevent POD effectively. However, larger, high-quality RCTs are needed to verify these findings and develop more interventions and drugs for preventing postoperative delirium. Title: One-Step Synthesis of 4-Octyl Itaconate through the Structure Control of Lipase Liu C, Wang Y, Liu J, Chen A, Xu J, Zhang R, Wang F, Nie K, Deng L Ref: J Org Chem, :, 2021 : PubMed ESTHER: Liu_2021_J.Org.Chem__ PubMedSearch: Liu 2021 J.Org.Chem PubMedID: 34085515 Abstract 4-Octyl itaconate is a novel antiviral and immunoregulatory small molecule showing great potential in the treatment of various autoimmune diseases and viral infections. It is difficult to selectively esterify the C4 carboxyl group of itaconate acid via one-step direct esterification using chemical catalysts, while the two-step route with itaconic anhydride as an intermediate is environmentally unfriendly and costly. This research investigated the one-step and green synthesis of 4-octyl itaconate through the structure control of lipase, obtaining 4-octyl itaconate with over 98% yield and over 99% selectivity. Multiscale molecular dynamics simulations were applied to investigate the reaction mechanism. The cavity pocket of lipases resulted in a 4-octyl itaconate selectivity by affecting distribution of substrates toward the catalytic site. Toluene could enhance monoesterification in the C4 carboxyl group and contribute to a nearly 100% conversion from itaconate acid into 4-octyl itaconate by adjusting the catalytic microenvironment around the lipase, producing a shrinkage effect on the channel. Title: Insecticidal Terpenes From the Essential Oils of Artemisia nakaii and Their Inhibitory Effects on Acetylcholinesterase Liu J, Hua J, Qu B, Guo X, Wang Y, Shao M, Luo S Ref: Front Plant Sci, 12:720816, 2021 : PubMed ESTHER: Liu_2021_Front.Plant.Sci_12_720816 PubMedSearch: Liu 2021 Front.Plant.Sci 12 720816 PubMedID: 34456959 Abstract Essential oils (EOs) are often the source of insecticidal substances of high efficiency and low toxicity. From gas chromatograph-mass spectrometer, column chromatography, and nuclear magnetic resonance spectra analyses, twenty terpenes were identified from the EOs of Artemisia nakaii. These comprised mostly monoterpenes (49.01%) and sesquiterpenes (50.76%). The terpenes at the highest concentrations in the EOs of A. nakaii were feropodin (200.46 +/- 1.42 microg/ml), (+)-camphor (154.93 +/- 9.72 microg/ml), beta-selinene (57.73 +/- 2.48 microg/ml), and 1,8-cineole (17.99 +/- 1.06 microg/ml), calculated using area normalization and external standards. The EOs were tested for biological activity and showed strong fumigant toxicity and significant antifeedant activity against the larvae of Spodoptera litura. Furthermore, the monoterpenes 1,8-cineole and (+)-camphor displayed significant fumigant activity against S. litura, with LC(50) values of 7.00 +/- 0.85 and 18.16 +/- 2.31 microl/L, respectively. Antifeedant activity of the sesquiterpenes feropodin and beta-selinene was obvious, with EC(50) values of 12.23 +/- 2.60 and 10.46 +/- 0.27 microg/cm(2), respectively. The EOs and beta-selinene were also found to inhibit acetylcholinesterase, with IC(50) values of 37.75 +/- 3.59 and 6.88 +/- 0.48 microg/ml, respectively. These results suggest that monoterpenes and sesquiterpenes from the EOs of A. nakaii could potentially be applied as a botanical pesticides in the control of S. litura. Title: Construction and characterization of CRISPR/Cas9 knockout rat model of carboxylesterase 2a gene Liu J, Shang X, Huang S, Xu Y, Lu J, Zhang Y, Liu Z, Wang X Ref: Molecular Pharmacology, :, 2021 : PubMed ESTHER: Liu_2021_Mol.Pharmacol__2 PubMedSearch: Liu 2021 Mol.Pharmacol 2 PubMedID: 34503976 Gene_locus related to this paper: ratno-LOC246252 Abstract Carboxylesterase 2 (CES2), an important metabolic enzyme, plays a critical role in drug biotransformation and lipid metabolism. Although CES2 is very important, few animal models have been generated to study its properties and functions. Rat Ces2 is similar to human CES2A-CES3A-CES4A gene cluster, with highly similar gene structure, function and substrate. In this report, CRISPR/Cas9 technology was firstly used to knock out rat Ces2a, a main subtype of Ces2 mostly distributed in liver and intestine. This model showed the absence of CES2A protein expression in liver. Further pharmacokinetic studies of diltiazem, a typical substrate of CES2A, confirmed the loss of function of CES2A both in vivo and in vitro. At the same time, the expression of CES2C and CES2J protein in liver decreased significantly. The body and liver weight of Ces2a knockout rats also increased, but the food intake did not change. Moreover, the deficiency of Ces2a led to obesity, insulin resistance and liver fat accumulation, which are consistent with the symptoms of nonalcoholic fatty liver disease (NAFLD). Therefore, this rat model is not only a powerful tool to study drug metabolism mediated by CES2, but also a good disease model to study NAFLD. Significance Statement Human CES2 plays a key role in the first-pass hydrolysis metabolism of most oral prodrugs as well as lipid metabolism. In this study, CRISPR/Cas9 technology was used to knock out Ces2a gene in rats for the first time. This model can be used not only in the study of drug metabolism and pharmacokinetics, but also as a disease model of NAFLD and other metabolic disorder. Title: Trelagliptin ameliorates IL-1beta-impaired chondrocyte function via the AMPK/SOX-9 pathway Liu J, Zuo Q, Li Z, Chen J, Liu F Ref: Mol Immunol, 140:70, 2021 : PubMed ESTHER: Liu_2021_Mol.Immunol_140_70 PubMedSearch: Liu 2021 Mol.Immunol 140 70 PubMedID: 34666245 Inhibitor(s) related to this paper: Trelagliptin Abstract Chondrocyte dysregulation plays a critical role in the development of osteoarthritis (OA). The pro-inflammatory cytokine interleukin-1beta (IL-1beta) activates chondrocytes and degrades the structural extracellular matrix (ECM). These events are the important mechanism of OA. Trelagliptin, a selective inhibitor of dipeptidyl Peptidase 4 (DPP-4) used for the treatment of type 2 diabetes mellitus (T2DM), has displayed a wide range of anti-inflammatory capacities. The effects of Trelagliptin in OA and chondrocytes have not been tested before. Here, we show that Trelagliptin mitigates IL-1beta-induced production of inflammatory cytokines such as interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha) in human chondrocytes. Trelagliptin ameliorates IL-1beta-induced oxidative stress by reducing the generation of reactive oxygen species (ROS). Particularly, the presence of Trelagliptin prevents IL-1beta-induced reduction of Acan genes and the protein Aggrecan. Moreover, we show that Trelagliptin restores IL-1beta-induced reduction of SOX-9 and that the knockdown of SOX-9 abolishes the protective effects of Trelagliptin. Mechanistically, we demonstrate that AMPK is required for the amelioration of Trelagliptin on SOX-9- reduction by IL-1beta. Collectively, our study demonstrates that the DPP-4 inhibitor Trelagliptin has a protective effect on chondrocyte function. Trelagliptin may have the potential role to antagonize chondrocyte-derived inflammation in OA. Title: Dose- and time-related effects of acute diisopropylfluorophosphate intoxication on forced swim behavior and sucrose preference in rats Liu J, Hester K, Pope C Ref: Neurotoxicology, 82:82, 2021 : PubMed ESTHER: Liu_2021_Neurotoxicol_82_82 PubMedSearch: Liu 2021 Neurotoxicol 82 82 PubMedID: 33232745 Abstract Acute intoxication by organophosphorus anticholinesterases (OPs) has been associated with depression and other neuropsychiatric disorders. We previously reported that adult male rats treated with diisopropylfluorophosphate (2.5 mg/kg, sc) showed acute cholinergic signs followed by changes (increased immobility/decreased swimming) in the forced swim test (a measure of behavioral despair) for at least one month. This study was conducted to evaluate the further persistence of changes in the forced swim test out to 4 months and to compare responses in a sucrose preference test, a measure of anhedonia. Adult male rats were treated with vehicle (peanut oil, 1 mL/kg, sc) or DFP (2.0, 2.25 or 2.5 mg/kg) followed by sacrifice 4 h later for measurement of OP-sensitive serine hydrolases (cholinesterase [ChE], fatty acid amide hydrolase [FAAH], and monoacylglycerol lipase [MAGL]) in hippocampus. Additional rats were treated similarly and evaluated for functional signs of acute toxicity from 30 min to 6 days, and then motor activity, forced swim behavior and sucrose preference at approximately 1 week, 1 month and 4 months after dosing. All dosages of DFP elicited serine hydrolase inhibition (ChE, 92-96 %; FAAH, 46-63 %; MAGL, 26-33 %). Body weight was reduced in all DFP-treated groups during the first two weeks, and lethality was noted with the higher dosages. Involuntary movements were elicited in all DFP treatment groups during the first week, but both time of onset and rate of recovery were dose-related. There was a significant reduction in ambulation at one week after the highest dosage (2.5 mg/kg), but no other significant locomotor changes were noted. Immobility was increased and swimming was decreased in the forced swim test at all three time-points by 2.25 mg/kg DFP, and at 2 of 3 time-points by the other dosages. While length of water deprivation and time after DFP dosing affected sucrose preference, DFP treatment had no main effect. We conclude that the forced swim test (a measure of behavioral despair/coping mechanism for inescapable stress) is a robust and persistent neurobehavioral consequence of acute DFP intoxication while sucrose preference, a measure of anhedonia and a common symptom of major clinical depression, is not affected. Title: Biodegradation and up-cycling of polyurethanes: Progress, challenges, and prospects Liu J, He J, Xue R, Xu B, Qian X, Xin F, Blank LM, Zhou J, Wei R and Jiang M <1 more author(s)> Liu J, He J, Xue R, Xu B, Qian X, Xin F, Blank LM, Zhou J, Wei R, Dong W, Jiang M (- 1) Ref: Biotechnol Adv, 48:107730, 2021 : PubMed ESTHER: Liu_2021_Biotechnol.Adv_48_107730 PubMedSearch: Liu 2021 Biotechnol.Adv 48 107730 PubMedID: 33713745 Abstract Polyurethanes (PUR) are ranked globally as the 6th most abundant synthetic polymer material. Most PUR materials are specifically designed to ensure long-term durability and high resistance to environmental factors. As the demand for diverse PUR materials is increasing annually in many industrial sectors, a large amount of PUR waste is also being generated, which requires proper disposal. In contrast to other mass-produced plastics such as PE, PP, and PET, PUR is a family of synthetic polymers, which differ considerably in their physical properties due to different building blocks (for example, polyester- or polyether-polyol) used in the synthesis. Despite its xenobiotic properties, PUR has been found to be susceptible to biodegradation by different microorganisms, albeit at very low rate under environmental and laboratory conditions. Discovery and characterization of highly efficient PUR-degrading microbes and enzymes capable of disassembling PUR polymer chains into oligo- and monomeric compounds is of fundamental importance for a circular plastic economy. In this review, the main methods used for screening PUR-degrading microbes and enzymes are summarized and compared in terms of their catalytic mechanisms. Furthermore, recycling and upcycling strategies of waste PUR polymers, including microbial conversion of PUR monomers into value added products, are presented. Title: A survey of insecticide resistance-conferring mutations in multiple targets in Anopheles sinensis populations across Sichuan, China Qian W, Liu N, Yang Y, Liu J, He J, Chen Z, Li M, Qiu X Ref: Parasit Vectors, 14:169, 2021 : PubMed ESTHER: Qian_2021_Parasit.Vectors_14_169 PubMedSearch: Qian 2021 Parasit.Vectors 14 169 PubMedID: 33743789 Abstract BACKGROUND: Sichuan province is located in the southwest of China, and was previously a malaria-endemic region. Although no indigenous malaria case has been reported since 2011, the number of imported cases is on the rise. Insecticide-based vector control has played a central role in the prevention of malaria epidemics. However, the efficacy of this strategy is gravely challenged by the development of insecticide resistance. Regular monitoring of insecticide resistance is essential to inform evidence-based vector control. Unfortunately, almost no information is currently available on the status of insecticide resistance and associated mechanisms in Anopheles sinensis, the dominant malaria vector in Sichuan. In this study, efforts were invested in detecting the presence and frequency of insecticide resistance-associated mutations in three genes that encode target proteins of several classes of commonly used insecticides. METHODS: A total of 446 adults of An. sinensis, collected from 12 locations across Sichuan province of China, were inspected for resistance-conferring mutations in three genes that respectively encode acetylcholinesterase (AChE), voltage-gated sodium channel (VGSC), and GABA receptor (RDL) by DNA Sanger sequencing. RESULTS: The G119S mutation in AChE was detected at high frequencies (0.40-0.73). The predominant ace-1 genotype was GGC/AGC (119GS) heterozygotes. Diverse variations at codon 1014 were found in VGSC, leading to three different amino acid substitutions (L1014F/C/S). The 1014F was the predominant resistance allele and was distributed in all 12 populations at varying frequencies from 0.03 to 0.86. The A296S mutation in RDL was frequently present in Sichuan, with 296SS accounting for more than 80% of individuals in six of the 12 populations. Notably, in samples collected from Chengdu (DJY) and Deyang (DYMZ), almost 30% of individuals were found to be resistant homozygotes for all three targets. CONCLUSIONS: Resistance-related mutations in three target proteins of the four main classes of insecticides were prevalent in most populations. This survey reveals a worrisome situation of multiple resistance genotypes in Sichuan malaria vector. The data strengthen the need for regular monitoring of insecticide resistance and establishing a region-customized vector intervention strategy. Title: Chemical composition of essential oils from Thymus mongolicus, Cinnamomum verum, and Origanum vulgare and their acaricidal effects on Haemaphysalis longicornis (Acari: Ixodidae) Qiao Y, Yu Z, Bai L, Li H, Zhang S, Liu J, Gao Z, Yang X Ref: Ecotoxicology & Environmental Safety, 224:112672, 2021 : PubMed ESTHER: Qiao_2021_Ecotoxicol.Environ.Saf_224_112672 PubMedSearch: Qiao 2021 Ecotoxicol.Environ.Saf 224 112672 PubMedID: 34416637 Abstract Chemical acaricides are mainly used in traditional tick control, which leads to the emergence of tick resistance and concurrently results in environmental pollution. In the present study, the chemical constituents of essential oils (EOs) from Thymus mongolicus, Cinnamomum verum, and Origanum vulgare was analyzed, and their potential application was evaluated to control the vector tick Haemaphysalis longicornis, which is widely distributed over vast areas of Eurasia, Australia, and New Zealand. Gas chromatography-mass spectrometry analysis revealed that the phenols thymol and carvacrol accounted for 34.66% and 75.72% of the EOs of T. mongolicus and O. vulgare, respectively, whereas trans-cinnamaldehyde (49.42%) was the main constituent of C. verum EO. Immersion tests showed that the EOs of C. verum and O. vulgare had significant acaricidal activity against larval H. longicornis, with the 50% lethal concentration (LC(50)) being 16.07 and 18.02 mg/mL, respectively, and the 95% lethal concentration (LC(95)) being 120.37 and 130.09 mg/mL, respectively. The EOs of O. vulgare and T. mongolicus showed significant acaricidal activity against unfed adult H. longicornis, with LC(50) being 43.50 and 44.21 mg/mL, respectively, and LC(95) being 113.66 and 137.99 mg/mL, respectively. The fumigant toxicity test showed significant acaricidal activity of the three EOs against both unfed and engorged nymphal and adult H. longicornis. Enzyme assays revealed that the EOs of both C. verum and O. vulgare significantly inhibited glutathione S-transferase activity (P < 0.05). In contrast, the activities of carboxylesterase and multifunction oxidases were significantly inhibited by EOs extracted from all three plants (P < 0.05). Taken together, these findings suggest that plant EOs may serve as an environment-friendly alternative for synthetic acaricides in future tick control. Title: The protonation state of Glu202 in acetylcholinesterase Wang J, Lai S, Kong Y, Yao W, Chen X, Liu J Ref: Proteins, :, 2021 : PubMed ESTHER: Wang_2021_Proteins__ PubMedSearch: Wang 2021 Proteins PubMedID: 34546589 Abstract Acetylcholinesterase (AChE) is the crucial enzyme in the central nervous system. It is the target of various organophosphorus nerve agents and pesticides, and the inhibition of AChE is a therapeutic strategy for the treatment of various neurological-related diseases. The Glu202 is a key residue adjacent to the catalytic His447 and plays important role in catalysis. Although the Glu202 has long been considered as negatively charged in many studies, more and more evidences support a protonated Glu202. However, Glu202 is freely accessible by solvent, and thus it seems more reasonable for Glu202 to majorly take the deprotonated state. In the present work, we carried out a series of molecular dynamics simulations with the Glu202 adopting different protonation states. Our results show that the protonated Glu202 is important in maintaining the key hydrogen bond network that supports the catalytic triad, whereas the deprotonated Glu202 results in the collapse of the key hydrogen bond network which consequently destabilizes the catalytic His447. We also notice that different protonation states of Glu202 merely alters the binding mode of ACh. However, since the catalytic His447 is disrupted if Glu202 is deprotonated, His447 can not facilitate the nucleophilic attack performed by Ser203. Therefore, the catalytic efficiency of ACh hydrolysis should be remarkably decreased if Glu202 is deprotonated. Our findings suggest that, when designing and developing highly active AChE inhibitors or proposing mechanistic hypotheses for AChE-catalyzed reactions, the protonated state of Glu202 should be considered. This article is protected by copyright. All rights reserved. Title: Resistance of Bemisia tabaci Mediterranean (Q-biotype) to pymetrozine: resistance risk assessment, cross-resistance to six other insecticides and detoxification enzyme assay Wang F, Liu J, Shuai S, Miao C, Chi B, Chen P, Wang K, Li H, Liu Y Ref: Pest Manag Sci, 77:2114, 2021 : PubMed ESTHER: Wang_2021_Pest.Manag.Sci_77_2114 PubMedSearch: Wang 2021 Pest.Manag.Sci 77 2114 PubMedID: 33332688 Abstract BACKGROUND: The whitefly Bemisia tabaci (Gennadius) is a severe pest that affects many field and glasshouse crops worldwide and has developed resistance to insecticides in most chemical classes. Pymetrozine, a neuroactive pyridine azomethine, is selective towards piercing-sucking pests in Hemiptera. The aim of this study was to assess the resistance of B. tabaci Mediterranean (MED) to pymetrozine in the laboratory. RESULTS: After successive selection of 18 generations of MED in the presence of using pymetrozine, there was an 11.28-fold increase in the median lethal concentration (LC(50) ). When the realized heritability (h(2) ) of B. tabaci to pymetrozine in the field was assumed to be the value estimated in the laboratory (h(2) = 0.1360) and the mortality was 70-90%, only 7.2-15.9 generations were estimated to be needed to obtain a ten-fold increase in resistance to pymetrozine. Compared with the susceptible populations (G(0) ), the Pyme-SEL strain (G(18) ) showed a low level of cross-resistance to neonicotinoids (nitenpyram, imidacloprid, acetamiprid, and thiamethoxam) and no cross-resistance to chlorpyrifos or abamectin. With the G(0) and the Pyme-SEL strains (G(11) and G(18) ) as test strains, the activity of multifunctional oxidase exhibited the greatest increase during selection, while the activities of carboxylesterase and glutathione-S-transferase did not change significantly. CONCLUSION: This study show that a potential risk of development of resistance to pymetrozine exists in B. tabaci after continuous application. During the application of pymetrozine to control B. tabaci in the field, the frequency of its use in combination with neonicotinoids should be used with caution. 2020 Society of Chemical Industry. Title: Influence of suspended sediment on the bioavailability of benzophenone-3: Focus on accumulation and multi-biological effects in Daphnia magna Yang H, Lu G, Yan Z, Liu J Ref: Chemosphere, 275:129974, 2021 : PubMed ESTHER: Yang_2021_Chemosphere_275_129974 PubMedSearch: Yang 2021 Chemosphere 275 129974 PubMedID: 33639549 Abstract The UV-filter benzophenone-3 (BP3) tends to associate with suspended sediment (SPS) due to hydrophobicity, which could alter its toxicological effects on non-target aquatic organisms. In this study, the freshwater cladoceran Daphnia magna (D. magna) was selected as a model organism to investigate the impacts of the source and composition of SPS on the accumulation and multiple toxicological effects (from the molecular level to individual level) of BP3. Among the three components of SPS, amorphous organic carbon (AOC) and minerals promoted the body burden of BP3, while black carbon (BC) inhibited the bioaccumulation. The inhibition effects of BP3 on swimming and feeding behaviors of D. magna were also enhanced due to the presence of AOC and BC. Compared with BP3 exposure alone, higher oxidative stress and neurotoxicity were observed in the presence of SPS containing AOC, BC and minerals, corresponding to that superoxide dismutase, catalase and glutathione-S-transferase activities were further induced, and acetylcholinesterase activity was inhibited. Furthermore, BP3 induced mRNA expression levels of the endocrine system (ecdysone receptor, cytochrome P450 CYP314) and metabolic system (toxicant nuclear receptor HR96, P-glycoprotein), and the presence of SPS containing AOC, BC and minerals exhibited an enhanced effect. Combined with all endpoints, evident relationship was observed between the bioaccumulation level and the response of individual behavior and molecular biomarkers. The results demonstrated that the effects of SPS compositions on bioaccumulation and toxicological effects of organic UV-filters should be considered in aquatic environments. Title: Toxic effects of subacute exposure to acrylamide on motor endplates of the gastrocnemius in rats Yanxian B, Gu Z, Zhang T, Luo Y, Zhang C, Luo L, Ma Y, Liu J Ref: Toxicology, :152934, 2021 : PubMed ESTHER: Yanxian_2021_Toxicology__152934 PubMedSearch: Yanxian 2021 Toxicology 152934 PubMedID: 34509579 Abstract Acrylamide (ACR) is a recognized toxin that is known to induce neurotoxicity in humans and experimental animals. This study aimed to investigate the toxic effects of subacute exposure of the motor endplate (MEP) of the gastrocnemius in rats to ACR. All rats were randomly divided into control, 9, 18, and 36 mg/kg ACR groups, and ACR was administered by gastric gavage for 21 days. The behavioral tests were performed weekly. On the 22(nd) day, the wet weight of the gastrocnemius was measured. The changes in muscle fiber structure, nerve endings, and MEP in the gastrocnemius were examined by hematoxylin-eosin (HE) and gold chloride staining. Acetylcholinesterase (AChE) content in the gastrocnemius was detected by AChE staining. The expression of AChE and calcitonin gene-related peptide was detected by immunohistochemistry and western blot. Rats exposed to ACR showed a significant increase in gait scores and hind limb splay distance compared with the control group, and the wet weight of the gastrocnemius was reduced, HE staining showed that the muscle fiber structure of the gastrocnemius became thin and the arrangement was dense with nuclear aggregation, gold chloride staining showed that nerve branches decreased and became thin, nerve fibers became short and light, the number of MEPs was decreased, the staining became light, and the structure was not clear. AChE staining showed that the number of MEPs was significantly reduced after exposure to ACR, the shape became small, and the AChE content decreased in a dose-dependent manner. Immunohistochemistry and western blot analysis results of the expression levels of AchE and CGRP showed a decreasing trend as compared to the control group with increasing ACR exposure dose. The reduction in protein levels may be the mechanism by which ACR has a toxic effect on the MEP in the gastrocnemius of rats. Title: Discovery of Novel Tacrine-Pyrimidone Hybrids as Potent Dual AChE/GSK-3 Inhibitors for the Treatment of Alzheimer's Disease Yao H, Uras G, Zhang P, Xu S, Yin Y, Liu J, Qin S, Li X, Allen S and Xu J <4 more author(s)> Yao H, Uras G, Zhang P, Xu S, Yin Y, Liu J, Qin S, Li X, Allen S, Bai R, Gong Q, Zhang H, Zhu Z, Xu J (- 4) Ref: Journal of Medicinal Chemistry, :, 2021 : PubMed ESTHER: Yao_2021_J.Med.Chem__ PubMedSearch: Yao 2021 J.Med.Chem PubMedID: 34024109 Inhibitor(s) related to this paper: ACHE-GSK-3-27g Abstract Based on a multitarget strategy, a series of novel tacrine-pyrimidone hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation results demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound 27g possessed excellent dual AChE/GSK-3 inhibition both in terms of potency and equilibrium (AChE: IC(50) = 51.1 nM; GSK-3beta: IC(50) = 89.3 nM) and displayed significant amelioration on cognitive deficits in scopolamine-induced amnesia mice and efficient reduction against phosphorylation of tau protein on Ser-199 and Ser-396 sites in glyceraldehyde (GA)-stimulated differentiated SH-SY5Y cells. Furthermore, compound 27g exhibited eligible pharmacokinetic properties, good kinase selectivity, and moderate neuroprotection against GA-induced reduction in cell viability and neurite damage in SH-SY5Y-derived neurons. The multifunctional profiles of compound 27g suggest that it deserves further investigation as a promising lead for the prospective treatment of AD. Title: Design, synthesis, and biological evaluation of novel xanthone-alkylbenzylamine hybrids as multifunctional agents for the treatment of Alzheimer's disease Zhang Z, Guo J, Cheng M, Zhou W, Wan Y, Wang R, Fang Y, Jin Y, Liu J, Xie SS Ref: Eur Journal of Medicinal Chemistry, 213:113154, 2021 : PubMed ESTHER: Zhang_2021_Eur.J.Med.Chem_213_113154 PubMedSearch: Zhang 2021 Eur.J.Med.Chem 213 113154 PubMedID: 33476932 Abstract In this study, a series of multifunctional hybrids against Alzheimer's disease were designed and obtained by conjugating the pharmacophores of xanthone and alkylbenzylamine through the alkyl linker. Biological activity results demonstrated that compound 4j was the most potent and balanced dual ChEs inhibitor with IC(50) values 0.85 microM and 0.59 microM for eeAChE and eqBuChE, respectively. Kinetic analysis and docking study indicated that compound 4j was a mixed-type inhibitor for both AChE and BuChE. Additionally, it exhibited good abilities to penetrate BBB, scavenge free radicals (4.6 trolox equivalent) and selectively chelate with Cu(2+) and Al(3+) at a 1:1.4 ligand/metal molar ratio. Importantly, after assessments of cytotoxic and acute toxicity, we found compound 4j could improve memory function of scopolamine-induced amnesia mice. Hence, the compound 4j can be considered as a promising lead compound for further investigation in the treatment of AD. Title: Effects of exogenous GR24 on biogas upgrading and nutrient removal by co-culturing microalgae with fungi under mixed LED light wavelengths Zhang W, Zhao C, Liu J, Sun S, Zhao Y, Wei J Ref: Chemosphere, 281:130791, 2021 : PubMed ESTHER: Zhang_2021_Chemosphere_281_130791 PubMedSearch: Zhang 2021 Chemosphere 281 130791 PubMedID: 34020195 Abstract To realize the synchronous purification of raw biogas and biogas slurry, the algal-fungal symbiont pellets were cultivated by supplementing strigolactone (GR24) under different mixed LED light wavelengths. The optimal light intensity was proved to be red and blue in the ratio of 5:5. The symbionts treated with 10(-9) M GR24 had the highest growth rate and mean daily productivity. The extracellular carbonic anhydrase activity and the content of chlorophyll were also affected by GR24 concentrations and mixed light wavelengths. With the induction of 10(-9) M GR24, the maximum removal efficiency of chemical oxygen demand, total nitrogen, and total phosphorus reached 76.35 +/- 6.87%, 78.77 +/- 7.13% and 79.49 +/- 7.43%, respectively. Besides, the CO(2) removal efficiency reached 59.32 +/- 5.19% when the concentration of GR24 was 10(-7) M. This work will be beneficial for large-scale biogas slurry purification and biogas upgrading using co-cultivation of microalgae and fungi. Title: Loading and Sustained Release of Pralidoxime Chloride from Swellable MIL-88B(Fe) and Its Therapeutic Performance on Mice Poisoned by Neurotoxic Agents Zhao D, Liu J, Zhang L, Zhou Y, Zhong Y, Yang Y, Huang C, Wang Y Ref: Inorg Chem, :, 2021 : PubMed ESTHER: Zhao_2021_Inorg.Chem__ PubMedSearch: Zhao 2021 Inorg.Chem PubMedID: 34969248 Abstract Maintaining a long-term continuous and stable reactivator blood concentration to treat organophosphorus nerve agent poisoning using acetylcholinesterase (AChE) reactivator pralidoxime chloride (2-PAM) is very important yet difficult. Because the flexible framework of MIL-88B(Fe) nanoparticles (NPs) can swell in polar solvents, pralidoxime chloride (2-PAM) was loaded in MIL-88B(Fe) NPs (size: ca. 500 nm) by stirring and incubation in deionized water to obtain 2-PAM@MIL-88B(Fe), which had a maximum drug loading capacity of 12.6 wt %. The as-prepared composite was characterized by IR, powder X-ray diffraction (P-XRD), scanning electron microscopy (SEM), -potential, Brunauer-Emmett-Teller (BET), and thermogravimetry/differential thermal analysis (TG/DTA). The results showed that under constant conditions, the maximum drug release rates of 2-PAM@MIL-88B(Fe) in absolute ethanol, phosphate-buffered saline (PBS) solution (pH = 7.4), and PBS solution (pH = 4) at 150 h were 51.7, 80.6, and 67.1%, respectively. This was because the composite showed different swelling behaviors in different solvents. In PBS solution with pH = 2, the 2-PAM@MIL-88B(Fe) framework collapsed after 53 h and released 100% of 2-PAM. For mice after intragastric poisoning with sarin (a neurotoxic agent), an atropine-assisted 2-PAM@MIL-88B(Fe) treatment experiment revealed that 2-PAM@MIL-88B(Fe) continuously released 2-PAM for more than 72 h so that poisoned AChE was continuously and steadily reactivated. The reactivation rate of AChE was 56.7% after 72 h. This composite is expected to provide a prolonged, stable therapeutic drug for the mid- and late-stage treatment of neurotoxic agent poisoning. Title: Development of a practical prediction scoring system for severe acute organophosphate poisoning Dong N, Liu J, Wang Z, Gao N, Pang L, Xing J Ref: J Appl Toxicol, :, 2020 : PubMed ESTHER: Dong_2020_J.Appl.Toxicol__ PubMedSearch: Dong 2020 J.Appl.Toxicol PubMedID: 32030807 Abstract Acute organophosphorus poisoning (AOPP) is a serious public health issue, especially in the rural areas. This study was designed to establish a scoring system to assess the risk of cases with severe AOPP. A retrospective cohort study was conducted at two independent hospitals. The derivation cohort included 444 patients with AOPP and the validation cohort included 274 patients. A risk score for patients with severe AOPP was developed. The rates of severe AOPP cases were 20.7% and 20.1% in the derivation and validation cohorts, respectively. A scoring system for severe AOPP risk was developed that included: (1) age >50 years, (2) white blood cell count of >15 x 10(9) /L, (3) plasma cholinesterase of <360 U/L, (4) plasma albumin of <35 g/L, (5) blood pH <7.3, and (6) lactic acid >3.0 mmol/L. The predicted score in severe cases of AOPP had good accuracy in both the derivation (area under the receiver operating characteristic curve [AUC] 0.88, 95% confidence interval [CI], 0.85-0.92) and validation cohorts (AUC 0.83, 95% CI, 0.77-0.90). A practical bedside prediction scoring system was developed for patients with severe AOPP. The routine use of this scoring system could rapidly assist in identifying patients at higher risk who require more intensive care or transfer to a larger better-equipped hospital. Title: Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer's disease Fu J, Bao F, Gu M, Liu J, Zhang Z, Ding J, Xie SS Ref: J Enzyme Inhib Med Chem, 35:118, 2020 : PubMed ESTHER: Fu_2020_J.Enzyme.Inhib.Med.Chem_35_118 PubMedSearch: Fu 2020 J.Enzyme.Inhib.Med.Chem 35 118 PubMedID: 31694418 Abstract A series of novel quinolinone derivatives bearing dithiocarbamate moiety were designed and synthesised as multifunctional AChE inhibitors for the treatment of AD. Most of these compounds exhibited strong and clearly selective inhibition to eeAChE. Among them, compound 4c was identified as the most potent inhibitor to both eeAChE and hAChE (IC50 = 0.22 muM for eeAChE; IC50 = 0.16 muM for hAChE), and it was also the best inhibitor to AChE-induced Abeta aggregation (29.02% at 100 muM) and an efficient inhibitor to self-induced Abeta aggregation (30.67% at 25 muM). Kinetic and molecular modelling studies indicated that compound 4c was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4c had good ability to cross the BBB, showed no toxicity on SH-SY5Y neuroblastoma cells and was well tolerated in mice at doses up to 2500 mg/kg (po). Title: HIV-1 Tat-Induced Astrocytic Extracellular Vesicle miR-7 Impairs Synaptic Architecture Hu G, Niu F, Liao K, Periyasamy P, Sil S, Liu J, Dravid SM, Buch S Ref: J Neuroimmune Pharmacol, 15:538, 2020 : PubMed ESTHER: Hu_2020_J.Neuroimmune.Pharmacol_15_538 PubMedSearch: Hu 2020 J.Neuroimmune.Pharmacol 15 538 PubMedID: 31401755 Abstract Although combination antiretroviral therapy (cART) has improved the health of millions of those living with HIV-1 (Human Immunodeficiency Virus, Type 1), the penetration into the central nervous system (CNS) of many such therapies is limited, thereby resulting in residual neurocognitive impairment commonly referred to as NeuroHIV. Additionally, while cART has successfully suppressed peripheral viremia, cytotoxicity associated with the presence of viral Transactivator of transcription (Tat) protein in tissues such as the brain, remains a significant concern. Our previous study has demonstrated that both HIV-1 Tat as well as opiates such as morphine, can directly induce synaptic alterations via independent pathways. Herein, we demonstrate that exposure of astrocytes to HIV-1 protein Tat mediates the induction and release of extracellular vesicle (EV) microRNA-7 (miR-7) that is taken up by neurons, leading in turn, to downregulation of neuronal neuroligin 2 (NLGN2) and ultimately to synaptic alterations. More importantly, we report that these impairments could be reversed by pretreatment of neurons with a neurotrophic factor platelet-derived growth factor-CC (PDGF-CC). Graphical Abstract. Title: IRREGULAR POLLEN EXINE2 Encodes a GDSL Lipase Essential for Male Fertility in Maize Huo Y, Pei Y, Tian Y, Zhang Z, Li K, Liu J, Xiao S, Chen H Ref: Plant Physiol, 184:1438, 2020 : PubMed ESTHER: Huo_2020_Plant.Physiol_184_1438 PubMedSearch: Huo 2020 Plant.Physiol 184 1438 PubMedID: 32913046 Abstract Anther cuticle and pollen exine are two physical barriers protecting plant reproductive cells against environmental stresses; defects in either often cause male sterility. Here, we report the characterization of a male-sterile mutant irregular pollen exine2 (ipe2) of maize (Zea mays), which displays shrunken anthers and no starch accumulation in mature pollen grains. We cloned the causal gene IPE2 and confirmed its role in male fertility in maize with a set of complementary experiments. IPE2 is specifically expressed in maize developing anthers during stages 8 to 9 and encodes an endoplasmic-reticulum-localized GDSL lipase. Dysfunction of IPE2 resulted in delayed degeneration of tapetum and middle layer, leading to defective formation of anther cuticle and pollen exine, and complete male sterility. Aliphatic metabolism was greatly altered, with the contents of lipid constituents, especially C16/C18 fatty acids and their derivatives, significantly reduced in ipe2 developing anthers. Our study elucidates GDSL function in anther and pollen development and provides a promising genetic resource for breeding hybrid maize. Title: A De Novo Designed Esterase with p-Nitrophenyl Acetate Hydrolysis Activity Li G, Xu L, Zhang H, Liu J, Yan J, Yan Y Ref: Molecules, 25:4658, 2020 : PubMed ESTHER: Li_2020_Molecules_25_4658 PubMedSearch: Li 2020 Molecules 25 4658 PubMedID: 33066055 Gene_locus related to this paper: aspor-cutas, fusso-cutas, hevbr-hnl Abstract Esterases are a large family of enzymes with wide applications in the industry. However, all esterases originated from natural sources, limiting their use in harsh environments or newly- emerged reactions. In this study, we designed a new esterase to develop a new protocol to satisfy the needs for better biocatalysts. The ideal spatial conformation of the serine catalytic triad and the oxygen anion hole at the substrate-binding site was constructed by quantum mechanical calculation. The catalytic triad and oxygen anion holes were then embedded in the protein scaffold using the new enzyme protocol in Rosetta 3. The design results were subsequently evaluated, and optimized designs were used for expression and purification. The designed esterase had significant lytic activities towards p-nitrophenyl acetate, which was confirmed by point mutations. Thus, this study developed a new protocol to obtain novel enzymes that may be useful in unforgiving environments or novel reactions. Title: Identification of key residues of carboxylesterase PxEst-6 involved in pyrethroid metabolism in Plutella xylostella (L.) Li Y, Sun H, Tian Z, Ye X, Li R, Li X, Zheng S, Liu J, Zhang Y Ref: J Hazard Mater, 407:124612, 2020 : PubMed ESTHER: Li_2020_J.Hazard.Mater_407_124612 PubMedSearch: Li 2020 J.Hazard.Mater 407 124612 PubMedID: 33338816 Gene_locus related to this paper: pluxy-f1c4b8 Abstract The long-term and excessive use of insecticides has led to severe environmental problems and the evolution of insecticide resistance in insects. Carboxylesterases (CarEs) are important detoxification enzymes conferring insecticide resistance on insects. Herein, the detoxification process of Plutella xylostella (L.) carboxylesterase 6 (PxEst-6), one representative P. xylostella carboxylesterase, is investigated with cypermethrin, bifenthrin, cyfluthrin and lambda-cyhalothrin. RT-qPCR shows that PxEst-6 is highly expressed in the midgut and cuticles of the third instar larvae. Exposure to pyrethroid insecticides resulted in PxEst-6 up-regulation in a short time. Metabolic assays indicate that PxEst-6 has the capacity to metabolize these pyrethroid insecticides. The combination of molecular docking, binding mode analyses and alanine mutations demonstrated that His451, Lys458 and Gln431 were key residues of PxEst-6 for metabolizing pyrethroids and the acetate groups derived from pyrethroids were key sites for being metabolized by PxEst-6. H451- and K458-derived hydrogen bond (H-bond) interactions with the pyrethroid acetate groups and the polar interactions with the pyrethroid acetate group provided by the Q431 sidechain were crucial to the pyrethroids' metabolism by PxEst-6. Our study contributes to revealing the reasons for pyrethroid resistance in P. xylostella, and provides a fundamental basis for the development of novel pyrethroid insecticides. Title: Multilevel ecotoxicity assessment of environmentally relevant bisphenol F concentrations in Daphnia magna Liu J, Shen J, Lu G, Xu X, Yang H, Yan Z, Chen W Ref: Chemosphere, 240:124917, 2020 : PubMed ESTHER: Liu_2020_Chemosphere_240_124917 PubMedSearch: Liu 2020 Chemosphere 240 124917 PubMedID: 31726617 Abstract With the pressure to ban or limit the use of Bisphenol A (BPA), substitutes such as bisphenol F (BPF) are applied to various commodities and generally detected in aquatic systems worldwide. To understand the potential ecological risk of BPF, the acute toxicity as well as behavioural, physiological and biochemical parameters of the water flea Daphnia magna were assessed. Following BPF exposure at concentrations ranging from 0.1mugL(-1) to 100mugL(-1), phenotypic traits including growth development, fecundity and swimming activity were significantly inhibited in response to exposure to sublethal concentrations (1-100mugL(-1)) of BPF, which had a positive relationship with the activity of antioxidant enzymes. Moreover, the acetylcholinesterase (AChE) activity, which was strictly associated with the behavioural changes, was clearly inhibited, which was also obviously related to the heart rate and thoracic limb activity. Compared to the toxicity of BPA, BPF induces similar toxic effects, and the health concerns regarding the use of these alternatives should be highlighted. Title: Enzymology, Histological and Ultrastructural Effects of Ar-Turmerone on Culex pipiens pallens Larvae Liu J, Fernandez D, Gao Y, Pierre S, Dai G Ref: Insects, 11:, 2020 : PubMed ESTHER: Liu_2020_Insects_11_ PubMedSearch: Liu 2020 Insects 11 PubMedID: 32486189 Abstract Our previous article demonstrated that ar-turmerone ((6S)-2-methyl-6-(4-methylphenyl)-2-hepten-4-one) extracted from Curcuma longa L. has a significant larvicidal activity against the fourth instar larvae of Culex pipiens pallens. To reveal the effects of ar-turmerone on C. pipiens pallens larvae, light microscopy and transmission electron microscopy were used to observe the histological and ultrastructure changes in muscle and digestive tissues of fourth instar larvae. It was also revealed by detecting the activity of the acetylcholinesterase (AChE) enzyme and three detoxifying enzymes, including carboxylesterase (CarE), glutathione-S-transferase (GST) and Cytochrome P450 monooxidases (P450). The observation under the light microscope showed that the larvae displayed a disruption of myofibril in ventral muscle cells, the disappearance of nucleolus in the malpighian tubule cells, and the exfoliation of the brush border in midgut epithelial cells, 24 h after treatment. The observation under the transmission electron microscope displayed disorganized Z-lines in the ventral muscle cells, and dissolved membrane of mitochondria, nuclear and endoplasmic reticulum in abdominal cells. The enzymatic activity results showed that ar-turmerone significantly increased the level of detoxifying enzymes, while the activity of AChE was not obviously affected. All the results suggest that the larvicidal mechanism of ar-turmerone is estimated to be stomach poison and the active sites might be the muscle and digestive tissues, and the mode of action of ar-turmerone may be unrelated to AChE. Title: The Chromosome-Based Rubber Tree Genome Provides New Insights into Spurge Genome Evolution and Rubber Biosynthesis Liu J, Shi C, Shi CC, Li W, Zhang QJ, Zhang Y, Li K, Lu HF, Zhu ST and Gao LZ <27 more author(s)> Liu J, Shi C, Shi CC, Li W, Zhang QJ, Zhang Y, Li K, Lu HF, Zhu ST, Xiao ZY, Nan H, Yue Y, Zhu XG, Wu Y, Hong XN, Fan GY, Tong Y, Zhang D, Mao CL, Liu YL, Hao SJ, Liu WQ, Lv MQ, Zhang HB, Liu Y, Hu-Tang GR, Wang JP, Wang JH, Sun YH, Ni SB, Chen WB, Zhang XC, Jiao YN, Eichler EE, Li GH, Liu X, Gao LZ (- 27) Ref: Mol Plant, 13:336, 2020 : PubMed ESTHER: Liu_2020_Mol.Plant_13_336 PubMedSearch: Liu 2020 Mol.Plant 13 336 PubMedID: 31838037 Gene_locus related to this paper: hevbr-a0a6a6mdr9 Abstract The rubber tree, Hevea brasiliensis, produces natural rubber that serves as an essential industrial raw material. Here, we present a high-quality reference genome for a rubber tree cultivar GT1 using single-molecule real-time sequencing (SMRT) and Hi-C technologies to anchor the -1.47-Gb genome assembly into 18 pseudochromosomes. The chromosome-based genome analysis enabled us to establish a model of spurge chromosome evolution, since the common paleopolyploid event occurred before the split of Hevea and Manihot. We show recent and rapid bursts of the three Hevea-specific LTR-retrotransposon families during the last 10 million years, leading to the massive expansion by -65.88% (-970 Mbp) of the whole rubber tree genome since the divergence from Manihot. We identify large-scale expansion of genes associated with whole rubber biosynthesis processes, such as basal metabolic processes, ethylene biosynthesis, and the activation of polysaccharide and glycoprotein lectin, which are important properties for latex production. A map of genomic variation between the cultivated and wild rubber trees was obtained, which contains -15.7 million high-quality single-nucleotide polymorphisms. We identified hundreds of candidate domestication genes with drastically lowered genomic diversity in the cultivated but not wild rubber trees despite a relatively short domestication history of rubber tree, some of which are involved in rubber biosynthesis. This genome assembly represents key resources for future rubber tree research and breeding, providing novel targets for improving plant biotic and abiotic tolerance and rubber production. Title: Biological uptake, depuration and biochemical effects of diclofenac and carbamazepine in Carassius carassius Nkoom M, Lu G, Liu J, Dong H Ref: Ecotoxicology & Environmental Safety, 205:111106, 2020 : PubMed ESTHER: Nkoom_2020_Ecotoxicol.Environ.Saf_205_111106 PubMedSearch: Nkoom 2020 Ecotoxicol.Environ.Saf 205 111106 PubMedID: 32818877 Abstract The uptake and depuration kinetics of diclofenac and carbamazepine alone at an environmentally relevant nominal concentration of 2 mug/L and in combination at a concentration ratio of 1:1 with total concentration of 4 mug/L were evaluated in Carassius carassius after 7 d uptake and depuration. Also, the biochemical effects of both drugs alone at nominal concentrations of 2 and 10 mug/L as well as in combination with total concentrations of 4 and 20 mug/L were investigated in Carassius carassius after 7 d exposure followed by 10 d recovery. In the single treatments, steady-state BCFs measured after the 7 d exposure were 73.05, 49.71, 38.01 and 24.93 L/kg for diclofenac and 9.25, 8.99, 5.29 and 4.11 L/kg for carbamazepine in the liver, brain, gill and muscle of Carassius carassius, respectively. Comparatively lower BCFs were measured in the tissues of Carassius carassius for both drugs in the combined treatments. Acetylcholinesterase activity in the brain was significantly induced by diclofenac while carbamazepine and the mixtures significantly inhibited it during all the exposure days as well as after the 10 d recovery in all treatments. This indicates that Carassius carassius could not recover from the neurotoxic effects caused by carbamazepine unlike the inductive effect caused by diclofenac which was recoverable after 10 days. A significant increase in the activities of 7-ethoxyresorufin O-deethylase and glutathione s-transferase for individual and mixed pharmaceuticals suggest that metabolism and detoxification of both drugs took place in the liver of Carassius carassius. Also, a significant increase in the activities of superoxide dismutase, catalase, glutathione reductase and malondialdehyde contents in the individual and mixture treatments mean that the antioxidant defence system of Carassius carassius was triggered to fight against oxidative stress but lipid peroxidation still occurred. However, Carassius carassius recovered from all these increases (superoxide dismutase, catalase, glutathione reductase and malondialdehyde) after the 10 d recovery, suggesting that oxidative damage is reversible. Our results indicate that both drugs at environmentally relevant concentrations might cause adverse effects in Carassius carassius and other fish species. Title: Thiol-suppressed I(2)-etching of AuNRs: acetylcholinesterase-mediated colorimetric detection of organophosphorus pesticides Qing Z, Li Y, Luo G, Hu J, Zou Z, Lei Y, Liu J, Yang R Ref: Mikrochim Acta, 187:497, 2020 : PubMed ESTHER: Qing_2020_Mikrochim.Acta_187_497 PubMedSearch: Qing 2020 Mikrochim.Acta 187 497 PubMedID: 32803418 Abstract For the first time it is demonstrated that sulfhydryl compounds can suppress longitudinal etching of gold nanorods via consuming oxidizers, which provides a new signaling mechanism for colorimetric sensing. As a proof of concept, a colorimetric assay is developed for detecting organophosphorus pesticides, which are most widely used in modern agriculture to improve food production but with high toxicity to animals and the ecological environment. Triazophos was selected as a model organophosphorus pesticide. In the absence of triazophos, the active acetylcholinesterase can catalyze the conversion of acetylthiocholine iodide to thiocholine whose thiol group can suppress the I(2)-induced etching of gold nanorods. When triazophos is present, the activity of AchE is inhibited, and I(2)-induced etching of gold nanorods results in triazophos concentration-dependent color change from brown to blue, pink, and red. The aspect ratio of gold nanorods reduced with gradually blue-shifted longitudinal absorption. There was a linear detection range from 0 to 117 nM (R(2) = 0.9908), the detection limit was 4.69 nM, and a good application potential was demonstrated by the assay of real water samples. This method will not only contribute to public monitoring of organophosphorus pesticides but also has verified a new signaling mechanism which will open up a new path to develop colorimetric detection methods. It has been first found that sulfhydryl compounds can suppress longitudinal etching of gold nanorods (AuNRs) via consuming oxidizers, which provides a new signaling mechanism for colorimetric sensing. As a proof of concept, a colorimetric assay is developed for sensitively detecting organophosphorus pesticides (OPs). It will not only contribute to public monitoring of OPs but also has verified a new signaling mechanism which will open up a new path to develop multicolor colorimetric methods. Title: Proteomic Analysis Reveals that EPHX1 Contributes to 5-Fluorouracil Resistance in a Human Hepatocellular Carcinoma Cell Line Sun R, Dong C, Li R, Chu H, Liu J, Hao D, Zhang L, Zhao B, Wang L, Zhang Y Ref: Proteomics Clin Appl, 14:e1900080, 2020 : PubMed ESTHER: Sun_2020_Proteomics.Clin.Appl_14_e1900080 PubMedSearch: Sun 2020 Proteomics.Clin.Appl 14 e1900080 PubMedID: 32067389 Gene_locus related to this paper: human-EPHX1 Abstract PURPOSE: The extensive drug resistance of hepatocellular carcinoma (HCC) has become a major cause of chemotherapy failure. A deeper understanding of the drug resistance mechanism of tumor cells is very significant for improving the clinical prognosis of patients with HCC. EXPERIMENTAL DESIGN: In this study, proteomic studies on the composition of 5-fluorouracil (5-Fu) resistant Bel/5Fu cell line and its parent Bel7402 cell line by using an ionic liquid assisted proteins extraction method with the advantage of extracting plasma membrane proteins to a wider extent are performed. Then the expression level and function of differentially expressed plasma membrane proteins are verified. RESULTS: In total, 25 plasma membrane proteins are shown differentially expressed in Bel/5Fu compared with Bel7402. Western blot analysis results further confirmed that the EPHX1 PLIN2 RAB27B SLC4A2 are upregulated in Bel/5Fu cells in accordance with the proteomics data. Moreover, cell viability assay and clonogenic survival assay results demonstrated that EPHX1 is closely related to the chemoresistance of Bel/5Fu to 5-Fu. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma membrane protein EPHX1 is closely related to the chemotherapy resistance of Bel/5Fu cells and can be used as a new drug target to improve the clinical prognosis of patients with HCC. Title: Bemisia tabaci (Hemiptera: Aleyrodidae) Insecticide Resistance in Shandong Province, China Wang F, Liu J, Chen P, Li HY, Ma JJ, Liu YJ, Wang K Ref: J Econ Entomol, 113:911, 2020 : PubMed ESTHER: Wang_2020_J.Econ.Entomol_113_911 PubMedSearch: Wang 2020 J.Econ.Entomol 113 911 PubMedID: 31800055 Abstract The Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) complex comprises important pests and virus vectors in agricultural crops worldwide. In China, B. tabaci has spread to more than 20 provinces and caused severe losses of vegetables, fruits, and ornamental plants. However, B. tabaci has developed resistance to many insecticidal classes in Shandong Province, eastern China. In this study, we investigated the cryptic species, insecticide resistance and detoxifying enzymes of B. tabaci from six representative locations exhibiting severe damage in Shandong. At four of the six locations, B. tabaci Mediterranean (MED) comprised 100% of the samples collected. In a further two locations, species composition was predominantly (>94%) MED with B. tabaci Middle East-Asia Minor 1 (MEAM1), comprising a low proportion (<6%) of the samples collected. For all field populations, avermectin was the most effective insecticide against adult B. tabaci, pyriproxyfen had a significant effect on B. tabaci eggs and field populations were susceptible to pymetrozine. Six field populations of B. tabaci have developed low-to-moderate resistance to neonicotinoids. The detoxifying enzyme activity of carboxylesterase, glutathione S-transferase, and multifunctional oxidase were quantified. Multifunctional oxidase and glutathione S-transferase activity were positively correlated with insecticide resistance in several B. tabaci populations. Title: Rhizoma Coptidis for Alzheimer's Disease and Vascular Dementia: A Literature Review Wang Z, Yang Y, Liu M, Wei Y, Liu J, Pei H, Li H Ref: Curr Vasc Pharmacol, 18:358, 2020 : PubMed ESTHER: Wang_2020_Curr.Vasc.Pharmacol_18_358 PubMedSearch: Wang 2020 Curr.Vasc.Pharmacol 18 358 PubMedID: 31291876 Abstract BACKGROUND: Alzheimer's disease (AD) and vascular dementia (VaD) are major types of dementia, both of which cause heavy economic burdens for families and society. However, no currently available medicines can control dementia progression. Rhizoma coptidis, a Chinese herbal medicine, has been used for >2000 years and is now gaining attention as a potential treatment for AD and VaD. METHODS: We reviewed the mechanisms of the active ingredients of Rhizoma coptidis and Rhizoma coptidis-containing Chinese herbal compounds in the treatment of AD and VaD. We focused on studies on ameliorating the risk factors and the pathological changes of these diseases. RESULTS: The Rhizoma coptidis active ingredients include berberine, palmatine, coptisine, epiberberine, jatrorrhizine and protopine. The most widely studied ingredient is berberine, which has extensive therapeutic effects on the risk factors and pathogenesis of dementia. It can control blood glucose and lipid levels, regulate blood pressure, ameliorate atherosclerosis, inhibit cholinesterase activity, Abeta generation, and tau hyperphosphorylation, decrease neuroinflammation and oxidative stress and alleviate cognitive impairment. Other ingredients (such as jatrorrhizine, coptisine, epiberberine and palmatine) also regulate blood lipids and blood pressure; however, there are relatively few studies on them. Rhizoma coptidis-containing Chinese herbal compounds like Huanglian-Jie-Du-Tang, Huanglian Wendan Decoction, Banxia Xiexin Decoction and Huannao Yicong Formula have anti-inflammatory and antioxidant stress activities, regulate insulin signaling, inhibit gamma-secretase activity, neuronal apoptosis, tau hyperphosphorylation, and Abeta deposition, and promote neural stem cell differentiation, thereby improving cognitive function. CONCLUSION: The "One-Molecule, One-Target" paradigm has suffered heavy setbacks, but a "multitarget- directed ligands" strategy may be viable. Rhizoma coptidis active ingredients and Rhizoma coptidiscontaining Chinese herbal compounds have multi-aspect therapeutic effects on AD and VaD. Title: Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G Ref: Cell Res, 30:269, 2020 : PubMed Title: Synergistic Degradation of Pyrethroids by the Quorum Sensing-Regulated Carboxylesterase of Bacillus subtilis BSF01 Xiao Y, Lu Q, Yi X, Zhong G, Liu J Ref: Front Bioeng Biotechnol, 8:889, 2020 : PubMed ESTHER: Xiao_2020_Front.Bioeng.Biotechnol_8_889 PubMedSearch: Xiao 2020 Front.Bioeng.Biotechnol 8 889 PubMedID: 32850741 Abstract The well-studied quorum sensing (QS) mechanism has established a complex knowledge system of how microorganisms behave collectively in natural ecosystems, which contributes to bridging the gap between the ecological functions of microbial communities and the molecular mechanisms of cell-to-cell communication. In particular, the ability of agrochemical degradation has been one most attractive potential of functional bacteria, but the interaction and mutual effects of intracellular degradation and intraspecific behavior remained unclear. In this study, we establish a connection between QS regulation and biodegradation by harnessing the previously isolated Bacillus subtilis BSF01 as a template which degrades various pyrethroids. First, we characterize the genetic and transcriptional basis of comA-involved QS system in B. subtilis BSF01 since the ComQXPA circuit coordinates group behaviors in B. subtilis isolates. Second, the genetic and transcriptional details of pyrethroid-degrading carboxylesterase CesB are defined, and its catalytic capacity is evaluated under different conditions. More importantly, we adopt DNA pull-down and yeast one-hybrid techniques to reveal that the enzymatic degradation of pyrethroids is initiated through QS signal regulator ComA binding to carboxylesterase gene cesB, highlighting the synergistic effect of QS regulation and pyrethroid degradation in B. subtilis BSF01. Taken together, the elucidated mechanism provides novel details on the intercellular response of functional bacteria against xenobiotic exposure, which opens up possibilities to facilitate the in-situ contaminant bioremediation via combining the QS-mediated strategies. Title: Simulated revelation of the adsorption behaviours of acetylcholinesterase on charged self-assembled monolayers Yang S, Liu J, Zheng H, Zhong J, Zhou J Ref: Nanoscale, :, 2020 : PubMed ESTHER: Yang_2020_Nanoscale__ PubMedSearch: Yang 2020 Nanoscale PubMedID: 32022070 Abstract An acetylcholinesterase (AChE)-based electrochemical biosensor, as a promising alternative to detect organophosphates (OPs) and carbamate pesticides, has gained considerable attention in recent years, due to the advantages of simplicity, rapidity, reliability and low cost. The bio-activity of AChE immobilized on the surface and the direct electron transfer (DET) rate between an enzyme and an electrode directly determined the analytical performances of the AChE-based biosensor, and experimental studies have shown that the charged surfaces have a strong impact on the detectability of the AChE-based biosensor. Therefore, it is very important to reveal the behaviour of AChE in bulk solution and on charged surfaces at the molecular level. In this work, the adsorption orientation and conformation of AChE from Torpedo californica (TcAChE) on oppositely charged self-assembled monolayers (SAMs), COOH-SAM and NH2-SAM with different surface charge densities, were investigated by parallel tempering Monte Carlo (PTMC) and all-atom molecular dynamics simulations (AAMD). Simulation results show that TcAChE could spontaneously and stably adsorb on two oppositely charged surfaces by the synergy of an electric dipole and charged residue patch, and opposite orientations were observed. The active-site gorge of TcAChE is oriented toward the surface with the "end-on" orientation and the active sites are close to the surface when it is adsorbed on the positively charged surface and the tunnel cost for the substrate is lower than that on the negatively charged surface and in bulk solution, while for TcAChE adsorbed on the negatively charged surface, the active site of TcAChE is far away from the surface and the active-site gorge is oriented toward the solution with a "back-on" orientation. It suggests that the positively charged surface could provide a better microenvironment for the efficient bio-catalytic reaction and quick DET between TcAChE and the electrode surface. Moreover, the RMSD, RMSF, dipole moment, gyration radius, eccentricity and superimposed structures show that only a slight conformational change occurred on the relatively flexible structure of TcAChE during simulations, and the native conformation is well preserved after adsorption. This work helps us better comprehend the adsorption mechanism of TcAChE on charged surfaces and might provide some guidelines for the development of new TcAChE-based amperometric biosensors for the detection of organophosphorus pesticides. Title: Extradural Contralateral C7 Nerve Root Transfer in a Cervical Posterior Approach for Treating Spastic Limb Paralysis: A Cadaver Feasibility Study Yang K, Jiang F, Zhang S, Zhao H, Shi Z, Liu J, Cao X Ref: Spine (Phila Pa 1976), 45:E608, 2020 : PubMed ESTHER: Yang_2020_Spine.(Phila.Pa.1976)_45_E608 PubMedSearch: Yang 2020 Spine.(Phila.Pa.1976) 45 E608 PubMedID: 31770316 Abstract STUDY DESIGN: Anatomic study in nine fresh-frozen cadavers. OBJECTIVE: To confirm the anatomical feasibility of transferring the extradural ventral roots (VRs) and dorsal roots (DRs) of contralateral C7 nerves to those of the ipsilateral C7 nerves respectively through a cervical posterior approach. SUMMARY OF BACKGROUND DATA: The contralateral C7 nerve root transfer technique makes breakthrough for treating spastic limb paralysis. However, its limitations include large surgical trauma and limited indications. METHODS: Nine fresh-frozen cadavers (four females and five males) were placed prone, and the feasibility of exposing the bilateral extradural C7 nerve roots, separation of the extradural C7 VR and DR, and transfer of the VR and DR of the contralateral C7 to those of the ipsilateral C7 on the dural mater were assessed. The pertinent distances and the myelography results of each specimen were analyzed. The acetylcholinesterase (AChE) and antineurofilament 200 (NF200) double immunofluorescent staining were preformed to determine the nerve fiber properties. RESULTS: A cervical posterior midline approach was made and the laminectomy was performed to expose the bilateral extradural C7 nerve roots. After the extradural C7 VR and DR are separated, the VR and DR of the contralateral C7 have sufficient lengths to be transferred to those of the ipsilateral C7 on the dural mater. The myelography results showed that the spinal cord is not compressed after the nerve anastomosis. The AChE and NF200 double immunofluorescent staining showed the distal ends of the contralateral C7 VRs were mostly motor nerve fibers, and the distal ends of the contralateral C7 DRs were mostly sensory nerve fibers. CONCLUSION: Extradural contralateral C7 nerve root transfer in a cervical posterior approach for treating spastic limb paralysis is anatomically feasible. LEVEL OF EVIDENCE: 5. Title: Identification of ovalbumin-derived peptides as multi-target inhibitors of AChE, BChE and BACE1 Yu Z, Dong W, Wu S, Shen J, Zhao W, Ding L, Liu J, Zheng F Ref: J Sci Food Agric, :, 2020 : PubMed ESTHER: Yu_2020_J.Sci.Food.Agric__ PubMedSearch: Yu 2020 J.Sci.Food.Agric PubMedID: 31997357 Abstract BACKGROUND: Alzheimer's disease (AD) is a kind of progressive neurodegenerative disease that occurs to the elderly. But there is no ideal treatment for AD. Thus, the purpose of this study is to identify anti-AD peptides from ovalbumin. RESULTS: The potential tripeptides IEK, LYR and CIK were selected for molecular docking. The '-CDOCKER_Energy' value of the best docking position of the tripeptide IEK, LYR and CIK interacting with acetylcholinesterase (AChE) were - 93.8119, -86.9556 and - 73.6370 kcal/mol, respectively. The '-CDOCKER_Energy' values for interaction with butyrylcholinesterase (BChE) were - 96.6386, -80.8392 and - 87.4341 kcal/mol, respectively. Most importantly, the '-CDOCKER_Energy' values for interaction with beta-site amyloid precursor protein cleavage enzyme1 (BACE1) were - 85.5903, -71.3342 and - 68.4290 kcal/mol, respectively. Overall, in vitro assays results demonstrated that peptide CIK exhibited impressive inhibitory activities against AChE, BChE, and BACE1, with the IC50 value of 6.76, 7.72, and 34.48 muM, respectively. Especially, CIK can be contacted with some peripheral anion sites (PAS) and catalytic sites on AChE, BChE and BACE1. CONCLUSION: Tripeptide CIK can effectively inhibit the activities of AChE, BChE and BACE1. Therefore, tripeptide CIK has the potential to effectively treat AD. This article is protected by copyright. All rights reserved. Title: Identification and molecular docking study of fish roe-derived peptides as potent BACE 1, AChE, and BChE inhibitors Yu Z, Ji H, Shen J, Kan R, Zhao W, Li J, Ding L, Liu J Ref: Food Funct, 11:6643, 2020 : PubMed ESTHER: Yu_2020_Food.Funct_11_6643 PubMedSearch: Yu 2020 Food.Funct 11 6643 PubMedID: 32656560 Abstract Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and beta-secretase 1 (BACE 1) play vital roles in the development and progression of Alzheimer's disease (AD). The objective of the present study was to identify fish roe-derived anti-AD peptides with activities against AChE, BChE, and BACE 1. Fish roe proteins were cleaved in silico by gastrointestinal proteases, and the released peptides were collected. Subsequently, the toxicity, solubility, and biological properties of these novel di- and tri-peptides were predicted and validated. Finally, potential anti-AD peptides were docked to targets, i.e., AChE, BChE, and BACE 1. A novel anti-AD tripeptide WIR with potent inhibition of AChE and BACE 1 was identified, with IC(50) values of 43.32 +/- 1.22 microM and 2.27 +/- 0.35 mM, respectively. In addition, the inhibition rate of WIR (at a concentration of 1.06 +/- 0.87 microM) against BChE was 33.5%, and the peptide WIR was able to simultaneously interact with AChE, BChE, and BACE 1. Residues Ser286 of AChE, Asp70 of BChE, and Thr231, Arg235 of BACE 1 played key roles in the interaction with peptide WIR. In summary, peptide WIR exhibits the potential to be an effective treatment for AD. Title: Optimization of chemoenzymatic Baeyer-Villiger oxidation of cyclohexanone to sigma-caprolactone using response surface methodology Zhang Y, Jiang W, Lv K, Sun Y, Gao X, Zhao Q, Ren W, Wang F, Liu J Ref: Biotechnol Prog, 36:e2901, 2020 : PubMed ESTHER: Zhang_2020_Biotechnol.Prog_36_e2901 PubMedSearch: Zhang 2020 Biotechnol.Prog 36 e2901 PubMedID: 31465150 Abstract sigma-Caprolactone (sigma-CL) has attracted a great deal of attention and a high product concentration is of great significance for reducing production cost. The optimization of sigma-CL synthesis through chemoenzymatic Baeyer-Villiger oxidation mediated by immobilized Trichosporon laibacchii lipase was studied using response surface methodology (RSM). The yield of sigma-CL was 98.06% with about 1.2 M sigma-CL concentration that has a substantial increase mainly due to both better stability of the cross-linked immobilized lipase used and the optimum reaction conditions in which the concentration of cyclohexanone was 1.22 M, the molar ratio of cyclohexanone:urea hydrogen peroxide (UHP) was 1:1.3, and the reaction temperature was 56.5 degreesC. Based on our experimental results, it can be safely concluded that there are three reactions in this reaction system, not just two reactions, in which the third reaction is that the acetic acid formed reacts with UHP to form peracetic acid in situ catalyzed by the immobilized lipase. A quadratic polynomial model based on RSM experimental results was developed and the R(2) value of the equation is 0.9988, indicating that model can predict the experimental results with high precision. The experimental results also show that the molar ratio of cyclohexanone to UHP has very significant impact on the yield of sigma-CL (p < .0006). Title: HFIP-Functionalized Co3 O4 Micro-Nano-Octahedra/rGO as a Double-Layer Sensing Material for Chemical Warfare Agents Alali KT, Liu J, Chen R, Liu Q, Zhang H, Li J, Hou J, Li R, Wang J Ref: Chemistry, 25:11892, 2019 : PubMed ESTHER: Alali_2019_Chemistry_25_11892 PubMedSearch: Alali 2019 Chemistry 25 11892 PubMedID: 31309626 Abstract Semiconductor metal oxides (SMO)-based gas-sensing materials suffer from insufficient detection of a specific target gas. Reliable selectivity, high sensitivity, and rapid response-recovery times under various working conditions are the main requirements for optimal gas sensors. Chemical warfare agents (CWA) such as sarin are fatal inhibitors of acetylcholinesterase in the nerve system. So, sensing materials with high sensitivity and selectivity toward CWA are urgently needed. Herein, micro-nano octahedral Co3 O4 functionalized with hexafluoroisopropanol (HFIP) were deposited on a layer of reduced graphene oxide (rGO) as a double-layer sensing materials. The Co3 O4 micro-nano octahedra were synthesized by direct growth from electrospun fiber templates calcined in ambient air. The double-layer rGO/Co3 O4 -HFIP sensing materials presented high selectivity toward DMMP (sarin agent simulant, dimethyl methyl phosphonate) versus rGO/Co3 O4 and Co3 O4 sensors after the exposure to various gases owing to hydrogen bonding between the DMMP molecules and Co3 O4 -HFIP. The rGO/Co3 O4 -HFIP sensors showed high stability with a response signal around 11.8 toward 0.5 ppm DMMP at 125 degrees C, and more than 75 % of the initial response was maintained under a saturated humid environment (85 % relative humidity). These results prove that these double-layer inorganic-organic composite sensing materials are excellent candidates to serve as optimal gas-sensing materials. Title: NOTUM inhibition increases endocortical bone formation and bone strength Brommage R, Liu J, Vogel P, Mseeh F, Thompson AY, Potter DG, Shadoan MK, Hansen GM, Jeter-Jones S and Liu Q <13 more author(s)> Brommage R, Liu J, Vogel P, Mseeh F, Thompson AY, Potter DG, Shadoan MK, Hansen GM, Jeter-Jones S, Cui J, Bright D, Bardenhagen JP, Doree DD, Moverare-Skrtic S, Nilsson KH, Henning P, Lerner UH, Ohlsson C, Sands AT, Tarver JE, Powell DR, Zambrowicz B, Liu Q (- 13) Ref: Bone Res, 7:2, 2019 : PubMed ESTHER: Brommage_2019_Bone.Res_7_2 PubMedSearch: Brommage 2019 Bone.Res 7 2 PubMedID: 30622831 Gene_locus related to this paper: human-NOTUM Inhibitor(s) related to this paper: LP-914822, LP-922056, LP-935001 Abstract The disability, mortality and costs caused by non-vertebral osteoporotic fractures are enormous. Existing osteoporosis therapies are highly effective at reducing vertebral but not non-vertebral fractures. Cortical bone is a major determinant of non-vertebral bone strength. To identify novel osteoporosis drug targets, we phenotyped cortical bone of 3 366 viable mouse strains with global knockouts of druggable genes. Cortical bone thickness was substantially elevated in Notum (-/-) mice. NOTUM is a secreted WNT lipase and we observed high NOTUM expression in cortical bone and osteoblasts but not osteoclasts. Three orally active small molecules and a neutralizing antibody inhibiting NOTUM lipase activity were developed. They increased cortical bone thickness and strength at multiple skeletal sites in both gonadal intact and ovariectomized rodents by stimulating endocortical bone formation. Thus, inhibition of NOTUM activity is a potential novel anabolic therapy for strengthening cortical bone and preventing non-vertebral fractures. Title: Myasthenia gravis and specific immunotherapy: monoclonal antibodies Cai XJ, Li ZW, Xi JY, Song HZ, Liu J, Zhu WH, Guo Y, Jiao Z Ref: Annals of the New York Academy of Sciences, 1452:18, 2019 : PubMed ESTHER: Cai_2019_Ann.N.Y.Acad.Sci_1452_18 PubMedSearch: Cai 2019 Ann.N.Y.Acad.Sci 1452 18 PubMedID: 31393614 Abstract Myasthenia gravis (MG) is an acquired autoimmune disease affecting the postsynaptic membrane of neuromuscular junctions and characterized by antibody-mediated T cell dependence and complement involvement. Cholinesterase inhibitors (e.g., pyridostigmine bromide), glucocorticoids, and azathioprine are currently recommended as first-line treatments for MG, though they have limitations, including potential toxicity and ineffectiveness in patients with refractory MG. In recent years, owing to an increasing understanding of MG pathogenesis the development and execution of clinical trials with novel biologics, including monoclonal antibodies (mAbs) that have demonstrated higher safety and more specificity, provide new opportunities for the treatment of MG. In this article, we review recent advances in MG pathogenesis and the mAbs that have been used for target-specific MG therapy. Title: Different durations of cognitive stimulation therapy for Alzheimer's disease: a systematic review and meta-analysis Chen J, Duan Y, Li H, Lu L, Liu J, Tang C Ref: Clin Interv Aging, 14:1243, 2019 : PubMed ESTHER: Chen_2019_Clin.Interv.Aging_14_1243 PubMedSearch: Chen 2019 Clin.Interv.Aging 14 1243 PubMedID: 31371930 Abstract Objective: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of cognitive stimulation therapy (CST) of different durations for Alzheimer's disease (AD). Methods: A comprehensive search was carried out in three databases. The primary outcome was Mini-Mental State Examination (MMSE) score. We conducted a meta-analysis with Review Manager, version 5.3 and assessed the methodological quality of the included studies using the Cochrane Collaboration Recommendations assessment tool. Results: Treatment effects from the meta-analysis showed that CST plus acetylcholinesterase inhibitors (ChEIs) was better than the control assessed by MMSE. In addition, the meta-analysis indicated that long-term CST was better than short-term or maintenance CST. Conclusion: Our study confirmed that the combination of CST and drug treatment for AD is effective in AD, regardless of whether short-term CST, maintenance CST, or long-term CST is used. The long-term CST appears to be more effective. Title: Tacrine-Hydrogen Sulfide Donor Hybrid Ameliorates Cognitive Impairment in the Aluminum Chloride Mouse Model of Alzheimer's Disease Cheng XJ, Gu JX, Pang YP, Liu J, Xu T, Li XR, Hua YZ, Newell KA, Huang XF and Liu Y <1 more author(s)> Cheng XJ, Gu JX, Pang YP, Liu J, Xu T, Li XR, Hua YZ, Newell KA, Huang XF, Yu Y, Liu Y (- 1) Ref: ACS Chem Neurosci, 10:3500, 2019 : PubMed ESTHER: Cheng_2019_ACS.Chem.Neurosci_10_3500 PubMedSearch: Cheng 2019 ACS.Chem.Neurosci 10 3500 PubMedID: 31244052 Abstract Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by progressive loss of memory and cognitive function, and is associated with the deficiency of synaptic acetylcholine, as well as chronic neuroinflmmation. Tacrine, a potent acetylcholinesterase (AChE) inhibitor, was previously a prescribed clinical therapeutic agent for AD, but it was recently withdrawn because it caused widespread hepatotoxicity. Hydrogen sulfide (H2S) has neuroprotective, hepatoprotective, and anti-inflammatory effects. In this study, we synthesized a new compound, a tacrine-H2S donor hybrid (THS) by introducing H2S-releasing moieties (ACS81) to tacrine. Subsequently, pharmacological and biological evaluations of THS were conducted in the aluminum trichloride (AlCl3)-induced AD mice model. We found that THS (15 mmol/kg) improved cognitive and locomotor activity in AD mice in the step-through test and open field test, respectively. THS showed strong AChE inhibitory activity in the serum and hippocampus of AD mice and induced increased hippocampal H2S levels. Furthermore, THS reduced mRNA expression of the proinflammatory cytokines, TNF-alpha, IL-6, and IL-1beta and increased synapse-associated proteins (synaptophysin and postsynaptic density protein 95) in the hippocampus of AD mice. Importantly, THS, unlike tacrine, did not increase liver transaminases (alanine transaminase and aspartate transaminase) or proinflammatory cytokines, indicating THS is much safer than tacrine. Therefore, the multifunctional effects of this new hybrid compound of tacrine and H2S indicate it is a promising compound for further research into the treatment of AD. Title: Molecular and phenotypic responses of male crucian carp (Carassius auratus) exposed to perfluorooctanoic acid Dong H, Lu G, Yan Z, Liu J, Ji Y Ref: Sci Total Environ, 653:1395, 2019 : PubMed ESTHER: Dong_2019_Sci.Total.Environ_653_1395 PubMedSearch: Dong 2019 Sci.Total.Environ 653 1395 PubMedID: 30759578 Abstract Perfluorooctanoic acid (PFOA) has long been produced and widely used due to its excellent water and oil repellent properties. However, this trend has facilitated to the ubiquitous existence of PFOA in environmental matrix, and the potential ecotoxicity on aquatic organisms has not been fully elucidated. To study the tissue-specific bioconcentration and the nervous system- and energy-related biochemical effects of PFOA, as well as the phenotypic alterations by this chemical, male crucian carp (Carassius auratus) were exposed to gradient concentrations of PFOA (nominal 0.2, 10, 500 and 25,000mug/L) in a flow-through apparatus for 7days. PFOA was enriched in tissues following an order of blood>kidney>/=liver>gill>brain>muscle. The bioconcentration factors ranged from 0.1 to 60.4. Acetylcholinesterase activity in the fish brain was inhibited, while liver carboxylesterase was induced in most cases and attenuated with time. The acyl-CoA oxidase activity was dose-dependently elevated and accompanied by a decline of ATP contents. PFOA treatments also inhibited the activity of the electron transport system (ETS). At the transcriptional level, ETS component complexes II and IV were concordantly depressed, and ATP synthesis was also downregulated. The mRNA level of peroxisome proliferator activated receptor alpha was increasingly upregulated, with related downstream genes upregulated in varying degrees. The phenotypes showed patterns of increased liver pathology and reduced swimming activity. In summary, PFOA leads to adverse effects in Carassius auratus related to multiple aspects, which may be associated with the nervous system, fundamental energy metabolism and other unpredictable factors. The results obtained in this study are expected to help clarify the PFOA toxic mechanisms on energy relevance. Title: Effects of Chlorpyrifos on Cholinesterase and Serine Lipase Activities and Lipid Metabolism in Brains of Rainbow Trout (Oncorhynchus mykiss) Greer JB, Magnuson JT, Hester K, Giroux M, Pope C, Anderson T, Liu J, Dang V, Denslow ND, Schlenk D Ref: Toxicol Sci, 172:146, 2019 : PubMed ESTHER: Greer_2019_Toxicol.Sci_172_146 PubMedSearch: Greer 2019 Toxicol.Sci 172 146 PubMedID: 31359069 Abstract Chlorpyrifos is an organophosphorus insecticide that elicits acute toxicity through inhibition of acetylcholinesterase (AChE), leading to acetylcholine accumulation and prolonged stimulation of cholinergic receptors throughout the central and peripheral nervous systems. Previous studies have indicated that neurodevelopment may also be impaired through alternative pathways, including reduction of cAMP catalyzed downstream events. The upstream initiating events that underlie non-cholinergic neurological actions of chlorpyrifos and other organophosphorus compounds remain unclear. To investigate the potential role of disruption of fatty acid signaling as a mechanism of toxicity, lipid metabolism and fatty acid profiles were examined to identify alterations that may play a critical role in upstream signaling in the CNS. Juvenile rainbow trout were treated for 7 days with nominal chlorpyrifos concentrations previously reported to diminish olfactory responses (10, 20, and 40 microg/L). While lethality was noted higher doses, measured chlorpyrifos concentrations of 1.38 microg/L (nominal concentration 10 microg/L) significantly reduced the activity of AChE and two serine lipases, monoacylglycerol lipase and fatty acid amide hydrolase in the brain. Reductions in lysophosphatidylethanolamines (16:0; 18:0, 18:1, and 22:6) derived from the phosphatidylethanolamines and free fatty acids (Palmitic acid16:0; Linolenic acid18:3; Eicosadienoic acid 20:2; Arachidonic acid 20:4; and Docosahexaenoic acid 22:6) were also noted, suggesting that chlorpyrifos inhibited the metabolism of selected phospholipid signaling precursors at sublethal concentrations. These results indicate that in addition to AChE inhibition, environmentally relevant chlorpyrifos exposure alters serine lipase activity and lipid metabolites in the trout brain, which may compromise neuronal signaling and impact neurobehavioral responses in aquatic animals. Title: Monoacylglycerol Lipase Inactivation by Using URB602 Mitigates Myocardial Damage in a Rat Model of Cardiac Arrest Hai K, Chen G, Gou X, Jang H, Gong D, Cheng Y, Gong C, Li X, Liu Y and Liu J <4 more author(s)> Hai K, Chen G, Gou X, Jang H, Gong D, Cheng Y, Gong C, Li X, Liu Y, Li H, Zhang G, Yang L, Ke B, Liu J (- 4) Ref: Critical Care Medicine, 47:e144, 2019 : PubMed ESTHER: Hai_2019_Crit.Care.Med_47_e144 PubMedSearch: Hai 2019 Crit.Care.Med 47 e144 PubMedID: 30431495 Abstract OBJECTIVES: Monoacylglycerol lipase participates in organ protection by regulating the hydrolysis of the endocannabinoid 2-arachidonoylglycerol. This study investigated whether blocking monoacylglycerol lipase protects against postresuscitation myocardial injury and improves survival in a rat model of cardiac arrest and cardiopulmonary resuscitation. DESIGN: Prospective randomized laboratory study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rat (n = 96). INTERVENTIONS: Rats underwent 8-minute asphyxia-based cardiac arrest and resuscitation. Surviving rats were randomly divided into cardiopulmonary resuscitation + URB602 group, cardiopulmonary resuscitation group, and sham group. One minute after successful resuscitation, rats in the cardiopulmonary resuscitation + URB602 group received a single dose of URB602 (5 mg/kg), a small-molecule monoacylglycerol lipase inhibitor, whereas rats in the cardiopulmonary resuscitation group received an equivalent volume of vehicle solution. The sham rats underwent all of the procedures performed on rats in the cardiopulmonary resuscitation and cardiopulmonary resuscitation + URB602 groups minus cardiac arrest and asphyxia. MEASUREMENTS AND MAIN RESULTS: Survival was recorded 168 hours after the return of spontaneous circulation (n = 22 in each group). Compared with vehicle treatment (31.8%), URB602 treatment markedly improved survival (63.6%) 168 hours after cardiopulmonary resuscitation. Next, we used additional surviving rats to evaluate myocardial and mitochondrial injury 6 hours after return of spontaneous circulation, and we found that URB602 significantly reduced myocardial injury and prevented myocardial mitochondrial damage. In addition, URB602 attenuated the dysregulation of endocannabinoid and eicosanoid metabolism 6 hours after return of spontaneous circulation and prevented the acceleration of mitochondrial permeability transition 15 minutes after return of spontaneous circulation. CONCLUSIONS: Monoacylglycerol lipase blockade may reduce myocardial and mitochondrial injury and significantly improve the resuscitation effect after cardiac arrest and cardiopulmonary resuscitation. Title: Novel chromanone-dithiocarbamate hybrids as multifunctional AChE inhibitors with beta-amyloid anti-aggregation properties for the treatment of Alzheimer's disease Jiang N, Ding J, Liu J, Sun X, Zhang Z, Mo Z, Li X, Yin H, Tang W, Xie SS Ref: Bioorg Chem, 89:103027, 2019 : PubMed ESTHER: Jiang_2019_Bioorg.Chem_89_103027 PubMedSearch: Jiang 2019 Bioorg.Chem 89 103027 PubMedID: 31176237 Abstract By connecting chromanone with dithiocarbamate moieties through flexible linkers, a series of hybrids as novel multifunctional AChE inhibitors have been designed and synthesized. Most of these compounds displayed strong and excellently selective inhibition to eeAChE as well as potent inhibition to self- and AChE-induced Abeta aggregation. Among them, compound 6c showed the best activity to inhibit eeAChE (IC50=0.10muM) and AChE-induced Abeta aggregation (33.02% at 100muM), and could effectively inhibit self-induced Abeta aggregation (38.25% at 25muM). Kinetic analysis and docking study indicated that compound 6c could target both the CAS and PAS, suggesting that it was a dual binding site inhibitor for AChE. Besides, it exhibited good ability to penetrate the BBB and low neurotoxicity in SH-SY5Y cells. More importantly, compound 6c was well tolerated in mice (2500mg/kg, po) and could attenuate the memory impairment in a scopolamine-induced mouse model. Overall, these results highlight 6c as a promising multifunctional agent for treating AD and also demonstrate that the dithiocarbamate is a valid scaffold for design of multifunctional AChE inhibitors. Title: A novel ABHD12 nonsense variant in Usher syndrome type 3 family with genotype-phenotype spectrum review Li T, Feng Y, Liu Y, He C, Liu J, Chen H, Deng Y, Li M, Li W and Ling J <8 more author(s)> Li T, Feng Y, Liu Y, He C, Liu J, Chen H, Deng Y, Li M, Li W, Song J, Niu Z, Sang S, Wen J, Men M, Chen X, Li J, Liu X, Ling J (- 8) Ref: Gene, 704:113, 2019 : PubMed ESTHER: Li_2019_Gene_704_113 PubMedSearch: Li 2019 Gene 704 113 PubMedID: 30974196 Gene_locus related to this paper: human-ABHD12 Abstract Usher syndrome (USH) is a clinically common autosomal recessive disorder characterized by retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction. In this study, we identified a Hunan family of Chinese descent with two affected members clinically diagnosed with Usher syndrome type 3 (USH3) displaying hearing, visual acuity, and olfactory decline. Whole-exome sequencing (WES) identified a nonsense variant in ABHD12 gene that was confirmed to be segregated in this family by Sanger sequencing and exhibited a recessive inheritance pattern. In this family, two patients carried homozygous variant in the ABHD12 (NM_015600: c.249C>G). Mutation of ABHD12, an enzyme that hydrolyzes an endocannabinoid lipid transmitter, caused incomplete PHARC syndrome, as demonstrated in previous reports. Therefore, we also conducted a summary based on variants in ABHD12 in PHARC patients, and in PHARC patients showing that there was no obvious correlation between the genotype and phenotype. We believe that this should be considered during the differential diagnosis of USH. Our findings predicted the potential function of this gene in the development of hearing and vision loss, particularly with regard to impaired signal transmission, and identified a novel nonsense variant to expand the variant spectrum in ABHD12. Title: Pediatric reference intervals of liver and renal function tests from birth to adolescence in Chinese children as performed on the Olympus AU5400 Liu J, Dai Y, Lee Y, Yuan E, Wang Q, Wang L, Su Y Ref: Clinica Chimica Acta, 490:142, 2019 : PubMed ESTHER: Liu_2019_Clin.Chim.Acta_490_142 PubMedSearch: Liu 2019 Clin.Chim.Acta 490 142 PubMedID: 30611730 Abstract BACKGROUND: The growth and development of children and adolescents influence values of liver and renal function tests. The purpose of this study was to determine age- and gender-specific reference intervals for liver and renal function tests in apparently healthy Chinese children and adolescents. METHODS: A total of 63,086 apparently healthy children and adolescents (0-15 y) were chosen as reference individuals in this study. The 15 biochemical analytes relating to liver and renal function were measured using an Olympus AU5400 analyzer. Reference intervals were partitioned according to age and/or gender subgroups using the Harris and Boyd's method and established using non-parametric methods. RESULTS: Our results showed that all analytes except for cholinesterase (ChE) and alpha1-microglobulin (alpha1-MG) required partitioning by age. Gender partitions were also required for alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), creatinine (Cre), and uric acid (UA). Age- and gender-appropriate reference intervals for liver and renal function tests were established for apparently healthy Chinese children and adolescents. CONCLUSIONS: When establishing pediatric reference intervals, partitioning by age and/or gender is essential. Those reference intervals can be adopted in other clinical laboratories after appropriate validation. Title: Systematic exploration of Astragalus membranaceus and Panax ginseng as immune regulators: Insights from the comparative biological and computational analysis Liu J, Nile SH, Xu G, Wang Y, Kai G Ref: Phytomedicine, :153077, 2019 : PubMed ESTHER: Liu_2019_Phytomedicine__153077 PubMedSearch: Liu 2019 Phytomedicine 153077 PubMedID: 31477352 Abstract BACKGROUND: Immune system plays a decisive role for defending various pathogenic microorganisms. Astragalus membranaceus (AM) and Panax ginseng (PG) are two tonic herbs used in traditional Chinese medicine (TCM) as immune booster and help to control diseases with their healthy synergistic effect on immune system. PURPOSE: This study was aimed to investigate the promote effect and molecular mechanisms of AM and PG on immune system as booster and to control the target diseases using animal and computational systematic study. METHODS: Computational models including absorption, distribution, metabolism, and elimination (ADME) with weighted ensemble similarity (WES) algorithm-based models and ClueGo network analysis were used to find the potential bioactive compounds targets and pathways, which were responsible for immune regulation. Viscera index analysis, proliferation activity of splenic lymphocytes and cytotoxic activity of NK cells assays were performed to validate the effect of AM and PG on immune system of long-term administrated mice. Metabonomic study of mice plasma was conducted to investigate effect of AM and PG on the endogenous metabolic perturbations, together with correlation analysis. RESULTS: AM and PG simultaneously showed the ability to strengthen the immune system function including enhancement of spleen and thymus index, proliferation of splenic lymphocytes and cytotoxic activity of NK cells. Besides, the different molecular mechanisms of AM and PG on immune regulation were also investigated by analyzing the potential bioactive compounds, enzymes actions and pathways. Quercetin, formononetin and kaempferol were the main immune-related compounds in AM, while ginsenoside Ra1, ginsenoside Rh1 and kaempferol in PG. About 10 target proteins were found close to immune regulation, including acetylcholinesterase (ACHE, common target in AM and PG), sphingosine kinase 1(SPHK1), cytidine deaminase (CDA), and Choline O-acetyltransferase (CHAT). Glycerophospholipid metabolism was regulated in both AM and PG groups. Pyrimidine metabolism and sphingolipid metabolism were considered as the special pathway in AM groups. Energy metabolism and glycerolipid metabolism were the special pathways in PG groups. CONCLUSION: A novel comprehensive molecular mechanism analysis method was established and applied to clarify the scientific connotation of AM and PG as immune regulation, with similar herbal tonic effect provided in clinical practice of TCM, which can provide a new line of research for drug development (immune booster) using AM and PG. Title: Pharmacological treatment of apathy in Lewy body disorders: A systematic review Liu J, Cooper CA, Weintraub D, Dahodwala N Ref: Parkinsonism Relat Disord, 60:14, 2019 : PubMed ESTHER: Liu_2019_Parkinsonism.Relat.Disord_60_14 PubMedSearch: Liu 2019 Parkinsonism.Relat.Disord 60 14 PubMedID: 30470658 Abstract INTRODUCTION: There are no approved treatments for apathy, a frequent and incapacitating symptom in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We reviewed the literature on the pharmacological treatment of apathy in PD and DLB to inform practice and future research. METHOD: We searched PubMed and PsycINFO using the terms "apathy", "treatment", and "Parkinson" or "Lewy body (bodies)." The results were filtered for "clinical trials" and "case reports." We included articles if apathy was measured as an outcome measure, before and after treatment. References of included articles were also reviewed. RESULTS: The PD search identified 19 articles: 13 randomized control trials (RCTs), 4 open-label studies, 1 case series, and 1 case report. Apathy was the primary outcome in 11 out of 19 studies. A decrease in apathy ratings was seen in 14 of the 19 studies. Of these 14 studies, 9 investigated medications with some dopaminergic effect. Three investigated acetylcholinesterase inhibitors (AChEIs) and found benefit in improving apathy. The DLB search identified 4 articles: 1 RCT, 2 open-label studies, and 1 case series. All 4 studies demonstrated decreased apathy and investigated AChEIs. CONCLUSIONS: We identified 23 studies that assessed the pharmacological treatment of apathy. In PD, agents with dopaminergic activity were the most studied and appeared to have the most benefit. AChEIs also appeared to have benefit in both PD and DLB but were less studied. Future studies of apathy treatment would benefit from larger samples and standardized assessments of apathy to define study populations and endpoints. Title: Bioconcentration of the antiepileptic drug carbamazepine and its physiological and biochemical effects on Daphnia magna Nkoom M, Lu G, Liu J, Yang H, Dong H Ref: Ecotoxicology & Environmental Safety, 172:11, 2019 : PubMed ESTHER: Nkoom_2019_Ecotoxicol.Environ.Saf_172_11 PubMedSearch: Nkoom 2019 Ecotoxicol.Environ.Saf 172 11 PubMedID: 30669069 Abstract Owing to its persistence, carbamazepine an antiepileptic drug is regularly detected in the aquatic environment. The motive for our research was to assess the bioconcentration, physiological and biochemical effects of carbamazepine in Daphnia magna. A 48h aqueous exposure of carbamazepine yielded bioconcentration factors of 202.56 and 19.95 in Daphnia magna for the respective nominal treatments of 5 and 100microg/L. Apparently, the inhibition of the capability of Daphnia magna to obtain food attributable to carbamazepine exposure will reduce their fitness to reproduce as well as to grow. Also, a significant alteration in the phototactic behaviour of Daphnia magna exposed to carbamazepine is maladaptive since it will increase their chance of being preyed upon in the surface water during daylight. Again, a significant decline in the acetylcholinesterase activity observed herein brings to light the neurotoxicity of carbamazepine to Daphnia magna. Moreover, significant inhibition of the superoxide dismutase, catalase and glutathione reductase activities coupled with the simultaneous induction of the malondialdehyde content imply that carbamazepine evoked a life-threatening oxidative stress that overpowered the antioxidant defence system of Daphnia magna. These observations confirm that carbamazepine can accumulate and consequently cause negative physiological and biochemical changes to wild Daphnia magna populations. Title: Bioconcentration, behavioral, and biochemical effects of the non-steroidal anti-inflammatory drug diclofenac in Daphnia magna Nkoom M, Lu G, Liu J, Dong H, Yang H Ref: Environ Sci Pollut Res Int, 26:5704, 2019 : PubMed ESTHER: Nkoom_2019_Environ.Sci.Pollut.Res.Int_26_5704 PubMedSearch: Nkoom 2019 Environ.Sci.Pollut.Res.Int 26 5704 PubMedID: 30612359 Abstract The non-steroidal anti-inflammatory drug (NSAID) diclofenac is one of the most frequently studied as well as controversially discussed pharmaceutically active drug on the subject of its relevance to the environment. This study was conducted to assess the bioconcentration potential of diclofenac and its behavioral and biochemical effects in Daphnia magna. The bioconcentration factors of diclofenac determined after 48 h of aqueous exposure in Daphnia magna were 70.94 and 8.02 for the nominal exposure concentrations of 5 and 100 mug/L, respectively. Diclofenac exposure obviously decreased the filtration and ingestion rates of the daphnids. A significant increase of the acetylcholinesterase activity that was observed in this study indicates that diclofenac might not have neurobehavioral toxicity in Daphnia magna. Significant induction of malondialdehyde content is an indication of overproduction of reactive oxygen species leading to oxidative damage in daphnids after diclofenac exposure. Moreover, significant inhibition of the superoxide dismutase, catalase, and glutathione reductase activities implies that the antioxidant defense system of Daphnia magna was overwhelmed. Also, significant inhibition of glutathione s-transferase activity might point to the fact that the enzyme was not capable to detoxify diclofenac in Daphnia magna. These findings indicate that diclofenac can accumulate and consequently stimulate behavioral and biochemical disturbances in Daphnia magna. Title: Anti-inflammatory treatment with a soluble epoxide hydrolase inhibitor attenuates seizures and epilepsy-associated depression in the LiCl-pilocarpine post-status epilepticus rat model Shen Y, Peng W, Chen Q, Hammock BD, Liu J, Li D, Yang J, Ding J, Wang X Ref: Brain Behavior & Immunity, 81:535, 2019 : PubMed ESTHER: Shen_2019_Brain.Behav.Immun_81_535 PubMedSearch: Shen 2019 Brain.Behav.Immun 81 535 PubMedID: 31306773 Abstract PURPOSE: This study aimed to investigate whether 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide hydrolase inhibitor with anti-inflammatory effects, could alleviate spontaneous recurrent seizures (SRS) and epilepsy-associated depressive behaviours in the lithium chloride (LiCl)-pilocarpine-induced post-status epilepticus (SE) rat model. METHODS: The rats were intraperitoneally (IP) injected with LiCl (127mg/kg) and pilocarpine (40mg/kg) to induce SE. A video surveillance system was used to monitor SRS in the post-SE model for 6weeks (from the onset of the 2nd week to the end of the 7th week after SE induction). TPPU (0.1mg/kg/d) was intragastrically given for 4weeks from the 21st day after SE induction in the SRS+0.1 TPPU group. The SRS+PEG 400 group was given the vehicle (40% polyethylene glycol 400) instead, and the control group was given LiCl and PEG 400 but not pilocarpine. The sucrose preference test (SPT) and forced swim test (FST) were conducted to evaluate the depression-like behaviours of rats. Immunofluorescent staining, enzyme-linked immunosorbent assay, and western blot analysis were performed to measure astrocytic and microglial gliosis, neuronal loss, and levels of soluble epoxide hydrolase (sEH), cytokines [tumour necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6], and cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB). RESULTS: The frequency of SRS was significantly decreased at 6weeks and 7weeks after SE induction in the 0.1TPP U group compared with the SRS+PEG 400 group. The immobility time (IMT) evaluated by FST was significantly decreased, whereas the climbing time (CMT) was increased, and the sucrose preference rate (SPR) evaluated by SPT was in an increasing trend. The levels of sEH, TNF-alpha, IL-1beta, and IL-6 in the hippocampus (Hip) and prefrontal cortex (PFC) were all significantly increased in the SRS+PEG 400 group compared with the control group; neuronal loss, astrogliosis, and microglial activation were also observed. The astrocytic and microglial activation and levels of the pro-inflammatory cytokines in the Hip and PFC were significantly attenuated in the TPPU group compared with the SRS+PEG 400 group; moreover, neuronal loss and the decreased CREB expression were significantly alleviated as well. CONCLUSION: TPPU treatment after SE attenuates SRS and epilepsy-associated depressive behaviours in the LiCl-pilocarpine induced post-SE rat model, and it also exerts anti-inflammatory effects in the brain. Our findings suggest a new therapeutic approach for epilepsy and its comorbidities, especially depression. Title: Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells Wan L, Xia T, Du Y, Liu J, Xie Y, Zhang Y, Guan F, Wu J, Wang X, Shi C Ref: FASEB Journal, :fj201802675R, 2019 : PubMed ESTHER: Wan_2019_FASEB.J__fj201802675R PubMedSearch: Wan 2019 FASEB.J fj201802675R PubMedID: 30970216 Abstract The mechanism of exosomes derived from activated hepatic stellate cells (HSCs) involved in liver fibrosis is poorly understood. We previously reported that hypoxia-inducible factor 1 (Hif-1) regulated HSC activation, and, therefore, we investigated in current work whether Hif-1 regulates exosome secretion and the metabolic switch of HSCs, thus affecting the metabolism of liver nonparenchymal cells. In this study, the characteristics of exosomes from HSCs were assessed via electron microscopy, Western blot analysis, and acetylcholinesterase activity. Confocal microscopy was used to measure the uptake of exosomes by quiescent HSCs, Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs). Hif-1alpha was inhibited via 2-ME or specific small interfering RNAs to investigate its role in exosomes derived from HSCs. It was determined that glucose transporter 1 and pyruvate kinase M2 were increasingly expressed in fibrotic liver samples, cell lysates, and exosomes derived from activated HSCs. Exosomes released from HSCs were associated with activation and glucose uptake of HSCs. Delivery of exosomes from activated HSCs induced glycolysis of quiescent HSCs, KCs, and LSECs. Disruption of Hif-1 expression suppressed the glycolysis effect delivered by exosomes. Conclusively, our results demonstrated that exosomes secreted by activated HSCs affect the metabolic switch of liver nonparenchymal cells via delivery of glycolysis-related proteins. These findings represent a novel mechanism that contributes to liver fibrosis and has significant implications for new diagnosis and treatment of liver diseases.-Wan, L., Xia, T., Du, Y., Liu, J., Xie, Y., Zhang, Y., Guan, F., Wu, J., Wang, X., Shi, C. Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exomes in metabolic switch of liver nonparenchymal cells. Title: Musa balbisiana genome reveals subgenome evolution and functional divergence Wang Z, Miao H, Liu J, Xu B, Yao X, Xu C, Zhao S, Fang X, Jia C and Jin Z <30 more author(s)> Wang Z, Miao H, Liu J, Xu B, Yao X, Xu C, Zhao S, Fang X, Jia C, Wang J, Zhang J, Li J, Xu Y, Ma W, Wu Z, Yu L, Yang Y, Liu C, Guo Y, Sun S, Baurens FC, Martin G, Salmon F, Garsmeur O, Yahiaoui N, Hervouet C, Rouard M, Laboureau N, Habas R, Ricci S, Peng M, Guo A, Xie J, Li Y, Ding Z, Yan Y, Tie W, D'Hont A, Hu W, Jin Z (- 30) Ref: Nat Plants, 5:810, 2019 : PubMed ESTHER: Wang_2019_Nat.Plants_5_810 PubMedSearch: Wang 2019 Nat.Plants 5 810 PubMedID: 31308504 Gene_locus related to this paper: musam-m0tuu7, musam-a0a804kav5 Abstract Banana cultivars (Musa ssp.) are diploid, triploid and tetraploid hybrids derived from Musa acuminata and Musa balbisiana. We presented a high-quality draft genome assembly of M. balbisiana with 430 Mb (87%) assembled into 11 chromosomes. We identified that the recent divergence of M. acuminata (A-genome) and M. balbisiana (B-genome) occurred after lineage-specific whole-genome duplication, and that the B-genome may be more sensitive to the fractionation process compared to the A-genome. Homoeologous exchanges occurred frequently between A- and B-subgenomes in allopolyploids. Genomic variation within progenitors resulted in functional divergence of subgenomes. Global homoeologue expression dominance occurred between subgenomes of the allotriploid. Gene families related to ethylene biosynthesis and starch metabolism exhibited significant expansion at the pathway level and wide homoeologue expression dominance in the B-subgenome of the allotriploid. The independent origin of 1-aminocyclopropane-1-carboxylic acid oxidase (ACO) homoeologue gene pairs and tandem duplication-driven expansion of ACO genes in the B-subgenome contributed to rapid and major ethylene production post-harvest in allotriploid banana fruits. The findings of this study provide greater context for understanding fruit biology, and aid the development of tools for breeding optimal banana cultivars. Title: Latrophilin mediates insecticides susceptibility and fecundity through two carboxylesterases, esterase4 and esterase6, in Tribolium castaneum Wei L, Gao S, Xiong W, Liu J, Mao J, Lu Y, Song X, Li B Ref: Bull Entomol Res, :1, 2019 : PubMed ESTHER: Wei_2019_Bull.Entomol.Res__1 PubMedSearch: Wei 2019 Bull.Entomol.Res 1 PubMedID: 30789108 Abstract Latrophilin (LPH) is known as an adhesion G-protein-coupled receptor which involved in multiple physiological processes in organisms. Previous studies showed that lph not only involved the susceptibility to anticholinesterase insecticides but also affected fecundity in Tribolium castaneum. However, its regulatory mechanisms in these biological processes are still not clear. Here, we identified two potential downstream carboxylesterase (cce) genes of Tclph, esterase4 and esterase6, and further characterized their interactions with Tclph. After treatment of T. castaneum larvae with carbofuran or dichlorvos insecticides, the transcript levels of Tcest4 and Tcest6 were significantly induced from 12 to 72 h. RNAi against Tcest4 or Tcest6 led to the higher mortality compared with the controls after the insecticides treatment, suggesting that these two genes play a vital role in detoxification of insecticides in T. castaneum. Furthermore, with insecticides exposure to Tclph knockdown beetles, the expression of Tcest4 was upregulated but Tcest6 was downregulated, indicating that beetles existed a compensatory response against the insecticides. Additionally, RNAi of Tcest6 resulted in 43% reductions in female egg laying and completely inhibited egg hatching, which showed the similar phenotype as that of Tclph knockdown. These results indicated that Tclph affected fecundity by positively regulating Tcest6 expression. Our findings will provide a new insight into the molecular mechanisms of Tclph involved in physiological functions in T. castaneum. Title: Hepatoprotective Potential of Partially Hydrolyzed Guar Gum against Acute Alcohol-Induced Liver Injury in Vitro and Vivo Wu C, Liu J, Tang Y, Li Y, Yan Q, Jiang Z Ref: Nutrients, 11:, 2019 : PubMed ESTHER: Wu_2019_Nutrients_11_ PubMedSearch: Wu 2019 Nutrients 11 PubMedID: 31035540 Abstract Natural polysaccharides, particularly galactomannans, are potential candidates for treatment of alcoholic liver diseases (ALD). However, applications are restricted due to the physicochemical properties associated with the high molecular weight. In this work, guar gum galactomannans were partially hydrolyzed by beta-mannanase, and the molecular mechanisms of hepatoprotective effects were elucidated both in vitro and in vivo. Release of lactate dehydrogenase and cytochrome C were attenuated by partially hydrolyzed guar gum (PHGG) in HepG2 cells, due to protected cell and mitochondrial membrane integrity. PHGG co-administration decreased serum amino transaminases and cholinesterase levels of acute alcohol intoxicated mice, while hepatic pathologic morphology was depleted. Activity of superoxide dismutase, catalase, and glutathione peroxidase was recovered to 198.2, 34.5, 236.0 U/mg protein, respectively, while malondialdehyde level was decreased by 76.3% (PHGG, 1000 mg/kgday). Co-administration of PHGG induced a 4.4-fold increment of p-AMPK expression, and lipid metabolism was mediated. PHGG alleviated toll-like-receptor-4-mediated inflammation via the signaling cascade of MyD88 and IkappaBalpha, decreasing cytokine production. Moreover, mediated expression of Bcl-2 and Bax was responsible for inhibited acute alcohol-induced apoptosis with suppressed cleavage of caspase 3 and PARP. Findings gained suggest that PHGG can be used as functional food supplement for the treatment of acute alcohol-induced liver injury. Title: HEV-LFS : A novel scoring model for patients with hepatitis E virus-related liver failure Wu J, Guo N, Zhang X, Xiong C, Liu J, Xu Y, Fan J, Yu J, Zhao X and Li L <4 more author(s)> Wu J, Guo N, Zhang X, Xiong C, Liu J, Xu Y, Fan J, Yu J, Zhao X, Liu B, Wang W, Zhang J, Cao H, Li L (- 4) Ref: J Viral Hepat, 26:1334, 2019 : PubMed ESTHER: Wu_2019_J.Viral.Hepat_26_1334 PubMedSearch: Wu 2019 J.Viral.Hepat 26 1334 PubMedID: 31294523 Abstract A noninvasive assessment method for acute or acute-on-chronic liver failure in patients with hepatitis E virus (HEV) infection is urgently needed. We aimed to develop a scoring model for diagnosing HEV patients who developed liver failure (HEV-LF) at different stages. A cross-sectional set of 350 HEV-LF patients were identified and enrolled, and the Guidelines for Diagnosis and Treatment of Liver Failure in China and the Asian Pacific Association for the Study of the Liver were adopted as references. HEV-LFS , a novel scoring model that incorporates data on cholinesterase (CHE), urea nitrogen (UREA), platelets and international normalized ratio was developed using a derived dataset. For diagnosing HEV-LF stages F1 to F3, the HEV-LFS scoring model (F1: 0.87; F2: 0.90; F3: 0.92) had a significantly higher AUROC than did the CLIF-C-ACLFs (F1: 0.65; F2: 0.56; F3: 0.51) and iMELD (F1: 0.70; F2: 0.57; F3: 0.51) scoring models, of which the HEV-LFS scoring model had the best sensitivity and specificity. In addition, the HEV-LFS scoring model was correlated with mortality, length of hospitalization and ICU stay. As the GDTLF score increased, the CHE level decreased and the UREA increased gradually. Encouragingly, a calibration curve showed good agreement between the derivation and validation sets. Notably, we also established a nomogram to facilitate the practical operability of the HEV-LFS scoring model in clinical settings. In conclusion, both CHE and UREA may be indicators for HEV-LF patients. The HEV-LFS scoring model is an efficient and accessible model for classifying HEV-LF at different stages. Title: Fluevirines E and F, two new alkaloids from Flueggea virosa Yang X, Liu J, Huo Z, Yuwen H, Li Y, Zhang Y Ref: Nat Prod Res, :1, 2019 : PubMed ESTHER: Yang_2019_Nat.Prod.Res__1 PubMedSearch: Yang 2019 Nat.Prod.Res 1 PubMedID: 30721084 Abstract Two new alkaloids, fluevirines E (1) and F (2), along with six known Securinega alkaloids, were isolated from the methanol extract of the twigs and leaves of Flueggea virosa. The structures and absolute configurations of the new compounds were elucidated by means of MS, NMR, and ECD analyses. Compound 1 is a new dimeric indole alkaloid while 2 is a new securinega-type alkaloid. The in vitro cytotoxic activities of the isolated alkaloids against several human cancer cell lines and their acetylcholinesterase inhibitory activity were also evaluated. Title: Bisphenol F-Induced Neurotoxicity toward Zebrafish Embryos Yuan L, Qian L, Qian Y, Liu J, Yang K, Huang Y, Wang C, Li Y, Mu X Ref: Environ Sci Technol, 53:14638, 2019 : PubMed ESTHER: Yuan_2019_Environ.Sci.Technol_53_14638 PubMedSearch: Yuan 2019 Environ.Sci.Technol 53 14638 PubMedID: 31702913 Abstract In this study, the influence of bisphenol F (BPF) toward central nervous system (CNS) was assessed using zebrafish embryos. We found that BPF could induce significant neurotoxicity toward zebrafish embryos, including inhibited locomotion, reduced moving distance, and CNS cell apoptosis at an effective concentration of 0.0005 mg/L. Immunofluorescence assay showed that both microglia and astrocyte in zebrafish brain were significantly activated by BPF, indicating the existence of neuroinflammatory response. Peripheral motor neuron development was significantly inhibited by BPF at 72 hpf. RNA-seq data indicated that neuronal developmental processes and cell apoptosis pathways were significantly affected by BPF exposure, which was consistent with the phenotypic results. Chip-seq assay implied that the transcriptional changes were not mediated by ERalpha. Additionally, no significant change was found in neurotransmitter levels (5-hydroxytryptamine, dopamine, and acetylcholine) or acetylcholinesterase (Ache) enzyme activity after BPF exposure, indicating that BPF may not affect neurotransmission. In conclusion, BPF could lead to abnormal neural outcomes during zebrafish early life stage through inducing neuroinflammation and CNS cell apoptosis even at environmentally relevant concentration. Title: A Review of Danshen Combined with Clopidogrel in the Treatment of Coronary Heart Disease Zhang Z, Wang Y, Tan W, Wang S, Liu J, Liu X, Wang X, Gao X Ref: Evid Based Complement Alternat Med, 2019:2721413, 2019 : PubMed ESTHER: Zhang_2019_Evid.Based.Complement.Alternat.Med_2019_2721413 PubMedSearch: Zhang 2019 Evid.Based.Complement.Alternat.Med 2019 2721413 PubMedID: 30911318 Abstract Objective: Danshen, the root of Salvia miltiorrhiza Bunge, is a traditional herbal medicine in China, which has been used to treat irregular menstruation, cold hernia, and abdominal pain for thousands of years. Danshen is frequently used in combination with drugs to treat cardiovascular diseases. Clopidogrel is a commonly used drug for treating coronary heart disease, but clopidogrel resistance restricts its development. Therefore, the clinical efficacy of Danshen combined with clopidogrel treats coronary heart disease and the relationship between Danshen and clopidogrel metabolism enzymes is suggested for future investigations. Materials and Methods: The information was collected by searching online databases, and the RevMan 5.3 software was used to perform meta-analysis. Results: Twenty-two articles, including 2587 patients, were enrolled after the evaluation. Meta-analysis showed that Danshen combined with clopidogrel was more effective than clopidogrel alone in treating coronary heart disease by improving clinical curative effect, reducing the frequency of angina pectoris, improving electrocardiogram results, shortening the duration of angina pectoris, and easing adverse reactions. Danshen inhibited carboxylesterase 1 and most enzyme of cytochrome P450, especially cytochrome P450 1A2, which may affect the metabolism of clopidogrel. Conclusion: Danshen combined with clopidogrel may compensate for individual differences of clopidogrel resistance among individuals in the treatment of coronary heart disease. Meanwhile, the inhibitory effect of Danshen on cytochrome P450 and carboxylesterase 1 could be partly responsible for the synergistic and attenuating effects of Danshen combined with clopidogrel. Title: Safety, efficacy, and pharmacokinetics of pradefovir for the treatment of chronic hepatitis B infection Zhang H, Liu J, Zhu X, Li X, Jin W, Chen H, Wu M, Li C, Liu C and Ding Y <1 more author(s)> Zhang H, Liu J, Zhu X, Li X, Jin W, Chen H, Wu M, Li C, Liu C, JunqiNiu, Ding Y (- 1) Ref: Antiviral Res, :104693, 2019 : PubMed ESTHER: Zhang_2019_Antiviral.Res__104693 PubMedSearch: Zhang 2019 Antiviral.Res 104693 PubMedID: 31838002 Abstract BACKGROUND & AIMS: Pradefovir is a liver targeted novel prodrug of adefovir (PMEA) developed to provide higher antiviral activity with reduced systemic toxicities. This study evaluated the tolerability, pharmacokinetics, and antiviral activity of pradefovir in patients with chronic hepatitis B (CHB) virus infection. METHODS: Non-cirrhotic, treatment-naive subjects with CHB were divided into five groups (10 patients each) and randomized within each group in a ratio of 6:2:2 to receive an ascending dose of 30, 60, 75, 90, or 120mg pradefovir, 10mg adefovir dipivoxil (ADV), or 300mg tenofovir disoproxil fumarate (TDF) once a day for 28 days. RESULTS: A total of 51 subjects were randomized and 49 subjects completed the study. The groups were well matched and included 39 males, of whom 71% were hepatitis B e-antigen-negative with a mean hepatitis B virus (HBV) DNA level of 6.4-7.16 log10 IU/mL. No subject experienced a serious adverse event or nephrotoxicity. The most frequently reported adverse event was asymptomatic reduction in blood cholinesterase levels in the pradefovir group which recovered without any treatment about 13+/-7 days after drug discontinuation. This adverse event was not observed in the ADV and TDF groups. The mean changes in serum HBV DNA were -2.78, -2.77, -3.08, -3.18, -3.44, -2.34, and -3.07 log10 IU/mL at 30, 60, 75, 90, and 120mg pradefovir, 10mg ADV and 300mg TDF, respectively, with plateau levels reached with 60mg pradefovir. Pradefovir and its metabolite PMEA showed linear pharmacokinetics proportional to the dose. The half-life of PMEA in the pradefovir group was 11.47-17.63h. CONCLUSIONS: Short-term use of pradefovir was well tolerated. A decline in HBV DNA levels was superior to TDF at higher doses of pradefovir. 30-60mg pradefovir is recommended for CHB treatment. CLINICAL TRIAL NUMBER: CTR20150224. Title: Kinetic model of the enzymatic Michael addition for synthesis of mitomycin analogs catalyzed by immobilized lipase from T. laibacchii Zhang Y, Zhao Y, Gao X, Jiang W, Li Z, Yao Q, Yang F, Wang F, Liu J Ref: Molecular Catalysis, 466:146, 2019 : PubMed ESTHER: Zhang_2019_Mol.Catal_466_146 PubMedSearch: Zhang 2019 Mol.Catal 466 146 Abstract The present study investigates the kinetic model of the enzymatic Michael addition of butylamine to 2-methyl-1,4-benzoquinone to form 2-methyl-3-n-butylaminoyl-1-hydro-4-quinone in citrate buffer solution (pH 7.0). The yield of the product of 98% was achieved, mainly due to the excellent regioselectivity of immobilized lipase from T. laibacchii. The immobilized preparation used here was obtained by a method of purification and in situ immobilization. Through the purification using a PEG 4000/ K2HPO4 aqueous two-phase system (ATPS), the T. laibacchii lipase was partitioned predominantly in the PEG-rich top phase where diatomite was added to achieve in situ immobilization via interfacial activation on the hydrophobic support. A proposed reaction mechanism of the Michael addition involves (1) the oxyanion hole polarizes the alpha,beta-unsaturated carbonyl of 2-methyl-1,4 -benzoquinone, increasing its electrophilic ability, (2) the catalytic histidine deprotonates the nucleophile n-butyl amine. A modified sequential mechanism including ordered and random sequential bi-bi was proposed for the first, and it is beneficial to add these modification mechanisms to the family of enzyme complex reaction mechanism because the mechanism is partly expanded. The kinetic parameters were directly obtained by combining the numerical integration toolbox ode45 to solve differential equations and the nonlinear optimization toolbox fmincon for error minimizing objective function. A very satisfactory agreement between experimental data and model results was obtained based on the modified random bi-bi mechanism, implying that the enzymatic Michael addition may follow the modified random bi-bi mechanism. The mass transfer limitations were investigated, and it is found that both internal and external mass transfer limitations could be ignored. Title: Urinary biomarkers for assessment of human exposure to monomeric aryl phosphate flame retardants Zhao F, Kang Q, Zhang X, Liu J, Hu J Ref: Environ Int, 124:259, 2019 : PubMed ESTHER: Zhao_2019_Environ.Int_124_259 PubMedSearch: Zhao 2019 Environ.Int 124 259 PubMedID: 30660026 Inhibitor(s) related to this paper: EHDPP Abstract While monomeric aryl organophosphate flame retardants (m-aryl-OPFRs) are used worldwide in a variety of consumer products, specific biomarkers for epidemiologic studies are lacking. To explore the potential of urinary hydroxylated metabolites of m-aryl-OPFRs as the biomarkers, we detected triphenyl phosphate (TPHP), 2-ethylhexyl diphenyl phosphate (EHDPP), and tricresyl phosphate (TCrP) in 259 whole blood samples and their 5 hydroxylated and 2 diester metabolites in the paired urine samples from the general population. 2-Ethyl-5-hydroxyhexyl diphenyl phosphate (5-OH-EHDPP), 4-hydroxyphenyl diphenyl phosphate (4-OH-TPHP), and 3-hydroxy-4-methylphenyl di-p-tolyl phosphate (3-OH-MDTP) were detected in >80% of urine samples after enzymatic hydrolysis of conjugates, and their concentrations showed significant positive correlations with the blood concentrations of their corresponding parent compounds, respectively. To characterize the temporal reliability, the m-aryl-OPFRs metabolites were also determined in urine samples repeated nine times from six volunteers over 3 months. Urinary 5-OH-EHDPP showed strong temporal reliability (creatinine-corrected intraclass correlation coefficients (ICCs), 0.77; 95% confidence interval [CI], 0.58 to 0.90), and urinary 3-OH-MDTP (creatinine-corrected ICC, 0.52; 95% CI, 0.37 to 0.87) and 4-OH-TPHP (0.56; 95% CI, 0.32 to 0.80) showed moderate-to-strong temporal reliability, while relatively weak temporal reliability was found for urinary DPHP (creatinine-corrected ICC, 0.37; 95% CI, 0.12 to 0.62). This study confirmed specific, reliable, and frequently detected biomarkers for TPHP and EHDPP and developed new biomarker of TCrP for future epidemiological research on health effects of m-aryl-OPFRs. Title: Comparative in vitro and in vivo effects of chlorpyrifos oxon in the outbred CD-1 mouse (Mus musculus) and great plains toad (Anaxyrus cognatus) Anderson T, Liu J, McMurry S, Pope C Ref: Environ Toxicol Chem, 37:1898, 2018 : PubMed ESTHER: Anderson_2018_Environ.Toxicol.Chem_37_1898 PubMedSearch: Anderson 2018 Environ.Toxicol.Chem 37 1898 PubMedID: 29573455 Abstract We compared biochemical, functional, and behavioral responses to the organophosphorus anticholinesterase chlorpyrifos oxon (CPO) in mice (Mus musculus, CD-1) and toads (Anaxyrus cognatus, Great Plains toad). Toads were substantially less sensitive to acute lethality of CPO based on the maximum tolerated (nonlethal) dose (toads, 77 mg/kg; mice, 5.9 mg/kg). Sublethal exposures led to classical signs of toxicity (increased involuntary movements, autonomic secretions) in mice but hypoactivity in toads. Motor performance in an inclined plane test was not affected by CPO in mice but was altered at the highest dosage in toads. Acetylcholinesterase (AChE), butyrylcholinesterase, monoacylglycerol lipase, and fatty acid amide hydrolase activities in brain were inhibited in mice but not in toads, and fatty acid amide hydrolase activity in the liver was inhibited in both species. Toad brain AChE was less sensitive to in vitro inhibition by CPO (50% inhibitory concentration [IC50; 20 min, 37 degrees C], 101 vs 7.8 nM; IC50 [20 min, 26 degrees C], 149 vs 6.2 nM), and studies of inhibitor kinetics indicated substantially lower anticholinesterase potency of CPO against the toad brain enzyme. Using an in vitro indirect inhibition assay, preincubation of CPO with toad brain homogenate was more effective than an equivalent mouse brain homogenate at reducing CPO potency. These data suggest that the relatively low sensitivity of toads to cholinergic toxicity is based on the low sensitivity of brain AChE, which in turn may be attributable to more effective target-site detoxification. Environ Toxicol Chem 2018;37:1898-1906. (c) 2018 SETAC. Title: Association of genetic polymorphisms of telomere binding proteins with cholinesterase activity in omethoate-exposed workers Ding M, Yang Y, Duan X, Wang S, Feng X, Wang T, Wang P, Liu S, Li L and Wang W <7 more author(s)> Ding M, Yang Y, Duan X, Wang S, Feng X, Wang T, Wang P, Liu S, Li L, Liu J, Tang L, Niu X, Zhang Y, Li G, Yao W, Cui L, Wang W (- 7) Ref: Ecotoxicology & Environmental Safety, 161:563, 2018 : PubMed ESTHER: Ding_2018_Ecotoxicol.Environ.Saf_161_563 PubMedSearch: Ding 2018 Ecotoxicol.Environ.Saf 161 563 PubMedID: 29929132 Abstract Omethoate, an organophosphorous pesticide, can cause a variety of health effects, especially the decrease of cholinesterase activity. The aim of this study is to explore the association of genetic polymorphisms of telomere binding proteins with cholinesterase activity in omethoate-exposed population. Cholinesterase activities in whole blood, red blood cell and plasma were detected using acetylthiocholine and dithio-bis-(nitrobenzoic acid) method; Genetic Genotyping of POT1 rs1034794, POT1 rs10250202, TERF1 rs3863242 and TERT rs2736098 were performed with PCR-RFLP. The cholinesterase activities of whole blood, red blood cells and plasma in exposure group are significantly lower than that of the control group (P<0.001). Multivariate analysis indicates that exposure group (b=-1.016, P<0.001), agender (b=0.365, P<0.001), drinking (b=0.271, P=0.004) and TERF1rs3863242 (b=-0.368, P=0.016) had an impact on cholinesterase activities. The results suggest that individual carrying AG+GG genotypes in TERF1 gene rs3863242 polymorphism were susceptible to damage in cholinesterase induced by omethoate. Title: Bioconcentration and effects of hexabromocyclododecane exposure in crucian carp (Carassius auratus) Dong H, Lu G, Yan Z, Liu J, Yang H, Nkoom M Ref: Ecotoxicology, 27:313, 2018 : PubMed ESTHER: Dong_2018_Ecotoxicology_27_313 PubMedSearch: Dong 2018 Ecotoxicology 27 313 PubMedID: 29404869 Abstract As a cycloaliphatic brominated flame retardant, hexabromocyclododecane (HBCD) has been widely used in building thermal insulation and fireproof materials. However, there is little information on the bioconcentration as well as effects with respect to HBCD exposure in the aquatic environment. To investigate the bioconcentration of HBCD in tissues (muscle and liver) and its biochemical and behavioural effects, juvenile crucian carp (Carassius auratus) were exposed to different concentrations of technical HBCD (nominal concentrations, 2, 20, 200 mug/L) for 7 days, using a flow-through exposure system. HBCD was found to concentrate in the liver and muscle with a terminal concentration of 0.60 +/- 0.22 mug/g lw (lipid weight) and 0.18 +/- 0.02 mug/g lw, respectively, at an environmentally-relevant concentration (2 mug/L). The total thyroxine and total triiodothyronine in the fish plasma were lowered as a result of exposure to the HBCD. Acetylcholinesterase activity in the brain was increased, while swimming activity was inhibited and shoaling inclination was enhanced after exposure to 200 mug/L HBCD. Feeding rate was suppressed in the 20 and 200 mug/L treatment groups. In summary, HBCD concentrations 10-100x higher than the current environmentally-relevant exposures induced adverse effects in the fish species tested in this study. These results suggest that increasing environmental concentrations and/or species with higher sensitivity than carp might be adversely affected by HBCD. Title: Bioactive polycyclic polyprenylated acylphloroglucinols from Hypericum perforatum Guo Y, Zhang N, Sun W, Duan X, Zhang Q, Zhou Q, Chen C, Zhu H, Luo Z and Zhang Y <3 more author(s)> Guo Y, Zhang N, Sun W, Duan X, Zhang Q, Zhou Q, Chen C, Zhu H, Luo Z, Liu J, Li XN, Xue Y, Zhang Y (- 3) Ref: Org Biomol Chem, 16:8130, 2018 : PubMed ESTHER: Guo_2018_Org.Biomol.Chem_16_8130 PubMedSearch: Guo 2018 Org.Biomol.Chem 16 8130 PubMedID: 30334059 Abstract Fifteen new polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperforatones A-O (1-15), along with 3 structurally related analogues (16-18), were isolated from the stems and leaves of Hypericum perforatum. Their structures and absolute configurations were established by a combination of NMR spectroscopic analyses, experimental and calculated electronic circular dichroism (ECD), modified Mosher's methods, Rh2(OCOCF3)4- and [Mo2(OAc)4]-induced ECD, X-ray crystallography, and the assistance of quantum chemical predictions (QCP) of 13C NMR chemical shifts. Compound 5 was found to be the first PPAP decorated by a rare 2,2,4,4,5-(pentamethyltetrahydrofuran-3-yl)methanol moiety and an oxepane ring. Furthermore, the isolates were screened for their acetylcholinesterase (AChE) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitory activities. Compounds 5, 10, 11, and 15 showed desirable AChE inhibitory activities (IC50 6.9-9.2 muM) and simultaneously inhibited BACE1 (at a concentration of 5 muM) with inhibition rates of 50.3%, 34.3%, 47.2%, and 34.6%, respectively. Interestingly, compound 5 showed the most balanced inhibitory activities against both AChE and BACE1 of all the tested compounds, which means that 5 could serve as the first valuable dual-targeted PPAP for the treatment of Alzheimer's disease. Preliminary molecular docking studies of 5 with BACE1 and AChE were also performed. Title: Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against Alzheimer's disease: Design, synthesis and biological evaluation He Q, Liu J, Lan JS, Ding J, Sun Y, Fang Y, Jiang N, Yang Z, Sun L and Xie SS <1 more author(s)> He Q, Liu J, Lan JS, Ding J, Sun Y, Fang Y, Jiang N, Yang Z, Sun L, Jin Y, Xie SS (- 1) Ref: Bioorg Chem, 81:512, 2018 : PubMed ESTHER: He_2018_Bioorg.Chem_81_512 PubMedSearch: He 2018 Bioorg.Chem 81 512 PubMedID: 30245233 Abstract A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC50 values of 0.0068muM and 0.0089muM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114microM for hAChE; 0.101microM for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold. Title: Design, synthesis and biological evaluation of new coumarin-dithiocarbamate hybrids as multifunctional agents for the treatment of Alzheimer's disease Jiang N, Huang Q, Liu J, Liang N, Li Q, Xie SS Ref: Eur Journal of Medicinal Chemistry, 146:287, 2018 : PubMed ESTHER: Jiang_2018_Eur.J.Med.Chem_146_287 PubMedSearch: Jiang 2018 Eur.J.Med.Chem 146 287 PubMedID: 29407958 Abstract A series of new coumarin-dithiocarbamate hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's Disease (AD). The biological assays indicated that most of them showed potent inhibition and excellent selectivity towards acetylcholinesterase (AChE), and could inhibit self-induced beta-amyloid (Abeta) aggregation. Especially, compound 4n presented the highest ability to inhibit AChE (IC50, 0.027muM for hAChE) and good inhibition of Abeta aggregation (40.19% at 25muM). Kinetic and molecular modeling studies revealed that 4n was a mixed-type inhibitor, which could interact simultaneously with the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. In addition, it also possessed specific metal-chelating ability, good BBB permeability and low toxicity on SH-SY5Y neuroblastoma cells. Moreover, compound 4n did not exhibit any acute toxicity in mice at doses up to 1000mg/kg, and could reverse the cognitive dysfunction of scopolamine-induced AD mice. As far as we know, 4n was the first reported dithiocarbamate derivative with multifunctional activity. Its excellent profiles in vitro and effectivity in vivo highlight this structurally distinct compound as a potential lead compound in the research of innovative multifunctional drugs for AD. Title: Predicting plant immunity gene expression by identifying the decoding mechanism of calcium signatures Lenzoni G, Liu J, Knight MR Ref: New Phytol, 217:1598, 2018 : PubMed ESTHER: Lenzoni_2018_New.Phytol_217_1598 PubMedSearch: Lenzoni 2018 New.Phytol 217 1598 PubMedID: 29218709 Abstract Calcium plays a key role in determining the specificity of a vast array of signalling pathways in plants. Cellular calcium elevations with different characteristics (calcium signatures) carry information on the identity of the primary stimulus, ensuring appropriate downstream responses. However, the mechanism for decoding calcium signatures is unknown. To determine this, decoding of the salicylic acid (SA)-mediated plant immunity signalling network controlling gene expression was examined. A dynamic mathematical model of the SA-mediated plant immunity network was developed. This model was used to predict responses to different calcium signatures; these were validated empirically using quantitative real-time PCR to measure gene expression. The mechanism for decoding calcium signatures to control expression of plant immunity genes enhanced disease susceptibility 1 (EDS1) and isochorismate synthase 1 (ICS1) was identified. Calcium, calmodulin, calmodulin-binding transcription activators (CAMTA)3 and calmodulin binding protein 60g (CBP60g) together amplify each calcium signature into three active signals, simultaneously regulating expression. The time required for calcium to return to steady-state level also quantitatively regulates gene expression. Decoding of calcium signatures occurs via nonlinear interactions between these active signals, producing a unique response in each case. Key properties of the calcium signatures are not intuitive, exemplifying the importance of mathematical modelling approaches. This approach can be applied to identifying the decoding mechanisms of other plant calcium signalling pathways. Title: [Clinical and genetic characteristics of congenital myasthenia syndrome with episodic apnea caused by CHAT gene mutation: a report of 2 cases] Liu ZM, Fang F, Ding CH, Zhang WH, Deng J, Chen CH, Wang X, Liu J, Li Z and Qian SY <2 more author(s)> Liu ZM, Fang F, Ding CH, Zhang WH, Deng J, Chen CH, Wang X, Liu J, Li Z, Jia XL, Zeng JS, Qian SY (- 2) Ref: Zhonghua Er Ke Za Zhi, 56:216, 2018 : PubMed ESTHER: Liu_2018_Zhonghua.Er.Ke.Za.Zhi_56_216 PubMedSearch: Liu 2018 Zhonghua.Er.Ke.Za.Zhi 56 216 PubMedID: 29518833 Abstract Objective: To investigate the clinical and genetic features of congenital myasthenia syndrome with episodic apnea (CMS-EA) caused by gene mutation of choline acetyltransferase (CHAT) Methods: The clinical data of 2 patients with congenital myasthenia syndrome were collected, and both were diagnosed from 2013 to 2015 in Beijing Children's Hospital, Capital Medical University. The clinical features and gene mutation characteristics were analyzed, and the patients were followed-up for therapeutic efficacy. Results: The two patients (case 1 and case 2) had the onset soon after birth and at 3 months after birth respectively. The two patients were admitted to the PICU due to dyspnea, cyanotic episodes that required intubation. The patients had repeated apnea and became ventilator dependent. Case 1 died due to refusal of any treatment. Case 2 had a tracheotomy, and gradually weaned from ventilator after using pyridostigmine. The hospitalization of case 2 lasted 162 days. Case 2 was followed up to the age of 3 years and 4 months, and was extubated and was maintained on oral neostigmine but still had fluctuating ptosis and minor physical and mental retardation. Both cases were negative for anti-AChR, anti-acetylcholinesterase, anti-MuSK antibodies. Neostigmine test was negative in case 1 and suspiciously positive in case 2. Low-frequency repetitive nerve stimulation testing of case 2 was negative. Cranial MRI scans of both cases showed brain atrophy-like change. Genetic testing showed compound heterozygous deletions (exon 4, 5, 6) and pathogenic variant c.914T>C (p.I305T) in CHAT in case 1, compound heterozygous variants c.1007T>C (p.I336T) and c.64C>T (p.Q22X) in CHAT in case 2. To our knowledge, compound heterozygous deletions (exon 4, 5, 6) and p.Q22X were novel, previously unreported variants. Conclusion: CMS-EA usually presents at birth or in the neonatal period with hypotonia, ptosis, dysphagia due to severe bulbar weakness, and respiratory insufficiency with cyanosis and apnea. Early treatment with pyridostigmine is helpful to the improvement of clinical symptoms and prognosis. Title: Developmental neurotoxicity of triphenyl phosphate in zebrafish larvae Shi Q, Wang M, Shi F, Yang L, Guo Y, Feng C, Liu J, Zhou B Ref: Aquat Toxicol, 203:80, 2018 : PubMed ESTHER: Shi_2018_Aquat.Toxicol_203_80 PubMedSearch: Shi 2018 Aquat.Toxicol 203 80 PubMedID: 30096480 Inhibitor(s) related to this paper: TPHP Abstract Triphenyl phosphate (TPhP), a typical organophosphate ester, is frequently detected in the environment and biota samples. It has been implicated as a neurotoxin as its structure is similar to neurotoxic organophosphate pesticides. The purpose of the present study was to investigate its potential developmental neurotoxicity in fish by using zebrafish larvae as a model. Zebrafish (Danio rerio) embryos were exposed to 0.8, 4, 20 and 100 mug/L of TPhP from 2 until 144 h post-fertilization. TPhP was found to have high bioconcentrations in zebrafish larvae after exposure. Further, it significantly reduced locomotor activity as well as the heart rate at the 100 mug/L concentration. TPhP exposure significantly altered the content of the neurotransmitters gamma-aminobutyric and histamine. Downregulation of the genes related to central nervous system development (e.g., alpha1-tubulin, mbp, syn2a, shha, and elavl3) as well as the corresponding proteins (e.g., alpha1-tubulin, mbp, and syn2a) was observed, but the gap-43 protein was found to upregulated. Finally, marked inhibition of total acetylcholinesterase activity, which is considered as a biomarker of neurotoxicant exposure, was also observed in the larvae. Our results indicate that exposure to environmentally relevant concentrations of TPhP can affect different parameters related to center nervous system development, and thus contribute to developmental neurotoxicity in early developing zebrafish larvae. Title: Study protocol for a randomised, double-blind, placebo-controlled 12-week pilot phase II trial of Sailuotong (SLT) for cognitive function in older adults with mild cognitive impairment Steiner GZ, Bensoussan A, Liu J, Hohenberg MI, Chang DH Ref: Trials, 19:522, 2018 : PubMed ESTHER: Steiner_2018_Trials_19_522 PubMedSearch: Steiner 2018 Trials 19 522 PubMedID: 30253809 Abstract BACKGROUND: Mild cognitive impairment (MCI) is a syndrome characterised by a decline in cognition but relatively intact activities of daily living. People with MCI have an increased risk of developing dementia, and MCI is often referred to as a transitional stage between healthy ageing and dementia. Currently, there are no pharmaceutical therapies approved by the US Federal Drug Administration for MCI. Randomised controlled trials on the two major classes of anti-dementia pharmaceuticals, cholinesterase inhibitors and glutamate receptor antagonists, have produced poor results in MCI cohorts. There is a need to test and evaluate new and promising treatments for MCI that target multiple aspects of the syndrome's multi-faceted pathophysiology. The primary aim of this study is to evaluate the efficacy of 12 weeks of treatment with a standardised herbal formula, Sailuotong (SLT), compared to placebo, on cognition in older adults with MCI. Secondary aims are to assess SLT's mechanisms of action via electroencephalography (EEG), autonomic function, brain blood flow, and inflammation, as well as its safety in this cohort. METHODS/DESIGN: The target cohort for this trial is community-dwelling older adults over the age of 60 years who meet the National Institute of Aging-Alzheimer's Association working group core clinical criteria for MCI due to Alzheimer's disease. Eighty participants will be recruited and randomly allocated via a permuted block strategy at a 1:1 ratio to either the treatment or placebo group. The co-primary cognitive outcome measures are Logical Memory Story A delayed recall (episodic memory), Letter Number Sequencing (perceptual processing speed), and both the Trail Making Test and Rey Complex Figure Test (executive function). Secondary outcome measures are EEG activity, autonomic function (via electrocardiogram, skin conductance, and peripheral pulse pressure), brain blood flow (via common carotid artery ultrasound), and serum concentrations of inflammatory cytokines. Analyses will be performed blind to group allocation. DISCUSSION: This study is a 12-week, randomised, double-blind, placebo-controlled trial. Primary and secondary outcome measures will be compared between treatment and placebo groups at baseline and endpoint. Data from this pilot study will inform a larger, more highly powered clinical trial if the findings are positive. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000371392 Registered on 10 March 2017. Title: Quorum Sensing System of Ruegeria mobilis Rm01 Controls Lipase and Biofilm Formation Su Y, Tang K, Liu J, Wang Y, Zheng Y, Zhang XH Ref: Front Microbiol, 9:3304, 2018 : PubMed ESTHER: Su_2018_Front.Microbiol_9_3304 PubMedSearch: Su 2018 Front.Microbiol 9 3304 PubMedID: 30687283 Abstract Quorum sensing (QS) promotes in situ extracellular enzyme (EE) activity via the exogenous signal N-acylhomoserine lactone (AHL), which facilitates marine particle degradation, but the species that engage in this regulatory mechanism remain unclear. Here, we obtained AHL-producing and AHL-degrading strains from marine particles. The strain Ruegeria mobilis Rm01 of the Roseobacter group (RBG), which was capable of both AHL producing and degrading, was chosen to represent these strains. We demonstrated that Rm01 possessed a complex QS network comprising AHL-based QS and quorum quenching (QQ) systems and autoinducer-2 (AI-2) perception system. Rm01 was able to respond to multiple exogenous QS signals through the QS network. By applying self-generated AHLs and non-self-generated AHLs and AI-2 QS signal molecules, we modulated biofilm formation and lipase production in Rm01, which reflected the coordination of bacterial metabolism with that of other species via eavesdropping on exogenous QS signals. These results suggest that R. mobilis might be one of the participators that could regulate EE activities by responding to QS signals in marine particles. Title: Unexpected protonation state of Glu197 discovered from simulations of tacrine in butyrylcholinesterase Wan X, Yao Y, Fang L, Liu J Ref: Phys Chem Chem Phys, 20:14938, 2018 : PubMed ESTHER: Wan_2018_Phys.Chem.Chem.Phys_20_14938 PubMedSearch: Wan 2018 Phys.Chem.Chem.Phys 20 14938 PubMedID: 29786716 Abstract Butyrylcholinesterase (BChE) has been actively involved in drug discoveries from many fields for decades. In the crystal structure of the BChE-tacrine complex, there is an unanticipated formyl-proline molecule resolved very close to tacrine, raising an essential question on how reliable it is to apply the binding pose in a crystal structure to analyze related experimental observations, in which no formyl-proline is actually involved. In this study, by performing a series of 100 ns molecular dynamics simulations, we demonstrate that it is safe to employ the structural information from this crystal structure to analyze related experimental observations. Surprisingly, Glu197 needs to be protonated to have the structures simulated appropriately. It should be noted that Glu197 has been commonly considered as deprotonated in diverse analyses due to its low pKa in aqueous solution, for which some interpretations are inconsistent or unclear. Our further investigation shows that the protonated Glu197 plays a very important role in preserving His438 within the catalytic triad through stabilizing a highly conserved water molecule. Interestingly, the catalytic triad and Glu197 have been long recognized for possibly deviating largely from the crystal structure, which might be catalytically deficient and is generally considered to result from the difference between the crystal and aqueous environment. Herein, our results suggest that the large deviations of the catalytic triad and Glu197 from the crystal structure are caused by the inappropriate protonation state of Glu197. This finding shall provide an important clue that has been long missing for a better understanding of BChE-related puzzles or even reconsideration of some BChE-catalyzed reaction mechanisms. Title: Design, synthesis, biological evaluation, and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors (part II) Wang J, Wang C, Wu Z, Li X, Xu S, Liu J, Lan Q, Zhu Z, Xu J Ref: Chemical Biology Drug Des, 91:756, 2018 : PubMed ESTHER: Wang_2018_Chem.Biol.Drug.Des_91_756 PubMedSearch: Wang 2018 Chem.Biol.Drug.Des 91 756 PubMedID: 29112799 Abstract A series of novel 4-isochromanone compounds bearing N-benzyl pyridinium moiety were designed and synthesized as acetylcholinesterase (AChE) inhibitors. The biological evaluation showed that most of the target compounds exhibited potent inhibitory activities against AChE. Among them, compound 1q possessed the strongest anti-AChE activity with an IC50 value of 0.15 nm and high AChE/BuChE selectivity (SI > 5,000). Moreover, compound 1q had low toxicity in normal nerve cells and was relatively stable in rat plasma. Together, the current finding may provide a new approach for the discovery of novel anti-Alzheimer's disease agents. Title: Anti-Alzheimers activity and molecular mechanism of albumin-derived peptides against AChE and BChE Yu Z, Wu S, Zhao W, Ding L, Fan Y, Shiuan D, Liu J, Chen F Ref: Food Funct, 9:1173, 2018 : PubMed ESTHER: Yu_2018_Food.Funct_9_1173 PubMedSearch: Yu 2018 Food.Funct 9 1173 PubMedID: 29363710 Abstract Alzheimer's disease (AD) is a global health issue affecting millions of elderly people worldwide. The aim of the present study was to identify novel anti-AD peptides isolated from albumin. Anti-AD activities of the peptides were evaluated via inhibitory activities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Furthermore, the potential molecular mechanisms of the KLPGF/AChE were investigated by CDOCKER of Discovery studio 2017. The results revealed that peptide KLPGF could effectively inhibit AChE with an inhibition rate of 61.23% at a concentration of 50 mug mL(-1). In addition, the peptide KLPGF came in contact with acylation sites and peripheral anion sites of AChE. The present study demonstrates that the peptide KLPGF could become a potential functional food intervention in AD. Title: Two birds, one stone: hesperetin alleviates chemotherapy-induced diarrhea and potentiates tumor inhibition Yu Y, Kong R, Cao H, Yin Z, Liu J, Nan X, Phan AT, Ding T, Zhao H, Wong STC Ref: Oncotarget, 9:27958, 2018 : PubMed ESTHER: Yu_2018_Oncotarget_9_27958 PubMedSearch: Yu 2018 Oncotarget 9 27958 PubMedID: 29963254 Abstract Chemotherapy-induced diarrhea (CID), with clinical high incidence, adversely affects the efficacy of cancer treatment and patients' quality of life. Our study demonstrates that the citrus flavonoid hesperetin (Hst) has a superior potential as a new agent to prevent and alleviate CID. In the animal model for irinotecan (CPT-11) induced CID, Hst could selectively inhibit intestinal carboxylesterase (CES2) and thus reduce the local conversion of CPT-11 to cytotoxic SN-38 which causes intestinal toxicity. Oral administration of Hst manifested an excellent anti-diarrhea efficacy, prohibiting 80% of severe and 100% of mild diarrhea in the CPT-11 administered tumor-bearing mice. In addition, a significant attenuation of intestinal inflammation contributed to the anti-diarrhea effect of Hst. Moreover, Hst was found to work synergistically with CPT-11 in tumor inhibition by suppressing the tumor's STAT3 activity and recruiting tumoricidal macrophages into the tumor microenvironment. The anti-intestinal inflammation and anti-STAT3 properties of Hst would contribute its broad benefits to the management of diarrhea caused by other chemo or targeted agents, and more importantly, enhance and reinforce the anti-tumor effects of these agents, to improve patient outcomes. Title: Amide Synthesis via Aminolysis of Ester or Acid with an Intracellular Lipase Zeng S, Liu J, Anankanbil S, Chen M, Guo Z, Adams JP, Snajdrova R, Li Z Ref: ACS Catal, 8:8856, 2018 : PubMed ESTHER: Zeng_2018_ACS.Catal_8_8856 PubMedSearch: Zeng 2018 ACS.Catal 8 8856 Gene_locus related to this paper: sphmc-SpL Abstract A unique lipase (SpL) from Sphingomonas sp. HXN-200 was discovered as the first intracellular enzyme for the aminolysis of ester or acid to produce amide. Reactions of a series of esters and amines with SpL gave the corresponding amides 3a-g in high yield with high activity. SpL also showed high enantioselectivity and high activity for enantioselective ester aminolysis, producing amides (R)-3h-j in high ee from the corresponding racemic ester or amine. Moreover, SpL was found to be highly active for the aminolysis of carboxylic acid, which was generally considered infeasible with the known aminolysis enzymes. The aminolysis of several carboxylic acids afforded the corresponding amides 3a, 3d, 3k, 3l, and 3n in good yield. The intracellular SpL was expressed in Escherichia coli cells to give an efficient whole-cell biocatalyst for amide synthesis. Remarkably, high catalytic activity was observed in the presence of water at 2-4% (v/v) for free enzyme and 16% (v/v) for whole cells, respectively. Accordingly, E. coli (SpL) wet cells were used as easily available and practical catalysts for the aminolysis of ester or acid, producing a group of useful and valuable amides in high concentration (up to 103 mM) and high yield. The newly discovered intracellular SpL with unique properties is a promising catalyst for green and efficient synthesis of amides. Title: Lipase-mediated direct in situ ring-opening polymerization of E-caprolactone formed by a chemo-enzymatic method Zhang Y, Lu P, Sun Q, Li T, Zhao L, Gao X, Wang F, Liu J Ref: J Biotechnol, 281:74, 2018 : PubMed ESTHER: Zhang_2018_J.Biotechnol_281_74 PubMedSearch: Zhang 2018 J.Biotechnol 281 74 PubMedID: 29908204 Abstract A novel method to synthesize poly(sigma-caprolactone) (PCL) through a three-step, lipase-mediated chemo-enzymatic reaction from cyclohexanone using an immobilized lipase from Trichosporon laibacchii (T. laibacchii) CBS5791 was developed. The immobilized preparation with 1280 U. g(-1) used here was obtained by a method of purification and in situ immobilization where the crude intracellular lipase (cell homogenate) was subjected to partial purification by an aqueous two-phase system (ATPS) consisting of 12% (w/w) polyethylene glycol (PEG) 4000 and 13% (w/w) potassium phosphate (K(2)HPO(4)) and then in situ immobilization directly on diatomite from the top PEG-rich phase of ATPS. In this multi-step process, the sigma-caprolactone (sigma-CL) produced by lipase-mediated one-pot two-step chemo-enzymatic oxidation of cyclohexanone was directly subjected to in situ ring-opening polymerization (ROP) started by adding highly hydrophobic solvents. It is necessary to note that sigma-CL synthesis and its subsequent ROP were catalyzed by the same lipase. The impact of various reaction parameters, e.g., solvent, cyclohexanone: hydrogen peroxide molar ratio, hydrogen peroxide forms and reaction temperature were investigated. Toluene was selected as a preferred solvent due to supporting the highest molecular weight (M(n) = 2168) and moderate sigma-CL conversion (65.42%). Through the optimization of reaction conditions, PCL was produced with a M(n) of 2283 at 50 degreesC for 24 h. These results reveal that this lipase-mediated direct ring-opening polymerization of in situ formed sigma-CL is an alternative route to the conventional synthesis of PCL. Title: Pharmacological Inhibition of Soluble Epoxide Hydrolase Ameliorates Chronic Ethanol-Induced Cardiac Fibrosis by Restoring Autophagic Flux Zhou C, Huang J, Li Q, Zhan C, He Y, Liu J, Wen Z, Wang DW Ref: Alcohol Clin Exp Res, 42:1970, 2018 : PubMed ESTHER: Zhou_2018_Alcohol.Clin.Exp.Res_42_1970 PubMedSearch: Zhou 2018 Alcohol.Clin.Exp.Res 42 1970 PubMedID: 30047995 Abstract BACKGROUND: Chronic drinking leads to myocardial contractile dysfunction and dilated cardiomyopathy, and cardiac fibrosis is a consequence of these alcoholic injuries. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) to less bioactive diols, and EETs have cardioprotective properties. However, the effects of sEH inhibition in ethanol (EtOH)-induced cardiac fibrosis are unknown. METHODS: This study was designed to investigate the role and underlying mechanisms of sEH inhibition in chronic EtOH feeding-induced cardiac fibrosis. C57BL/6J mice were fed a 4% Lieber-DeCarli EtOH diet for 8 weeks, and the sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) was administered throughout the experimental period. RESULTS: The results showed that chronic EtOH intake led to cardiac dilatation, collagen deposition, and autophagosome accumulation, while TPPU administration ameliorated these effects. In vitro, treating primary cardiac fibroblasts (CFs) with EtOH resulted in CF activation, including alpha smooth muscle actin overexpression, collagen synthesis, and cell migration. Moreover, EtOH disturbed CF autophagic flux, as evidenced by the increased LC3 II/I ratio and SQSTM1 expression, and by the enhanced autophagosome accumulation. TPPU treatment prevented the activation of CF induced by EtOH and restored the impaired autophagic flux by suppressing mTOR activation. CONCLUSIONS: Taken together, these findings suggest that sEH pharmacological inhibition may be a unique therapeutic strategy for treating EtOH-induced cardiac fibrosis. Title: Molecular cloning and expression analysis of a prawn (Macrobrachium rosenbergii) juvenile hormone esterase-like carboxylesterase following immune challenge Zhu XJ, Xiong Y, He W, Jin Y, Qian YQ, Liu J, Dai ZM Ref: Fish Shellfish Immunol, 80:10, 2018 : PubMed ESTHER: Zhu_2018_Fish.Shellfish.Immunol_80_10 PubMedSearch: Zhu 2018 Fish.Shellfish.Immunol 80 10 PubMedID: 29803663 Abstract Methyl farnesoate (MF), the crustacean juvenile hormone (JH), plays critical roles in various physiological processes in crustaceans. The titer of MF is precisely regulated by specific carboxylesterase. Here, we report for the first time that the cloning and expression analysis of a JH esterase-like carboxylesterase from the prawn Macrobrachium rosenbergii (named as MrCXE). MrCXE contained a 1935-bp open reading frame (ORF) conceptually translated into a 644-amino acids protein. MrCXE protein shared the highest identity (36%) with JH esterase-like carboxylesterase from the swimming crab, Portunus trituberculatus and exhibited the typical motifs of JH esterase-like carboxylesterases. MrCXE was most abundantly expressed in hepatopancreas, the major tissue for MF metabolism. MrCXE was expressed at a low level in gut and was not detected in other tissues. Additionally, MrCXE expression was upregulated in hepatopancreas by eyestalk ablation to increase MF level. Furthermore, the mRNA level of MrCXE was significantly increased in the hepatopancreas when challenged by the bacterial pathogens Aeromonas hydrophila and Vibrio parahaemolyticus. To our knowledge, this is the first report that the JH esterase-like carboxylesterase is involved in the innate immune response of the crustaceans. Title: The impacts of pesticide and nicotine exposures on functional brain networks in Latino immigrant workers Bahrami M, Laurienti PJ, Quandt SA, Talton J, Pope CN, Summers P, Burdette JH, Chen H, Liu J and Simpson SL <2 more author(s)> Bahrami M, Laurienti PJ, Quandt SA, Talton J, Pope CN, Summers P, Burdette JH, Chen H, Liu J, Howard TD, Arcury TA, Simpson SL (- 2) Ref: Neurotoxicology, 62:138, 2017 : PubMed ESTHER: Bahrami_2017_Neurotoxicol_62_138 PubMedSearch: Bahrami 2017 Neurotoxicol 62 138 PubMedID: 28583619 Abstract Latino immigrants that work on farms experience chronic exposures to potential neurotoxicants, such as pesticides, as part of their work. For tobacco farmworkers there is the additional risk of exposure to moderate to high doses of nicotine. Pesticide and nicotine exposures have been associated with neurological changes in the brain. Long-term exposure to cholinesterase-inhibiting pesticides, such as organophosphates and carbamates, and nicotine place this vulnerable population at risk for developing neurological dysfunction. In this study we examined whole-brain connectivity patterns and brain network properties of Latino immigrant workers. Comparisons were made between farmworkers and non-farmworkers using resting-state functional magnetic resonance imaging data and a mixed-effects modeling framework. We also evaluated how measures of pesticide and nicotine exposures contributed to the findings. Our results indicate that despite having the same functional connectivity density and strength, brain networks in farmworkers had more clustered and modular structures when compared to non-farmworkers. Our findings suggest increased functional specificity and decreased functional integration in farmworkers when compared to non-farmworkers. Cholinesterase activity was associated with population differences in community structure and the strength of brain network functional connections. Urinary cotinine, a marker of nicotine exposure, was associated with the differences in network community structure. Brain network differences between farmworkers and non-farmworkers, as well as pesticide and nicotine exposure effects on brain functional connections in this study, may illuminate underlying mechanisms that cause neurological implications in later life. Title: Genomic adaptation to polyphagy and insecticides in a major East Asian noctuid pest Cheng T, Wu J, Wu Y, Chilukuri RV, Huang L, Yamamoto K, Feng L, Li W, Chen Z and Mita K <28 more author(s)> Cheng T, Wu J, Wu Y, Chilukuri RV, Huang L, Yamamoto K, Feng L, Li W, Chen Z, Guo H, Liu J, Li S, Wang X, Peng L, Liu D, Guo Y, Fu B, Li Z, Liu C, Chen Y, Tomar A, Hilliou F, Montagne N, Jacquin-Joly E, d'Alencon E, Seth RK, Bhatnagar RK, Jouraku A, Shiotsuki T, Kadono-Okuda K, Promboon A, Smagghe G, Arunkumar KP, Kishino H, Goldsmith MR, Feng Q, Xia Q, Mita K (- 28) Ref: Nat Ecol Evol, 1:1747, 2017 : PubMed ESTHER: Cheng_2017_Nat.Ecol.Evol_1_1747 PubMedSearch: Cheng 2017 Nat.Ecol.Evol 1 1747 PubMedID: 28963452 Abstract The tobacco cutworm, Spodoptera litura, is among the most widespread and destructive agricultural pests, feeding on over 100 crops throughout tropical and subtropical Asia. By genome sequencing, physical mapping and transcriptome analysis, we found that the gene families encoding receptors for bitter or toxic substances and detoxification enzymes, such as cytochrome P450, carboxylesterase and glutathione-S-transferase, were massively expanded in this polyphagous species, enabling its extraordinary ability to detect and detoxify many plant secondary compounds. Larval exposure to insecticidal toxins induced expression of detoxification genes, and knockdown of representative genes using short interfering RNA (siRNA) reduced larval survival, consistent with their contribution to the insect's natural pesticide tolerance. A population genetics study indicated that this species expanded throughout southeast Asia by migrating along a South India-South China-Japan axis, adapting to wide-ranging ecological conditions with diverse host plants and insecticides, surviving and adapting with the aid of its expanded detoxification systems. The findings of this study will enable the development of new pest management strategies for the control of major agricultural pests such as S. litura. Title: ANNALS EXPRESS: Gestational age-specific reference intervals for 15 biochemical measurands during normal pregnancy in China Dai Y, Liu J, Yuan E, Lee Y, Wang Q, Jia L, Wang L, Su Y Ref: Annals of Clinical Biochemistry, :4563217738801, 2017 : PubMed ESTHER: Dai_2017_Ann.Clin.Biochem__4563217738801 PubMedSearch: Dai 2017 Ann.Clin.Biochem 4563217738801 PubMedID: 29153025 Abstract AIMS: Physiological changes that occur during pregnancy can influence biochemical parameters. Therefore, using reference intervals based on specimens from non-pregnant women to interpret laboratory results during pregnancy may be inappropriate. This study aimed to establish essential to establish reference intervals for a range of analytes during pregnancy. Title: Clinical emergency treatment of 68 critical patients with severe organophosphorus poisoning and prognosis analysis after rescue Dong H, Weng YB, Zhen GS, Li FJ, Jin AC, Liu J Ref: Medicine (Baltimore), 96:e7237, 2017 : PubMed ESTHER: Dong_2017_Medicine.(Baltimore)_96_e7237 PubMedSearch: Dong 2017 Medicine.(Baltimore) 96 e7237 PubMedID: 28640122 Abstract This study reports the clinical emergency treatment of 68 critical patients with severe organophosphorus poisoning, and analyzes the prognosis after rescue.The general data of 68 patients with severe organophosphorus poisoning treated in our hospital were retrospectively analyzed. These patients were divided into 2 groups: treatment group, and control group. Patients in the control group received routine emergency treatment, while patients in the treatment group additionally received hemoperfusion plus hemodialysis on the basis of routine emergency treatment. The curative effects in these 2 groups and the prognosis after rescue were compared.Compared with the control group, atropinization time, recovery time of cholinesterase activity, recovery time of consciousness, extubation time, and length of hospital stay were shorter (P < .05); the total usage of atropine was significantly lower (P < .05); Glasgow Coma Score was significantly higher (P < .05); acute physiology and chronic health score (APACHE II) was significantly lower (P < .05); and mortality and poisoning rebound rate was significantly lower (P < .05) in the treatment group.Hemoperfusion and hemodialysis on the basis of routine emergency treatment for critical patients with organophosphorus poisoning can improve rescue outcomes and improve the prognosis of patients, which should be popularized. Title: Tricyclic Polyprenylated Acylphloroglucinols from St John's Wort, Hypericum perforatum Guo Y, Zhang N, Chen C, Huang J, Li XN, Liu J, Zhu H, Tong Q, Zhang J and Zhang Y <2 more author(s)> Guo Y, Zhang N, Chen C, Huang J, Li XN, Liu J, Zhu H, Tong Q, Zhang J, Luo Z, Xue Y, Zhang Y (- 2) Ref: Journal of Natural Products, 80:1493, 2017 : PubMed ESTHER: Guo_2017_J.Nat.Prod_80_1493 PubMedSearch: Guo 2017 J.Nat.Prod 80 1493 PubMedID: 28445039 Abstract The new polyprenylated acylphloroglucinol derivatives 1-15 and the known furohyperforin (16) were isolated from the stems and leaves of Hypericum perforatum. Their structures were determined by analyses of NMR and HRESIMS data. Their absolute configurations were elucidated by a combination of electronic circular dichroism (ECD) and Rh2(OCOCF3)4-induced ECD, as well as X-ray diffraction crystallography. The new hyperforatin F (9) contains a unique acetyl functionality at C-1 of the bicyclo[3.3.1]nonane core. Hyperforatins G (10) and H (11) are similarly the first examples of naturally occurring [3.3.1]-type polycyclic prenylated acylphloroglucinols possessing a carbonyl functionality at C-32. The compounds were tested for their acetylcholinesterase (AChE) inhibitory activities and cytotoxic activities against a panel of human tumor cell lines. Compounds 3, 5, 6, 8, and 9 exerted moderate inhibitory activities (IC50 3.98-9.13 muM) against AChE. Title: Polyionic complexes of butyrylcholinesterase and poly-l-lysine-g-poly(ethylene glycol): Comparative kinetics of catalysis and inhibition and in vitro inactivation by proteases and heat Hester K, Liu J, Flynn N, Sultatos LG, Geng L, Brimijoin S, Ramsey JD, Hartson S, Ranjan A, Pope C Ref: Chemico-Biological Interactions, 275:86, 2017 : PubMed ESTHER: Hester_2017_Chem.Biol.Interact_275_86 PubMedSearch: Hester 2017 Chem.Biol.Interact 275 86 PubMedID: 28756151 Abstract We previously reported that recombinant human butyrylcholinesterase (rhBChE) complexed with a series of copolymers of poly-l-lysine (PLL) with grafted (polyethylene) glycol (PEG) (i.e., PLL-g-PEG) showed reduced catalytic activity but relatively similar concentration-dependent inactivation of the organophosphorus inhibitor paraoxon. Herein, we compared the kinetics of catalysis (using butyrylthiocholine as the substrate) and inhibition (using four different inhibitors) of free and copolymer-complexed rhBChE. Using scanning electron microscopy, polyionic complexes of rhBChE with three different PLL-g-PEG copolymers (based on PLL size) appeared as spheroid-shaped particles with relatively similar particle sizes (median diameter = 35 nm). Relatively similar particle sizes were also noted using dynamic light scattering (mean = 26-35 nm). The three copolymer-complexed enzymes exhibited reduced kcat (30-33% reduction), but no significant changes in Km. Inhibitory potency (as reflected by the bimolecular rate constant, ki) was similar among the free and copolymer-complexed enzymes when paraoxon was the inhibitor, whereas statistically significant reductions in ki (16-60%) were noted with the other inhibitors. Sensitivity to inactivation by proteases and heat was also compared. Copolymer-complexed enzymes showed lesser time-dependent inactivation by the proteases trypsin and pronase and by heat compared to the free enzyme. Understanding the unique properties of PLL-g-PEG-BChE complexes may lead to enhanced approaches for use of BChE and other protein bioscavengers. Title: Design, synthesis and biological activity of novel donepezil derivatives bearing N-benzyl pyridinium moiety as potent and dual binding site acetylcholinesterase inhibitors Lan JS, Zhang T, Liu Y, Yang J, Xie SS, Liu J, Miao ZY, Ding Y Ref: Eur Journal of Medicinal Chemistry, 133:184, 2017 : PubMed ESTHER: Lan_2017_Eur.J.Med.Chem_133_184 PubMedSearch: Lan 2017 Eur.J.Med.Chem 133 184 PubMedID: 28388521 Abstract A series of new donepezil derivatives were designed synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase and self-induced beta-amyloid (Abeta) aggregation, and moderate antioxidant activity. Especially, compound 5b presented the greatest ability to inhibit cholinesterase (IC50, 1.9 nM for eeAChE and 0.8 nM for hAChE), good inhibition of Abeta aggregation (53.7% at 20 muM) and good antioxidant activity (0.54 trolox equivalents). Kinetic and molecular modeling studies indicated that compound 5b was a mixed-type inhibitor, binding simultaneously to the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, compound 5b could reduce PC12 cells death induced by oxidative stress and Abeta (1-42). Moreover, in vivo experiments showed that compound 5b was nontoxic and tolerated at doses up to 2000 mg/kg. These results suggested that compound 5b might be an excellent multifunctional agent for AD treatment. Title: Malassezia globosa MgMDL2 lipase: Crystal structure and rational modification of substrate specificity Lan D, Xu H, Xu J, Dubin G, Liu J, Iqbal Khan F, Wang Y Ref: Biochemical & Biophysical Research Communications, 488:259, 2017 : PubMed ESTHER: Lan_2017_Biochem.Biophys.Res.Commun_488_259 PubMedSearch: Lan 2017 Biochem.Biophys.Res.Commun 488 259 PubMedID: 28433636 Gene_locus related to this paper: malgo-a8puy5 Abstract Lipases play an important role in physiological metabolism and diseases, and also have multiple industrial applications. Rational modification of lipase specificity may increase the commercial utility of this group of enzymes, but is hindered by insufficient mechanistic understanding. Here, we report the 2.0 A resolution crystal structure of a mono- and di-acylglycerols lipase from Malassezia globosa (MgMDL2). Interestingly, residues Phe278 and Glu282 were found to involve in substrate recognition because mutation on each residue led to convert MgMDL2 to a triacylglycerol (TAG) lipase. The Phe278Ala and Glu282Ala mutants also acquired ability to synthesize TAGs by esterification of glycerol and fatty acids. By in silicon analysis, steric hindrance of these residues seemed to be key factors for the altered substrate specificity. Our work may shed light on understanding the unique substrate selectivity mechanism of mono- and di-acylglycerols lipases, and provide a new insight for engineering biocatalysts with desired catalytic behaviors for biotechnological application. Title: Application of hemoperfusion in severe acute organophosphorus pesticide poisoning Li Z, Wang G, Zhen G, Zhang Y, Liu J, Liu S Ref: Turk J Med Sci, 47:1277, 2017 : PubMed ESTHER: Li_2017_Turk.J.Med.Sci_47_1277 PubMedSearch: Li 2017 Turk.J.Med.Sci 47 1277 PubMedID: 29156874 Abstract Background/aim: The aim of this research is to investigate the clinical efficacy of hemoperfusion in the treatment of severe acute organophosphorus pesticide poisoning (AOPP). Materials and methods: Patients meeting the inclusion criteria were divided into Groups 1 and 2 according to whether hemoperfusion was applied or not. Group 2 was observed as the control group. Conventional therapy for AOPP was given to Groups 1 and 2. Besides conventional treatment, patients in Group 1 were also treated with hemoperfusion therapy. Cholinesterase activity and blood glucose concentration were tested before hemoperfusion and for the first 3 days afterwards. The recovery time of 50% cholinesterase was recorded. At the same time, the incidence and mortality of intermediate syndrome was observed and compared. Results: The incidence and mortality of intermediate syndrome in Group 1 was obviously decreased, and the recovery time of cholinesterase activity was significantly shortened compared with Group 2. Conclusion: Hemoperfusion, used for treating severe AOPP, contributes to the improvement of cholinesterase activity, low incidence and mortality of intermediate syndrome, and increase in curative rate. Title: A new facet of NDRG1 in pancreatic ductal adenocarcinoma: Suppression of glycolytic metabolism Liu W, Zhang B, Hu Q, Qin Y, Xu W, Shi S, Liang C, Meng Q, Xiang J and Xu J <9 more author(s)> Liu W, Zhang B, Hu Q, Qin Y, Xu W, Shi S, Liang C, Meng Q, Xiang J, Liang D, Ji S, Liu J, Hu P, Liu L, Liu C, Long J, Ni Q, Yu X, Xu J (- 9) Ref: Int J Oncol, 50:1792, 2017 : PubMed ESTHER: Liu_2017_Int.J.Oncol_50_1792 PubMedSearch: Liu 2017 Int.J.Oncol 50 1792 PubMedID: 28350132 Abstract N-myc downstream-regulated gene 1 (NDRG1) is known as tumor/metastasis suppressor in a variety of cancers including pancreas, being involved in angiogenesis, cancer growth and metastasis. However, the precise molecular mechanism how NDRG1 exerts its inhibitory function in pancreatic cancer remains unclear. In this investigation, we demonstrated that K-Ras plays a vital role in modulating NDRG1 protein level in PDAC cancer cells in vitro, which is mediated through ERK signaling. Noteworthy, K-Ras downstream Akt/mTOR signaling is inhibited upon NDRG1 overexpression, resulting in decease of HIF1alpha level. Moreover, NDRG1 has a unique role in modulating cancer metabolism of pancreatic ductal adenocarcinoma (PDAC). The mechanism accounting for NDRG1 in modulating aerobic glycolysis, at least partly, relied on its regulation of glycolysis genes including GLUT1, HK2, LDHA and PDK1. Additionally, NDRG1 is shown to suppress the activity of HIF1alpha, which is responsible for regulation of glycolysis enzymes. The current study is the first to elucidate a unique facet of the potent tumor/metastasis suppressor NDRG1 in the regulation of PDAC glycolysis, leading to important insights into the mechanism by which NDRG1 exert inhibitory function in PDAC. Title: Interaction of erythromycin and ketoconazole on the neurological, biochemical and behavioral responses in crucian carp Liu J, Cai Y, Lu G, Dan X, Wu D, Yan Z Ref: Environ Toxicol Pharmacol, 55:14, 2017 : PubMed ESTHER: Liu_2017_Environ.Toxicol.Pharmacol_55_14 PubMedSearch: Liu 2017 Environ.Toxicol.Pharmacol 55 14 PubMedID: 28802958 Abstract The presence of pharmaceuticals in the aquatic environment has received great attention due to their potential impacts on public health. The single, as well as the combined toxicities of erythromycin (ERY) and ketoconazole (KCZ) on the bioaccumulation, biochemical and behavioral responses, were examined in crucian carp. This study focused on the uptake of contaminants, acetylcholinesterase (AChE) activity in the brain, swimming and shoaling behavior of fish. After 14days of binary exposure, the addition of KCZ at nominal concentrations of 0.2, 2 and 20mug/L significantly increased the accumulation of ERY in the brain of the fish and the bioconcentration factor of 2.08 was 2.6-fold higher than that calculated from the ERY-alone exposure. The brain AChE activity was significantly inhibited by ERY and KCZ with a significant correlation with respect to the accumulative concentration of the contaminants. The inhibition rates of swimming activity to KCZ were increased with a corresponding increase in the exposure concentration of KCZ in the single exposure. However, this manner was altered by the combined exposure. In addition, shoaling was significantly enhanced by KCZ-alone exposure, which was significantly correlated with the swimming activity. This study indicates that the mixture of the contaminants may cause endocrine disrupting effects and behavior modification especially in fish with known ecological and evolutionary consequences. Title: Synthesis, characterization, bioactivity and potential application of phenolic acid grafted chitosan: A review Liu J, Pu H, Liu S, Kan J, Jin C Ref: Carbohydr Polym, 174:999, 2017 : PubMed ESTHER: Liu_2017_Carbohydr.Polym_174_999 PubMedSearch: Liu 2017 Carbohydr.Polym 174 999 PubMedID: 28821158 Abstract In recent years, increasing attention has been paid to the grafting of phenolic acid onto chitosan in order to enhance the bioactivity and widen the application of chitosan. Here, we present a comprehensive overview on the recent advances of phenolic acid grafted chitosan (phenolic acid-g-chitosan) in many aspects, including the synthetic method, structural characterization, biological activity, physicochemical property and potential application. In general, four kinds of techniques including carbodiimide based coupling, enzyme catalyzed grafting, free radical mediated grafting and electrochemical methods are frequently used for the synthesis of phenolic acid-g-chitosan. The structural characterization of phenolic acid-g-chitosan can be determined by several instrumental methods. The physicochemical properties of chitosan are greatly altered after grafting. As compared with chitosan, phenolic acid-g-chitosan exhibits enhanced antioxidant, antimicrobial, antitumor, anti-allergic, anti-inflammatory, anti-diabetic and acetylcholinesterase inhibitory activities. Notably, phenolic acid-g-chitosan shows potential applications in many fields as coating agent, packing material, encapsulation agent and bioadsorbent. Title: The Genome of Medicinal Plant Macleaya cordata Provides New Insights into Benzylisoquinoline Alkaloids Metabolism Liu X, Liu Y, Huang P, Ma Y, Qing Z, Tang Q, Cao H, Cheng P, Zheng Y and Zeng J <19 more author(s)> Liu X, Liu Y, Huang P, Ma Y, Qing Z, Tang Q, Cao H, Cheng P, Zheng Y, Yuan Z, Zhou Y, Liu J, Tang Z, Zhuo Y, Zhang Y, Yu L, Huang J, Yang P, Peng Q, Zhang J, Jiang W, Zhang Z, Lin K, Ro DK, Chen X, Xiong X, Shang Y, Huang S, Zeng J (- 19) Ref: Mol Plant, 10:975, 2017 : PubMed ESTHER: Liu_2017_Mol.Plant_10_975 PubMedSearch: Liu 2017 Mol.Plant 10 975 PubMedID: 28552780 Gene_locus related to this paper: 9magn-a0a200rdw7, 9magn-a0a200qd12, 9magn-a0a200pqd0, 9magn-a0a200q3h1, 9magn-a0a200r223, 9magn-a0a200qv20 Abstract The overuse of antibiotics in animal agriculture and medicine has caused a series of potential threats to public health. Macleaya cordata is a medicinal plant species from the Papaveraceae family, providing a safe resource for the manufacture of antimicrobial feed additive for livestock. The active constituents from M. cordata are known to include benzylisoquinoline alkaloids (BIAs) such as sanguinarine (SAN) and chelerythrine (CHE), but their metabolic pathways have yet to be studied in this non-model plant. The active biosynthesis of SAN and CHE in M. cordata was first examined and confirmed by feeding (13)C-labeled tyrosine. To gain further insights, we de novo sequenced the whole genome of M. cordata, the first to be sequenced from the Papaveraceae family. The M. cordata genome covering 378 Mb encodes 22,328 predicted protein-coding genes with 43.5% being transposable elements. As a member of basal eudicot, M. cordata genome lacks the paleohexaploidy event that occurred in almost all eudicots. From the genomics data, a complete set of 16 metabolic genes for SAN and CHE biosynthesis was retrieved, and 14 of their biochemical activities were validated. These genomics and metabolic data show the conserved BIA metabolic pathways in M. cordata and provide the knowledge foundation for future productions of SAN and CHE by crop improvement or microbial pathway reconstruction. Title: Enzymatic synthesis of lysophosphatidylcholine with n-3 polyunsaturated fatty acid from sn-glycero-3-phosphatidylcholine in a solvent-free system Liu Y, Zhang Q, Guo Y, Liu J, Xu J, Li Z, Wang J, Wang Y, Xue C Ref: Food Chem, 226:165, 2017 : PubMed ESTHER: Liu_2017_Food.Chem_226_165 PubMedSearch: Liu 2017 Food.Chem 226 165 PubMedID: 28254008 Abstract The n-3 polyunsaturated fatty acids (PUFA)-rich lysophosphatidylcholine (LPC) was successfully synthesized by Thermomyces lanuginosus lipase (TL IM)-catalyzed esterification of glycerylphosphorylcholine (GPC) and n-3 PUFA-rich fatty acids in a solvent-free system. Effects of reaction temperature, enzyme loading and substrate mole ratio on the yield of LPC and incorporation of n-3 PUFA were evaluated. The acyl-specificities of five enzymes were tested for direct esterification of n-3 PUFA, and Lipozyme TL IM was found to be more effective than others for production of LPC with n-3 PUFA. Substrate mole ratio and reaction temperature, however, had no significant effect on the incorporation. The maximal yield of LPC was obtained under the following conditions: temperature 45 degC, enzyme loading 15% by weight and substrate mole ratio (GPC/n-3 PUFA) 1:20. Furthermore, the composition of products were further investigated in the study. The 1-acyl-sn-glycero-3-lysophosphatidylcholine (2-LPC) was predominant in the mixtures at early stages of reaction, whereas less increment of 2-acyl-sn-glycero-3-lysophosphatidylcholine (1-LPC) and PC was observed at later stages. Title: Bioconcentration and multi-biomarkers of organic UV filters (BM-DBM and OD-PABA) in crucian carp Ma B, Lu G, Liu J, Yan Z, Yang H, Pan T Ref: Ecotoxicology & Environmental Safety, 141:178, 2017 : PubMed ESTHER: Ma_2017_Ecotoxicol.Environ.Saf_141_178 PubMedSearch: Ma 2017 Ecotoxicol.Environ.Saf 141 178 PubMedID: 28343007 Abstract Organic UV filters (OUV-Fs) are increasingly used in sunscreens and personal care products. In the present work, the bioconcentration and multi-biomarker effects of butyl methoxydibenzoylmethane (BM-DBM) and ethylhexyl dimethyl p-aminobenzoate (OD-PABA) were investigated in crucian carp (Carassius auratus). The fish were exposed to various concentrations of BM-DBM (3.88, 35.61, 181.85 and 337.15mug/L), OD-PABA (4.66, 53.83, 264.22 and 459.32mug/L) and their mixture (2.31+2.79, 23.69+26.18, 97.37+134.81 and 193.93+246.08mug/L) for 28 days. The maximal concentrations of two OUV-Fs were detected in the fish liver, followed by the brain, kidney, gill and muscle in most cases. The maximal BCF values of OD-PABA calculated in various exposure concentrations were 0.37 - 101.21 in single exposure groups and 0.11 - 31.09 in mixed exposure groups. Acetylcholinesterase (AChE) activity was significantly inhibited by BM-DBM as well as the mixtures at all of the exposure concentrations and by OD-PABA at higher concentrations (>/=264.22mug/L) during 28 days of exposure. The maximal inhibition rates of AChE activity reached 64.04% for BM-DBM, 41.05% for OD-PABA and 61.50% for the mixtures at the highest concentration, which indicated that these two OUV-Fs might damage the central nervous system. Concerning oxidative stress status, BM-DBM and the mixtures significantly increased superoxide dismutase (SOD) and glutathione reductase (GR) activities and inhibited catalase (CAT) activity, while OD-PABA caused a significant increase of GR and CAT activities. AChE and GR activities seemed to be more sensitive biomarkers for BM-DBM and OD-PABA. Title: Rational Design of a Red-Emissive Fluorophore with AIE and ESIPT Characteristics and Its Application in Light-Up Sensing of Esterase Peng L, Xu S, Zheng X, Cheng X, Zhang R, Liu J, Liu B, Tong A Ref: Analytical Chemistry, 89:3162, 2017 : PubMed ESTHER: Peng_2017_Anal.Chem_89_3162 PubMedSearch: Peng 2017 Anal.Chem 89 3162 PubMedID: 28192960 Abstract The development of red fluorophores with efficient solid-state emission is still challenging. Herein, a red fluorophore 1 with aggregation-induced emission (AIE) and excited-state intramolecular proton transfer (ESIPT) characteristics is rationally designed and facilely synthesized by attaching an electron-donor diethylamine and an electron-acceptor maleonitrile group to salicyladazine. In contrast to many red fluorophores which undergo serious aggregation-caused quenching (ACQ), compound 1 emits bright red fluorescence (lambdaem = 650 nm, PhiF = 24.3%) in the solid state with a large Stokes shift of 174 nm. Interestingly, control compounds 2 and 3, which have similar structures as 1, exhibit obvious aggregation-caused quenching (ACQ) characteristics. The difference in the crystal structures of 1, 2, and 3 reveals that the interplanar spacing among molecules plays a decisive role in realizing the AIE characteristics of 1. Moreover, when the hydroxyl group of 1 was substituted by an esterase reactive acetoxyl, a fluorescence light-up probe 4 was developed for sensing of esterase based on the selective reaction between 4 and esterase to generate the AIE and ESIPT active molecule 1. The linear range for in vitro quantification of esterase is 0.01-0.15 U/mL with a detection limit of 0.005 U/mL. Probe 4 was also successfully applied to image esterase in mitochondria of living cells. Title: Scallop genome provides insights into evolution of bilaterian karyotype and development Wang S, Zhang J, Jiao W, Li J, Xun X, Sun Y, Guo X, Huan P, Dong B and Bao Z <42 more author(s)> Wang S, Zhang J, Jiao W, Li J, Xun X, Sun Y, Guo X, Huan P, Dong B, Zhang L, Hu X, Sun X, Wang J, Zhao C, Wang Y, Wang D, Huang X, Wang R, Lv J, Li Y, Zhang Z, Liu B, Lu W, Hui Y, Liang J, Zhou Z, Hou R, Li X, Liu Y, Li H, Ning X, Lin Y, Zhao L, Xing Q, Dou J, Mao J, Guo H, Dou H, Li T, Mu C, Jiang W, Fu Q, Fu X, Miao Y, Liu J, Yu Q, Li R, Liao H, Kong Y, Jiang Z, Chourrout D, Bao Z (- 42) Ref: Nat Ecol Evol, 1:120, 2017 : PubMed ESTHER: Wang_2017_Nat.Ecol.Evol_1_120 PubMedSearch: Wang 2017 Nat.Ecol.Evol 1 120 PubMedID: 28812685 Gene_locus related to this paper: mizye-a0a210qls6, mizye-a0a210qis3, mizye-a0a210qg00, mizye-a0a210ped6, mizye-a0a210q4h5, mizye-a0a210q4h9, mizye-a0a210q4j1, mizye-a0a210qf86, mizye-a0a210q332, mizye-a0a210pqn0, mizye-a0a210q7t5, mizye-a0a210pij5, mizye-a0a210qyk8, mizye-a0a210pwl7, mizye-a0a210q8u5, mizye-a0a210r5n9, mizye-a0a210qbv2, mizye-a0a210pu25, mizye-a0a210pek1, mizye-a0a210pul3, mizye-a0a210pum3, mizye-a0a210ptr6, mizye-a0a210ptq5, mizye-a0a210ptc4.1, mizye-a0a210ptc4.2, mizye-a0a210ptv1, mizye-a0a210ptv7, mizye-a0a210qgl6, mizye-a0a210qg90, mizye-a0a210ptq0, mizye-a0a210qg72, mizye-a0a210ptb1, mizye-a0a210pjd3, mizye-a0a210qg92, mizye-a0a210q8v2, mizye-a0a210qg93, mizye-a0a210q160.1, mizye-a0a210q160.2, mizye-a0a210qes4, mizye-a0a210pk25, mizye-a0a210q1b8, mizye-a0a210q110, mizye-a0a210r503, mizye-P021348901.1, mizye-P021348901.2 Abstract Reconstructing the genomes of bilaterian ancestors is central to our understanding of animal evolution, where knowledge from ancient and/or slow-evolving bilaterian lineages is critical. Here we report a high-quality, chromosome-anchored reference genome for the scallop Patinopecten yessoensis, a bivalve mollusc that has a slow-evolving genome with many ancestral features. Chromosome-based macrosynteny analysis reveals a striking correspondence between the 19 scallop chromosomes and the 17 presumed ancestral bilaterian linkage groups at a level of conservation previously unseen, suggesting that the scallop may have a karyotype close to that of the bilaterian ancestor. Scallop Hox gene expression follows a new mode of subcluster temporal co-linearity that is possibly ancestral and may provide great potential in supporting diverse bilaterian body plans. Transcriptome analysis of scallop mantle eyes finds unexpected diversity in phototransduction cascades and a potentially ancient Pax2/5/8-dependent pathway for noncephalic eyes. The outstanding preservation of ancestral karyotype and developmental control makes the scallop genome a valuable resource for understanding early bilaterian evolution and biology. Title: Biological effects of citalopram in a suspended sediment-water system on Daphnia magna Yang H, Lu G, Yan Z, Liu J, Ma B, Dong H Ref: Environ Sci Pollut Res Int, 24:21180, 2017 : PubMed ESTHER: Yang_2017_Environ.Sci.Pollut.Res.Int_24_21180 PubMedSearch: Yang 2017 Environ.Sci.Pollut.Res.Int 24 21180 PubMedID: 28733820 Abstract Suspended sediment (SPS) plays an important role in the aquatic ecosystems. Selective serotonin uptake inhibitors (SSRIs) are commonly used antidepressants and are frequently detected in aquatic environments. However, the biological effects of SSRIs in the presence of SPS are not well understood. To fill this gap, an SPS-water system was constructed to investigate the effects of citalopram (CIT) on Daphnia magna in the presence of SPS with different concentrations (0.1, 0.5, 1 g l(-1)) and organic carbon contents (0.5, 1, 1.5, 2%). A dialysis bag was applied in the exposure system to control the same dissolved concentration of CIT and prevent SPS from entering into the bag. The dissolved CIT concentration obviously decreased in the SPS-water system during the exposure period. The presence of SPS significantly increased the immobilization of D. magna, and the immobilization rates were positively correlated with the SPS concentration and negatively correlated with the organic carbon content in SPS. For a single exposure, CIT significantly increased superoxide dismutase (SOD) activity and inhibited acetylcholinesterase (AChE) activity in D. magna, while SPS itself did not change the SOD and AChE activities. In the SPS-water system, SOD activity was significantly suppressed, indicating that the SPS-CIT combination could result in oxidative damage. However, SPS did not enhance the neurotoxicity of D. magna that was induced by CIT. These results suggest that SPS exerts a vital role on the biological effects of CIT and the contaminants sorbed on SPS should be taken into consideration. Title: Amaryllidaceae alkaloids with new framework types from Zephyranthes candida as potent acetylcholinesterase inhibitors Zhan G, Liu J, Zhou J, Sun B, Aisa HA, Yao G Ref: Eur Journal of Medicinal Chemistry, 127:771, 2017 : PubMed ESTHER: Zhan_2017_Eur.J.Med.Chem_127_771 PubMedSearch: Zhan 2017 Eur.J.Med.Chem 127 771 PubMedID: 27823880 Abstract Three new Amaryllidaceae alkaloids, named zephycandidines I-III (1-3), were isolated from Zephyranthes candida. The structures of 1-3 were elucidated by spectroscopic analyses including HRESIMS, 1H NMR, 13C NMR, DEPT, HSQC, 1H-1H COSY, HMBC, ROESY, and electronic circular dichroism (ECD), as well as ECD calculation. The absolute configuration of 1 was finally established by single crystal X-ray diffraction using Cu Kalpha radiation. Zephycandidines I (1) and III (3) with new framework types represent the first example of 7-phenyl-hexahydroindole and 5,2'-dimethyl-biphenyl-2-ylamine alkaloids, respectively, and their plausible biosynthetic pathway are proposed. Zephycandidine II (2) is the first C3a-phenyl-hexahydroindole type alkaloid isolated from the genus of Zephyranthes. These new alkaloids 1-3 were evaluated for their acetylcholinesterase (AChE) inhibitory activities, and 3 showed potent AChE inhibitory activity with an IC50 value of 8.82 muM, suggesting that the framework of 5,2'-dimethyl-biphenyl-2-ylamine in 3 may be a potential group for the AChE inhibitory activity. The docking studies of 1-3 and galanthamine with AChE revealed that interactions with W286 and Y337 are necessary for the AChE inhibitory activity. Title: Acetylcholinesterase Inhibitory Alkaloids from the Whole Plants of Zephyranthes carinata Zhan G, Zhou J, Liu J, Huang J, Zhang H, Liu R, Yao G Ref: Journal of Natural Products, 80:2462, 2017 : PubMed ESTHER: Zhan_2017_J.Nat.Prod_80_2462 PubMedSearch: Zhan 2017 J.Nat.Prod 80 2462 PubMedID: 28898076 Abstract Eleven new alkaloids (1-11), classified as the 12-acetylplicamine (1), N-deformyl-seco-plicamine (2), plicamine (3-6), 4a-epi-plicamine (7), seco-plicamine (8), and lycorine (9-11) framework types, along with 15 known alkaloids (12-26) were isolated from the whole plants of Zephyranthes carinata. The structures of the new alkaloids 1-11 were established by extensive spectroscopic data interpretation. The absolute configurations of 9 and 10 were defined by single-crystal X-ray diffraction analysis. Zephycarinatines A (1), B (2), and G (7) represent the first examples of 12-acetylplicamine, N-deformyl-seco-plicamine, and 4a-epi-plicamine alkaloids, respectively. Alkaloids 6, 11, 17, and 20-23 exhibited AChE inhibitory activities with IC50 values ranging from 1.21 to 184.05 muM, and a preliminary structure-activity relationship is discussed. Title: Crystal structure of a lipase from Streptomyces sp. strain W007 - implications for thermostability and regiospecificity Zhao Z, Hou S, Lan D, Wang X, Liu J, Khan FI, Wang Y Ref: Febs J, 284:3506, 2017 : PubMed ESTHER: Zhao_2017_FEBS.J_284_3506 PubMedSearch: Zhao 2017 FEBS.J 284 3506 PubMedID: 28857479 Gene_locus related to this paper: 9actn-h0b8d4 Abstract MAS1 from marine Streptomyces sp. strain W007 belongs to the bacterial lipase I.7 subfamily and is characterized as a thermostable and nonregiospecific lipase. To shed light on the catalytic mechanism of MAS1, we determined its crystal structure with closed conformation in two crystal forms at 2.3 A resolution. MAS1 adopts the canonical alpha/beta hydrolase core fold with its catalytic triad being formed by S109, D200 and H232. Structural analysis and biochemical assays revealed that disulfide bonds and salt bridges play a vital role in the thermostability of MAS1. In addition, we discovered that the replacement of H108 with a tryptophan converts MAS1 from a nonregiospecific to an sn-1,3-specific lipase, suggesting the functional importance of the second position from the conserved pentapeptide motif in defining the regiospecificity of MAS1. Our present study provides insights into the molecular basis for the thermostability and regiospecificity of MAS1, and it may aid in the rational design of thermostable or regiospecific lipases for potential industrial applications. DATABASE: Structural data are available in the Protein Data Bank database under the accession numbers 5H6B and 5H6G. Title: Is it possible to reverse aged acetylcholinesterase inhibited by organophosphorus compounds? Insight from the theoretical study An Y, Zhu Y, Yao Y, Liu J Ref: Phys Chem Chem Phys, 18:9838, 2016 : PubMed ESTHER: An_2016_Phys.Chem.Chem.Phys_18_9838 PubMedSearch: An 2016 Phys.Chem.Chem.Phys 18 9838 PubMedID: 27000635 Abstract The main treatment for organophosphorus (OP) compound poisoning in clinics is to restore the activity of acetylcholinesterase (AChE) through oxime-induced reactivation of the phosphorylated OP-AChE adduct. It suffers from a competitive and irreversible aging reaction of the phosphorylated OP-AChE adduct, resulting in permanent inactivity of AChE. However, it was recently reported that N-methyl-2-methoxypyridinium species can act as methylating agents to methylate the methyl methane-phosphonate monoanion, in which the reaction mimics the reverse of the aging reaction of the phosphorylated OP-AChE adduct. If the aging reaction could be really reversed, the efficiency for the OP detoxification should be significantly improved, bringing up the possibility to develop an agent to reverse the aging process of the phosphorylated OP-AChE adduct. However, such a reaction with the N-methyl-2-methoxypyridinium species in the enzyme is still not reported so far. It is of great interest to know whether or not this reaction is observable in the enzyme, and more importantly, if it turns out to be not observable in the enzyme, why such a reaction proceeds quickly in aqueous solution but not in the enzyme. In the present study, we performed DFT calculations and quantum mechanical/molecular mechanical (QM/MM) calculations to reveal the fundamental mechanism for the methylation of both the methyl methane-phosphonate monoanion and the aged sarin-AChE adduct by N-methyl-2-methoxypyridinium species, respectively. The obtained results support the SN2 reaction mechanism, not the stepwise mechanism, for the methylation of the methyl methane-phosphonate monoanion by 9 reported N-methyl-2-methoxypyridinium compounds. The calculated free energy barriers are in good agreement with the experimental data. The methylation of the aged sarin-AChE adduct by one N-methyl-2-methoxypyridinium compound (labeled as compound 2) also employs the SN2 reaction mechanism with an extremely high free energy barrier of 30.4 +/- 3.5 (or 26.6) kcal mol(-1), implying that this reaction in the enzyme hardly occurs. Our results clearly show that compound 2 forms a strong pi-pi stacking interaction with the aromatic ring of the W86 residue of AChE, making itself unable to approach sarin for the reverse of the aging process. On the basis of the structure and mechanism, several possible strategies have been suggested for designing methylating agents with higher activity against the aged sarin-AChE adduct. Title: Neuroligin-1 Knockdown Suppresses Seizure Activity by Regulating Neuronal Hyperexcitability Fang M, Wei JL, Tang B, Liu J, Chen L, Tang ZH, Luo J, Chen GJ, Wang XF Ref: Molecular Neurobiology, 53:270, 2016 : PubMed ESTHER: Fang_2016_Mol.Neurobiol_53_270 PubMedSearch: Fang 2016 Mol.Neurobiol 53 270 PubMedID: 25428619 Abstract Abnormally synchronized synaptic transmission in the brain leads to epilepsy. Neuroligin-1 (NL1) is a synaptic cell adhesion molecule localized at excitatory synapses. NL1 modulates synaptic transmission and determines the properties of neuronal networks in the mammalian central nervous system. We showed that the expression of NL1 and its binding partner neurexin-1beta was increased in temporal lobe epileptic foci in patients and lithium-pilocarpine-treated epileptic rats. We investigated electrophysiological and behavioral changes in epileptic rats after lentivirally mediated NL1 knockdown in the hippocampus to determine whether NL1 suppression prevented seizures and, if so, to explore the probable underlying mechanisms. Our behavioral studies revealed that NL1 knockdown in epileptic rats reduced seizure severity and increased seizure latency. Whole-cell patch-clamp recordings of CA1 pyramidal neurons in hippocampal slices from NL1 knockdown epileptic rats revealed a decrease in spontaneous action potential frequency and a decrease in miniature excitatory postsynaptic current (mEPSC) frequency but not amplitude. The amplitude of N-methyl-D-aspartate receptor (NMDAR)-dependent EPSCs was also selectively decreased. Notably, NL1 knockdown reduced total NMDAR1 expression and the surface/total ratio in the hippocampus of epileptic rats. Taken together, these data indicate that NL1 knockdown in epileptic rats may reduce the frequency and severity of seizures and suppress neuronal hyperexcitability via changes in postsynaptic NMDARs. Title: Analyses of the Binding between Water Soluble C60 Derivatives and Potential Drug Targets through a Molecular Docking Approach Junaid M, Almuqri EA, Liu J, Zhang H Ref: PLoS ONE, 11:e0147761, 2016 : PubMed ESTHER: Junaid_2016_PLoS.One_11_e0147761 PubMedSearch: Junaid 2016 PLoS.One 11 e0147761 PubMedID: 26829126 Abstract Fullerene C60, a unique sphere-shaped molecule consisting of carbon, has been proved to have inhibitory effects on many diseases. However, the applications of C60 in medicine have been severely hindered by its complete insolubility in water and low solubility in almost all organic solvents. In this study, the water-soluble C60 derivatives and the C60 binding protein's structures were collected from the literature. The selected proteins fall into several groups, including acetylcholinesterase, glutamate racemase, inosine monophosphate dehydrogenase, lumazine synthase, human estrogen receptor alpha, dihydrofolate reductase and N-myristoyltransferase. The C60 derivatives were docked into the binding sites in the proteins. The binding affinities of the C60 derivatives were calculated. The bindings between proteins and their known inhibitors or native ligands were also characterized in the same way. The results show that C60 derivatives form good interactions with the binding sites of different protein targets. In many cases, the binding affinities of C60 derivatives are better than those of known inhibitors and native ligands. This study demonstrates the interaction patterns of C60 derivatives and their binding partners, which will have good impact on the fullerene-based drug discovery. Title: Bacterial Expression and Kinetic Analysis of Carboxylesterase 001D from Helicoverpa armigera Li Y, Liu J, Lu M, Ma Z, Cai C, Wang Y, Zhang X Ref: Int J Mol Sci, 17:, 2016 : PubMed ESTHER: Li_2016_Int.J.Mol.Sci_17_ PubMedSearch: Li 2016 Int.J.Mol.Sci 17 PubMedID: 27049381 Gene_locus related to this paper: helam-d5kxa9 Abstract Carboxylesterasesare an important class of detoxification enzymes involved in insecticide resistance in insects. A subgroup of Helicoverpa armigera esterases, known as Clade 001, was implicated in organophosphate and pyrethroid insecticide resistance due to their overabundance in resistant strains. In this work, a novel carboxylesterasegene 001D of H. armigera from China was cloned, which has an open reading frame of 1665 nucleotides encoding 554 amino acid residues. We used a series of fusion proteins to successfully express carboxylesterase 001D in Escherichia coli. Three different fusion proteins were generated and tested. The enzyme kinetic assay towards 1-naphthyl acetate showed all three purified fusion proteins are active with a Kcat between 0.35 and 2.29 s(-1), and a Km between 7.61 and 19.72 muM. The HPLC assay showed all three purified fusion proteins had low but measurable hydrolase activity towards beta-cypermethrin and fenvalerate insecticides (specific activities ranging from 0.13 to 0.67 muM.min(-1).(muM(-1).protein)). The enzyme was stable up to 40 degrees C and at pH 6.0-11.0. The results imply that carboxylesterase 001D is involved in detoxification, and this moderate insecticide hydrolysis may suggest that overexpression of the gene to enhance insecticide sequestration is necessary to allow carboxylesterases to confer resistance to these insecticides in H. armigera. Title: Increased Lipoprotein-associated phospholipase A2 activity portends an increased risk of resistant hypertension Li Z, Liu J, Shen Y, Zeng F, Zheng D Ref: Lipids Health Dis, 15:15, 2016 : PubMed ESTHER: Li_2016_Lipids.Health.Dis_15_15 PubMedSearch: Li 2016 Lipids.Health.Dis 15 15 PubMedID: 26801405 Abstract BACKGROUND: To investigate the relationship between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and incidence of resistant hypertension (RH). Title: Bioconcentration and metabolism of ketoconazole and effects on multi-biomarkers in crucian carp (Carassius auratus) Liu J, Lu G, Yang H, Yan Z, Wang Y, Wang P Ref: Chemosphere, 150:145, 2016 : PubMed ESTHER: Liu_2016_Chemosphere_150_145 PubMedSearch: Liu 2016 Chemosphere 150 145 PubMedID: 26901470 Abstract The tissue distribution, bioconcentration, metabolism and biological effects of the antifungal medication ketoconazole were investigated in fish, crucian carp (Carassius auratus) were exposed to a series of nominal concentrations (0.2, 2 and 20 mug/L) for 14 days. The ultra-high performance liquid chromatography tandem triple quadrupole mass spectroscopy (UPLC/MS/MS) analysis was used to determine the bioconcentration of ketoconazole and its metabolites in fish. The highest tissue concentration of ketoconazole was observed in the liver with the bioconcentration factor of 257.2, which is lower than the estimated BCF value. The ability of crucian carp to metabolize ketoconazole was confirmed and the results pointed out the existence of seven metabolites likely formed via oxidation of imidazole ring and the metabolic alteration of the piperazine rings. In addition, acetylcholinesterase, 7-ethoxyresorufin O-deethylase, superoxide dismutase and glutathione S-transferase changed significantly after 3, 7 and 14 days of exposure (P < 0.05), which indicated that the accumulation and metabolism of ketoconazole in fish tissues may account for the biological effects. Title: Acute restraint stress provokes sudden cardiac death in normotensive rats and enhances susceptibility to arrhythmogenic effects of adrenaline in spontaneously hypertensive rats Liu J, Hakucho A, Liu X, Fujimiya T Ref: Leg Med (Tokyo), 21:19, 2016 : PubMed ESTHER: Liu_2016_Leg.Med.(Tokyo)_21_19 PubMedSearch: Liu 2016 Leg.Med.(Tokyo) 21 19 PubMedID: 27497329 Abstract BACKGROUND: A high incidence of cardiovascular events and sudden cardiac death (SCD) has been reported following unexpected acute psychosocial stress. The possible pathways by which acute restraint stress (ARS), a kind of acute psychosocial stress, leads to SCD were determined. Title: Transcriptome differences between fiber-type and seed-type Cannabis sativa variety exposed to salinity Liu J, Qiao Q, Cheng X, Du G, Deng G, Zhao M, Liu F Ref: Physiol Mol Biol Plants, 22:429, 2016 : PubMed ESTHER: Liu_2016_Physiol.Mol.Biol.Plants_22_429 PubMedSearch: Liu 2016 Physiol.Mol.Biol.Plants 22 429 PubMedID: 27924117 Abstract The industrial hemp varieties 'Yunma 5' and 'Bamahuoma,' which demonstrate growth vigor and environmental adaptability, have been primarily cultivated in Yunnan and Guangxi, China, respectively, for fiber and seeds. The results of physiological measurements showed the phenotypic differences between the two varieties in response to salt stress. RNA-Seq analysis was first performed on leaves of both varieties sampled at four time intervals (0, 2, 4, 6 days) after treatment with salt (500 mM NaCl) We identified 220 co-up-regulated differentially expressed genes (DEGs) in the two varieties, while 26 up-regulated DEGs and 24 down-regulated DEGs were identified exclusively in the single varieties after 2 days of salt stress. Among the 220 DEGs, we identified 22 transcription factors, including key transcription factors involved in salt stress, such as MYB, NAC, GATA, and HSF. We applied gene expression profile analysis and found that 'Yunma 5' and 'Bamahuoma' have variety-specific pathways for resisting salt stress. The DEGs of 'Yunma 5' were enriched in spliceosome and amino acid metabolism genes, while the DEGs of 'Bamahuoma' were enriched in fatty acid metabolism, amino acid metabolism, and endoplasmic reticulum protein processing pathway. Although there were common DEGs, such as genes encoding cysteine protease and alpha/beta-hydrolase superfamily, the two varieties' responses to salt stress impacted different metabolic pathways. The DEGs that were co-expressed in both varieties under stress may provide useful insights into the tolerance of cultivated hemp and other bast fiber crops to saline soil conditions. These transcriptomes also represent reference sequences for industrial hemp. Title: Fluoxetine reduces CES1, CES2, and CYP3A4 expression through decreasing PXR and increasing DEC1 in HepG2 cells Shang W, Liu J, Chen R, Ning R, Xiong J, Liu W, Mao Z, Hu G, Yang J Ref: Xenobiotica, 46:393, 2016 : PubMed ESTHER: Shang_2016_Xenobiotica_46_393 PubMedSearch: Shang 2016 Xenobiotica 46 393 PubMedID: 26340669 Gene_locus related to this paper: human-CES1 Abstract 1. This study investigated the mechanisms of the decreases of carboxylesterases (CES) and cytochrome P4503A4 (CYP3A4) and the enzymatic activities induced by fluoxetine (FLX) in HepG2 cells. We found that FLX decreased the carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) expression and the hydrolytic activity. 2. FLX decreased the pregnane X receptor (PXR) expression which regulated the target genes such as CYP3A4, whereas increased the differentiated embryonic chondrocyte-expressed gene 1 (DEC1) expression. 3. FLX repressed the PXR at transcriptional level. 4. Overexpression of PXR alone increased the expression of CES1, CES2, and CYP3A4 and attenuated the decreases of CES1, CES2, and CYP3A4 induced by FLX. On the contrary, knockdown of PXR alone decreased the expression of CES1, CES2, and CYP3A4 and almost abolished the decreases of CES1, CES2, and CYP3A4 induced by FLX. 5. Knockdown of DEC1 alone increased the expression of PXR and CYP3A4 and almost abolished the decreases of CES1, CES2, and CYP3A4 induced by FLX. 6. Taken together, the decreases of CES and CYP3A4 expression and enzymatic activities induced by FLX are through decreasing PXR and increasing DEC1 in HepG2 cells. Title: Lipase-Driven Epoxidation Is A Two-Stage Synergistic Process Tang, Q, Popowicz GM, Wang X, Liu J, Pavlidis IV, Wang Y Ref: ChemistrySelect, 4:836, 2016 : PubMed ESTHER: Tang_2016_ChemistrySelect_4_836 PubMedSearch: Tang 2016 ChemistrySelect 4 836 Gene_locus related to this paper: penca-mdgli Abstract Lipases show high stability in lipophilic solvents and catalyze reactions at the water-oil interfaces, which are of great industrial interest. One promising application of lipases is the production of epoxides from alkenes and hydrogen peroxide. So far, little attention has been given to uncover the reaction mechanism for this in detail at the molecular level. Here, we present structural and mutational analysis of a lipase from Penicillium camembertii that indicates a two-stage synergistic mechanism for this reaction. Surprisingly, a mutant devoid of the catalytic serine retains a fraction of activity while histidine from the catalytic triad is absolutely critical to maintain the enzyme activity. Histidine appears to perform a dual-activation role acting both towards hydrogen peroxide and the catalytic serine. These results thus allow a better understanding of enzymatic epoxidation and engineering of more potent, stable and selective enzymes. Title: Novel nonquaternary reactivators showing reactivation efficiency for soman-inhibited human acetylcholinesterase Wei Z, Liu YQ, Wang YA, Li WH, Zhou XB, Zhao J, Huang CQ, Li XZ, Liu J and Li S <1 more author(s)> Wei Z, Liu YQ, Wang YA, Li WH, Zhou XB, Zhao J, Huang CQ, Li XZ, Liu J, Zheng ZB, Li S (- 1) Ref: Toxicol Lett, 246:1, 2016 : PubMed ESTHER: Wei_2016_Toxicol.Lett_246_1 PubMedSearch: Wei 2016 Toxicol.Lett 246 1 PubMedID: 26809136 Abstract Soman is a highly toxic nerve agent with strong inhibition of acetylcholinesterase (AChE), but of the few reactivators showing antidotal efficiency for soman-inhibited AChE presently are all permanently charged cationic oximes with poor penetration of the blood-brain barrier. To overcome this problem, uncharged reactivators have been designed and synthesized, but few of them were efficient for treating soman poisoning. Herein, we used a dual site biding strategy to develop more efficient uncharged reactivators. The ortho-hydroxylbenzaldoximes were chosen as reactivation ligands of AChE to prevent the secondary poisoning of AChE, and simple aromatic groups were used as peripheral site ligands of AChE, which were linked to the oximes in a similar way as that found in the reactivator HI-6. The in vitro experiment demonstrated that some of the resulting conjugates have robust activity against soman-inhibited AChE, and oxime 8b was highlighted as the most efficient one. Although not good as HI-6 in vitro, these new compounds hold promise for development of more efficient centrally acting reactivators for soman poisoning due to their novel nonquaternary structures, which are predicted to be able to cross the blood-brain barrier. Title: Characteristics of carboxylesterase genes and their expression-level between acaricide-susceptible and resistant Tetranychus cinnabarinus (Boisduval) Wei P, Shi L, Shen G, Xu Z, Liu J, Pan Y, He L Ref: Pestic Biochem Physiol, 131:87, 2016 : PubMed ESTHER: Wei_2016_Pestic.Biochem.Physiol_131_87 PubMedSearch: Wei 2016 Pestic.Biochem.Physiol 131 87 PubMedID: 27265830 Gene_locus related to this paper: tetur-t1jth5, tetur-t1kth5, tetur-t1kwe1, tetur-t1kx09, tetur-t1kxr8, tetur-t1l430, tetur-t1kgp1, tetur-t1l0m8, tetur-t1knw0, tetur-t1kgp7, tetur-t1l013, tetur-t1jz51, tetur-t1kg31, tetur-t1knv9, tetur-t1jrz3, tetur-t1k786, tetur-t1jth6, tetur-t1jtg9, tetur-t1kpg7, tetur-t1jvb8, tetur-t1kvj7 Abstract Carboxylesterases (CarEs) play important roles in metabolism and detoxification of dietary and environmental xenobiotics in insects and mites. On the basis of the Tetranychuscinnabarinus transcriptome dataset, 23 CarE genes (6 genes are full sequence and 17 genes are partial sequence) were identified. Synergist bioassay showed that CarEs were involved in acaricide detoxification and resistance in fenpropathrin- (FeR) and cyflumetofen-resistant (CyR) strains. In order to further reveal the relationship between CarE gene's expression and acaricide-resistance in T. cinnabarinus, we profiled their expression in susceptible (SS) and resistant strains (FeR, and CyR). There were 8 and 4 over-expressed carboxylesterase genes in FeR and CyR, respectively, from which the over-expressions were detected at mRNA level, but not DNA level. Pesticide induction experiment elucidated that 4 of 8 and 2 of 4 up-regulated genes were inducible with significance in FeR and CyR strains, respectively, but they could not be induced in SS strain, which indicated that these genes became more enhanced and effective to withstand the pesticides' stress in resistant T. cinnabarinus. Most expression-changed and all inducible genes possess the Abhydrolase_3 motif, which is a catalytic domain for hydrolyzing. As a whole, these findings in current study provide clues for further elucidating the function and regulation mechanism of these carboxylesterase genes in T. cinnabarinus' resistance formation. Title: Zephycandidine A, the First Naturally Occurring Imidazo[1,2-f]phenanthridine Alkaloid from Zephyranthes candida, Exhibits Significant Anti-tumor and Anti-acetylcholinesterase Activities Zhan G, Qu X, Liu J, Tong Q, Zhou J, Sun B, Yao G Ref: Sci Rep, 6:33990, 2016 : PubMed ESTHER: Zhan_2016_Sci.Rep_6_33990 PubMedSearch: Zhan 2016 Sci.Rep 6 33990 PubMedID: 27658482 Abstract Zephycandidine A (1), the first naturally occurring imidazo[1,2-f]phenanthridine alkaloid, was isolated from Zephyranthes candida (Amaryllidaceae). The structure of 1 was elucidated by spectroscopic analyses and NMR calculation, and a plausible biogenetic pathway for zephycandidine A (1) was proposed. Zephycandidine A (1) exhibited significant cytotoxicity against five cancer cell lines with IC50 values ranging from 1.98 to 7.03 muM with selectivity indices as high as 10 when compared to the normal Beas-2B cell. Further studies suggested that zephycandidine A (1) induces apoptosis in leukemia cells by the activation of caspase-3, upregulation of Bax, downregulation of Bcl-2, and degradation of PARP expression. In addition, zephycandidine A (1) showed acetylcholinesterase (AChE) inhibitory activity, and the docking studies of zephycandidine A (1) and galanthamine (2) with AChE revealed that interactions with W286 and Y337 are necessary. Title: [Role of alpha7 nicotinic acetylcholine receptor in attenuation of endotoxin induced delirium with dexmedetomidine in mice] Zhang X, Li Z, Sun X, Jin F, Liu J, Li J Ref: Zhonghua Wei Zhong Bing Ji Jiu Yi Xue, 28:127, 2016 : PubMed ESTHER: Zhang_2016_Zhonghua.Wei.Zhong.Bing.Ji.Jiu.Yi.Xue_28_127 PubMedSearch: Zhang 2016 Zhonghua.Wei.Zhong.Bing.Ji.Jiu.Yi.Xue 28 127 PubMedID: 26911944 Abstract OBJECTIVE: To observe the role of alpha7 nicotinic acetylcholine receptor (alpha7nAChR) in the protection against delirium by the use of dexmedetomidine (DEX) in endotoxin derived delirium and its mechanism. Title: Artificial hydrolase based on carbon nanotubes conjugated with peptides Zhang Q, He X, Han A, Tu Q, Fang G, Liu J, Wang S, Li H Ref: Nanoscale, 8:16851, 2016 : PubMed ESTHER: Zhang_2016_Nanoscale_8_16851 PubMedSearch: Zhang 2016 Nanoscale 8 16851 PubMedID: 27714071 Abstract An artificial enzyme was constructed by attaching short peptides with active sites (SHELKLKLKL, WLKLKLKL) onto carbon nanotubes (CNT). It was found that the combination of SHE amino acids was essential to form a catalytic triad. W was also incorporated into this artificial enzyme and acted as a substrate binding site, thus producing an enzyme model with synergism of 67.7% catalytic groups and 32.3% binding groups, CNT-(SHE/W)2:1-LKLKLKL. When the peptide SHELKLKLKL was attached with the catalytic triad site close to the surface of CNT, the composite had higher activity than a leucine-attached system terminated with the catalytic triad site, suggesting that CNT not only served as a platform for attaching active amino acids, but also created a hydrophobic microenvironment and facilitated the proton transfer process to enhance the catalytic activity. The artificial enzyme exhibited Michaelis-Menten behaviour, indicating that it was indeed a mimic of the corresponding natural enzyme. This work showed that a well-designed combination of CNT and short peptides containing active sites can mimic a natural enzyme. Title: Decreased carboxylesterases expression and hydrolytic activity in type 2 diabetic mice through Akt/mTOR/HIF-1alpha/Stra13 pathway Chen R, Wang Y, Ning R, Hu J, Liu W, Xiong J, Wu L, Liu J, Hu G, Yang J Ref: Xenobiotica, 45:782, 2015 : PubMed ESTHER: Chen_2015_Xenobiotica_45_782 PubMedSearch: Chen 2015 Xenobiotica 45 782 PubMedID: 25801056 Abstract 1. This study investigated the alteration of carboxylesterases in type 2 diabetes. We found that the carboxylesterase 1d (Ces1d) and carboxylesterase 1e (Ces1e) expression and the capacity of hydrolytic activity of liver and intestine decreased, whereas the Akt/mTOR/HIF-1alpha/ Stra13 (DEC1) signaling was activated in T2D mice. Consistently, high insulin could give rise to the same results in the high-glucose DMEM condition, which mimicked T2D, in primary mouse hepatocytes. 2. Perifosine or rapamycin almost abolished the decrease of the Ces1d and Ces1e expression and the hydrolytic activity induced by the insulin in the primary mouse hepatocytes. 3. The responsiveness of human hepatoma (HepG2) cells to high insulin in high-glucose condition was similar to that of primary mouse hepatocytes in terms of the altered expression of carboxylesterases. 4. The knockdown of HIF-1alpha or DEC1 with shRNA construct abrogated the decrease of the CES1 and CES2 expression induced by the insulin in high glucose condition in HepG2 cells. 5. Taken together, the decreased carboxylesterases expression and hydrolytic activity in T2D mice are through the Akt/mTOR/HIF-1alpha/Stra13 (DEC1) pathway. Title: Structure of product-bound SMG1 lipase: active site gating implications Guo S, Xu J, Pavlidis IV, Lan D, Bornscheuer UT, Liu J, Wang Y Ref: Febs J, 282:4538, 2015 : PubMed ESTHER: Guo_2015_FEBS.J_282_4538 PubMedSearch: Guo 2015 FEBS.J 282 4538 PubMedID: 26365206 Gene_locus related to this paper: malgo-a8puy1 Abstract Monoacylglycerol and diacylglycerol lipases are industrially interesting enzymes, due to the health benefits that arise from the consumption of diglycerides compared to the traditional triglyceride oils. Most lipases possess an alpha-helix (lid) directly over the catalytic pocket which regulates the activity of the enzyme. Generally, lipases exist in active and inactive conformations, depending on the positioning of this lid subdomain. However, lipase SMG1, a monoacylglycerol and diacylglycerol specific lipase, has an atypical activation mechanism. In the present study we were able to prove by crystallography, in silico analysis and activity tests that only two positions, residues 102 and 278, are responsible for a gating mechanism that regulates the active and inactive states of the lipase, and that no significant structural changes take place during activation except for oxyanion hole formation. The elucidation of the gating effect provided data enabling the rational design of improved lipases with 6-fold increase in the hydrolytic activity toward diacylglycerols, just by providing additional substrate stabilization with a single mutation (F278N or F278T). Due to the conservation of F278 among the monoacylglycerol and diacylglycerol lipases in the Rhizomucor miehei lipase-like family, the gating mechanism described herein might represent a general mechanism applicable to other monoacylglycerol and diacylglycerol lipases as well. DATABASE: Structural data are available in the Protein Data Bank under the accession numbers 4ZRE (F278D mutant) and 4ZRD (F278N mutant). Title: Acetylcholinesterase inhibitory dimeric indole derivatives from the marine actinomycetes Rubrobacter radiotolerans Li JL, Huang L, Liu J, Song Y, Gao J, Jung JH, Liu Y, Chen G Ref: Fitoterapia, 102:203, 2015 : PubMed ESTHER: Li_2015_Fitoterapia_102_203 PubMedSearch: Li 2015 Fitoterapia 102 203 PubMedID: 25655350 Abstract Investigation of the bioactive secondary metabolites of the marine actinomycetes Rubrobacter radiotolerans led to the isolation and characterization of two naturally rare dimeric indole derivatives (1 and 2). The structures of these new compounds were elucidated by spectroscopic data interpretation, and the absolute configurations were assigned by CD calculations. The acetylcholinesterase (AchE) inhibitory activity of compounds 1 and 2 was evaluated, both of which showed moderate activity with IC50 values of 11.8 and 13.5muM, respectively. Title: Enzyme-Instructed Intracellular Molecular Self-Assembly to Boost Activity of Cisplatin against Drug-Resistant Ovarian Cancer Cells Li J, Kuang Y, Shi J, Zhou J, Medina JE, Zhou R, Yuan D, Yang C, Wang H and Xu B <3 more author(s)> Li J, Kuang Y, Shi J, Zhou J, Medina JE, Zhou R, Yuan D, Yang C, Wang H, Yang Z, Liu J, Dinulescu DM, Xu B (- 3) Ref: Angew Chem Int Ed Engl, 54:13307, 2015 : PubMed ESTHER: Li_2015_Angew.Chem.Int.Ed.Engl_54_13307 PubMedSearch: Li 2015 Angew.Chem.Int.Ed.Engl 54 13307 PubMedID: 26365295 Abstract Anticancer drug resistance demands innovative approaches that boost the activity of drugs against drug-resistant cancers without increasing the systemic toxicity. Here we show the use of enzyme-instructed self-assembly (EISA) to generate intracellular supramolecular assemblies that drastically boost the activity of cisplatin against drug-resistant ovarian cancer cells. We design and synthesize small peptide precursors as the substrates of carboxylesterase (CES). CES cleaves the ester bond pre-installed on the precursors to form the peptides that self-assemble in water to form nanofibers. At the optimal concentrations, the precursors themselves are innocuous to cells, but they double or triple the activity of cisplatin against the drug-resistant ovarian cancer cells. This work illustrates a simple, yet fundamental, new way to introduce non-cytotoxic components into combination therapies with cisplatin without increasing the systemic burden or side effects. Title: Design, synthesis and evaluation of novel 5,6,7-trimethoxyflavone-6-chlorotacrine hybrids as potential multifunctional agents for the treatment of Alzheimer's disease Liao S, Deng H, Huang S, Yang J, Wang S, Yin B, Zheng T, Zhang D, Liu J and Deng Z <2 more author(s)> Liao S, Deng H, Huang S, Yang J, Wang S, Yin B, Zheng T, Zhang D, Liu J, Gao G, Ma J, Deng Z (- 2) Ref: Bioorganic & Medicinal Chemistry Lett, 25:1541, 2015 : PubMed ESTHER: Liao_2015_Bioorg.Med.Chem.Lett_25_1541 PubMedSearch: Liao 2015 Bioorg.Med.Chem.Lett 25 1541 PubMedID: 25724825 Abstract A series of 5,6,7-trimethoxyflavone-6-chlorotacrine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that the target compounds exhibited good acetylcholinesterase (AChE) inhibitory potencies, high selectivity toward AChE over butyrylcholinesterase (BCHE), potential antioxidant activities and significant inhibitory potencies of self-induced beta-amyloid peptide (Abeta) aggregation. In particular, compound 14c had the strongest AChE inhibitory activity with IC50 value of 12.8nM, potent inhibition of self-induced Abeta1-42 aggregation with inhibition ratio of 33.8% at 25muM. Moreover, compound 14c acted as an antioxidant, as well as a neuroprotectant. Furthermore, 14c could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 14c might be a potential multifunctional candidate for the treatment of AD. Title: Comparative effects of parathion and chlorpyrifos on endocannabinoid and endocannabinoid-like lipid metabolites in rat striatum Liu J, Parsons L, Pope C Ref: Neurotoxicology, 50:20, 2015 : PubMed ESTHER: Liu_2015_Neurotoxicol_50_20 PubMedSearch: Liu 2015 Neurotoxicol 50 20 PubMedID: 26215119 Abstract Parathion and chlorpyrifos are organophosphorus insecticides (OPs) that elicit acute toxicity by inhibiting acetylcholinesterase (AChE). The endocannabinoids (eCBs, N-arachidonoylethanolamine, AEA; 2-arachidonoylglycerol, 2AG) are endogenous neuromodulators that regulate presynaptic neurotransmitter release in neurons throughout the central and peripheral nervous systems. While substantial information is known about the eCBs, less is known about a number of endocannabinoid-like metabolites (eCBLs, e.g., N-palmitoylethanolamine, PEA; N-oleoylethanolamine, OEA). We report the comparative effects of parathion and chlorpyrifos on AChE and enzymes responsible for inactivation of the eCBs, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and changes in the eCBs AEA and 2AG and eCBLs PEA and OEA, in rat striatum. Adult, male rats were treated with vehicle (peanut oil, 2ml/kg, sc), parathion (27mg/kg) or chlorpyrifos (280mg/kg) 6-7 days after surgical implantation of microdialysis cannulae into the right striatum, followed by microdialysis two or four days later. Additional rats were similarly treated and sacrificed for evaluation of tissue levels of eCBs and eCBLs. Dialysates and tissue extracts were analyzed by LC-MS/MS. AChE and FAAH were extensively inhibited at both time-points (85-96%), while MAGL activity was significantly but lesser affected (37-62% inhibition) by parathion and chlorpyrifos. Signs of toxicity were noted only in parathion-treated rats. In general, chlorpyrifos increased eCB levels while parathion had no or lesser effects. Early changes in extracellular AEA, 2AG and PEA levels were significantly different between parathion and chlorpyrifos exposures. Differential changes in extracellular and/or tissue levels of eCBs and eCBLs could potentially influence a number of signaling pathways and contribute to selective neurological changes following acute OP intoxications. Title: Molecular Simulation Study of Feruloyl Esterase Adsorption on Charged Surfaces: Effects of Surface Charge Density and Ionic Strength Liu J, Peng C, Yu G, Zhou J Ref: Langmuir, 31:10751, 2015 : PubMed ESTHER: Liu_2015_Langmuir_31_10751 PubMedSearch: Liu 2015 Langmuir 31 10751 PubMedID: 26379082 Abstract The surrounding conditions, such as surface charge density and ionic strength, play an important role in enzyme adsorption. The adsorption of a nonmodular type-A feruloyl esterase from Aspergillus niger (AnFaeA) on charged surfaces was investigated by parallel tempering Monte Carlo (PTMC) and all-atom molecular dynamics (AAMD) simulations at different surface charge densities (+/-0.05 and +/-0.16 C.m(-2)) and ionic strengths (0.007 and 0.154 M). The adsorption energy, orientation, and conformational changes were analyzed. Simulation results show that whether AnFaeA can adsorb onto a charged surface is mainly controlled by electrostatic interactions between AnFaeA and the charged surface. The electrostatic interactions between AnFaeA and charged surfaces are weakened when the ionic strength increases. The positively charged surface at low surface charge density and high ionic strength conditions can maximize the utilization of the immobilized AnFaeA. The counterion layer plays a key role in the adsorption of AnFaeA on the negatively charged COOH-SAM. The native conformation of AnFaeA is well preserved under all of these conditions. The results of this work can be used for the controlled immobilization of AnFaeA. Title: Characterization of large structural genetic mosaicism in human autosomes Machiela MJ, Zhou W, Sampson JN, Dean MC, Jacobs KB, Black A, Brinton LA, Chang IS, Chen C and Chanock SJ <188 more author(s)> Machiela MJ, Zhou W, Sampson JN, Dean MC, Jacobs KB, Black A, Brinton LA, Chang IS, Chen C, Chen K, Cook LS, Crous Bou M, De Vivo I, Doherty J, Friedenreich CM, Gaudet MM, Haiman CA, Hankinson SE, Hartge P, Henderson BE, Hong YC, Hosgood HD, 3rd, Hsiung CA, Hu W, Hunter DJ, Jessop L, Kim HN, Kim YH, Kim YT, Klein R, Kraft P, Lan Q, Lin D, Liu J, Le Marchand L, Liang X, Lissowska J, Lu L, Magliocco AM, Matsuo K, Olson SH, Orlow I, Park JY, Pooler L, Prescott J, Rastogi R, Risch HA, Schumacher F, Seow A, Setiawan VW, Shen H, Sheng X, Shin MH, Shu XO, VanDen Berg D, Wang JC, Wentzensen N, Wong MP, Wu C, Wu T, Wu YL, Xia L, Yang HP, Yang PC, Zheng W, Zhou B, Abnet CC, Albanes D, Aldrich MC, Amos C, Amundadottir LT, Berndt SI, Blot WJ, Bock CH, Bracci PM, Burdett L, Buring JE, Butler MA, Carreon T, Chatterjee N, Chung CC, Cook MB, Cullen M, Davis FG, Ding T, Duell EJ, Epstein CG, Fan JH, Figueroa JD, Fraumeni JF, Jr., Freedman ND, Fuchs CS, Gao YT, Gapstur SM, Patino-Garcia A, Garcia-Closas M, Gaziano JM, Giles GG, Gillanders EM, Giovannucci EL, Goldin L, Goldstein AM, Greene MH, Hallmans G, Harris CC, Henriksson R, Holly EA, Hoover RN, Hu N, Hutchinson A, Jenab M, Johansen C, Khaw KT, Koh WP, Kolonel LN, Kooperberg C, Krogh V, Kurtz RC, Lacroix A, Landgren A, Landi MT, Li D, Liao LM, Malats N, McGlynn KA, McNeill LH, McWilliams RR, Melin BS, Mirabello L, Peplonska B, Peters U, Petersen GM, Prokunina-Olsson L, Purdue M, Qiao YL, Rabe KG, Rajaraman P, Real FX, Riboli E, Rodriguez-Santiago B, Rothman N, Ruder AM, Savage SA, Schwartz AG, Schwartz KL, Sesso HD, Severi G, Silverman DT, Spitz MR, Stevens VL, Stolzenberg-Solomon R, Stram D, Tang ZZ, Taylor PR, Teras LR, Tobias GS, Viswanathan K, Wacholder S, Wang Z, Weinstein SJ, Wheeler W, White E, Wiencke JK, Wolpin BM, Wu X, Wunder JS, Yu K, Zanetti KA, Zeleniuch-Jacquotte A, Ziegler RG, de Andrade M, Barnes KC, Beaty TH, Bierut LJ, Desch KC, Doheny KF, Feenstra B, Ginsburg D, Heit JA, Kang JH, Laurie CA, Li JZ, Lowe WL, Marazita ML, Melbye M, Mirel DB, Murray JC, Nelson SC, Pasquale LR, Rice K, Wiggs JL, Wise A, Tucker M, Perez-Jurado LA, Laurie CC, Caporaso NE, Yeager M, Chanock SJ (- 188) Ref: American Journal of Human Genetics, 96:487, 2015 : PubMed ESTHER: Machiela_2015_Am.J.Hum.Genet_96_487 PubMedSearch: Machiela 2015 Am.J.Hum.Genet 96 487 PubMedID: 25748358 Abstract Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population. Title: In vitro characterization of cationic copolymer-complexed recombinant human butyrylcholinesterase Pope C, Uchea C, Flynn N, Poindexter K, Geng L, Brimijoin S, Hartson S, Ranjan A, Ramsey JD, Liu J Ref: Biochemical Pharmacology, 98:531, 2015 : PubMed ESTHER: Pope_2015_Biochem.Pharmacol_98_531 PubMedSearch: Pope 2015 Biochem.Pharmacol 98 531 PubMedID: 26456723 Abstract Effective use of exogenous human BChE as a bioscavenger for organophosphorus toxicants (OPs) is hindered by its limited availability and rapid clearance. Complexes made from recombinant human BChE (rhBChE) and copolymers may be useful in addressing these problems. We used in vitro approaches to compare enzyme activity, sensitivity to inhibition, stability and bioscavenging capacity of free enzyme and copolymer-rhBChE complexes (C-BCs) based on one of nine different copolymers, from combinations of three molecular weights (MW) of poly-l-lysine (PLL; high MW, 30-70kDa; medium MW, 15-30kDa; low MW, 4-15kDa) and three grafting ratios of poly(ethylene glycol) (PEG; 2:1, 10:1, 20:1). Retarded protein migration into acrylamide gels stained for BChE activity was noted with all copolymers as the copolymer-to-protein ratio was increased. BChE activity of C-BCs was lower relative to free enzyme, with the 2:1 grafting ratio showing generally greater reduction. Free enzyme and C-BCs showed relatively similar in vitro sensitivity to inhibition by paraoxon, but use of the 20:1 grafting ratio led to lower potencies. Through these screening assays we selected three C-BCs (high, medium and low MW; 10:1 grafting) for further characterizations. BChE activity was higher in C-BCs made with the medium and low compared to high MW-based copolymer. C-BCs generally showed higher stability than free enzyme when maintained for long periods at 37 degrees C or following incubation with chymotrypsin. Free enzyme and C-BCs were similarly effective at inactivating paraoxon in vitro. While these results are promising for further development, additional studies are needed to evaluate in vivo performance. Title: The genomes of two key bumblebee species with primitive eusocial organization Sadd BM, Barribeau SM, Bloch G, de Graaf DC, Dearden P, Elsik CG, Gadau J, Grimmelikhuijzen CJ, Hasselmann M and Worley KC <134 more author(s)> Sadd BM, Barribeau SM, Bloch G, de Graaf DC, Dearden P, Elsik CG, Gadau J, Grimmelikhuijzen CJ, Hasselmann M, Lozier JD, Robertson HM, Smagghe G, Stolle E, Van Vaerenbergh M, Waterhouse RM, Bornberg-Bauer E, Klasberg S, Bennett AK, Camara F, Guigo R, Hoff K, Mariotti M, Munoz-Torres M, Murphy T, Santesmasses D, Amdam GV, Beckers M, Beye M, Biewer M, Bitondi MM, Blaxter ML, Bourke AF, Brown MJ, Buechel SD, Cameron R, Cappelle K, Carolan JC, Christiaens O, Ciborowski KL, Clarke DF, Colgan TJ, Collins DH, Cridge AG, Dalmay T, Dreier S, du Plessis L, Duncan E, Erler S, Evans J, Falcon T, Flores K, Freitas FC, Fuchikawa T, Gempe T, Hartfelder K, Hauser F, Helbing S, Humann FC, Irvine F, Jermiin LS, Johnson CE, Johnson RM, Jones AK, Kadowaki T, Kidner JH, Koch V, Kohler A, Kraus FB, Lattorff HM, Leask M, Lockett GA, Mallon EB, Antonio DS, Marxer M, Meeus I, Moritz RF, Nair A, Napflin K, Nissen I, Niu J, Nunes FM, Oakeshott JG, Osborne A, Otte M, Pinheiro DG, Rossie N, Rueppell O, Santos CG, Schmid-Hempel R, Schmitt BD, Schulte C, Simoes ZL, Soares MP, Swevers L, Winnebeck EC, Wolschin F, Yu N, Zdobnov EM, Aqrawi PK, Blankenburg KP, Coyle M, Francisco L, Hernandez AG, Holder M, Hudson ME, Jackson L, Jayaseelan J, Joshi V, Kovar C, Lee SL, Mata R, Mathew T, Newsham IF, Ngo R, Okwuonu G, Pham C, Pu LL, Saada N, Santibanez J, Simmons D, Thornton R, Venkat A, Walden KK, Wu YQ, Debyser G, Devreese B, Asher C, Blommaert J, Chipman AD, Chittka L, Fouks B, Liu J, O'Neill MP, Sumner S, Puiu D, Qu J, Salzberg SL, Scherer SE, Muzny DM, Richards S, Robinson GE, Gibbs RA, Schmid-Hempel P, Worley KC (- 134) Ref: Genome Biol, 16:76, 2015 : PubMed ESTHER: Sadd_2015_Genome.Biol_16_76 PubMedSearch: Sadd 2015 Genome.Biol 16 76 PubMedID: 25908251 Abstract BACKGROUND: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Title: Effects of thyroxine and donepezil on hippocampal acetylcholine content, acetylcholinesterase activity, synaptotagmin-1 and SNAP-25 expression in hypothyroid adult rats Wang F, Zeng X, Zhu Y, Ning D, Liu J, Liu C, Jia X, Zhu D Ref: Mol Med Rep, 11:775, 2015 : PubMed ESTHER: Wang_2015_Mol.Med.Rep_11_775 PubMedSearch: Wang 2015 Mol.Med.Rep 11 775 PubMedID: 25371181 Abstract A growing number of studies have revealed that neurocognitive impairment, induced by adult-onset hypothyroidism, may not be fully restored by traditional hormone substitution therapies, including thyroxine (T4). The present study has investigated the effect of T4 and donepezil (DON; an acetylcholinesterase (AChE) inhibitor) treatment on the hypothyroidism-induced alterations of acetylcholine (ACh) content and AChE activity. Furthermore, we examined synaptotagmin-1 (syt-1) and SNAP-25 expression in the hippocampus of adult rats. Adding 0.05% propylthiouracil to their drinking water for five weeks induced hypothyroidism in the rat models. From the fourth week, the rats were treated with T4, DON or a combination of both. Concentration of ACh and the activity of AChE was determined colorimetrically. The results demonstrated that hypothyroidism induced a signi fi cant decrease of Ach content and AChE activity (by 17 and 34%, respectively), which were restored to control values by T4 administration. DON treatment also restored Ach to the normal level. Protein levels of syt-1 and SNAP-25 were determined by immunohistochemistry. The results demonstrated that syt-1 was expressed at significantly lower levels in hypothyroid rats, while SNAP-25 levels were notably higher compared with the controls. Two-week treatment with T4 alone failed to normalize the expression levels of these two proteins, while co-administration of T4 and DON was able to induce this effect. These data suggested that the thyroid hormone, T4, may have a direct effect on the metabolism of hippocampal ACh in adult rats, and that the DON treatment may facilitate the recovery of synaptic protein impairments induced by hypothyroidism. Title: Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors Wang C, Wu Z, Cai H, Xu S, Liu J, Jiang J, Yao H, Wu X, Xu J Ref: Bioorganic & Medicinal Chemistry Lett, 25:5212, 2015 : PubMed ESTHER: Wang_2015_Bioorg.Med.Chem.Lett_25_5212 PubMedSearch: Wang 2015 Bioorg.Med.Chem.Lett 25 5212 PubMedID: 26454504 Abstract A series of novel 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors have been designed and synthesized. The screening results showed that most of the compounds exhibited potent anti-AChE activity in the range of nM concentrations. The 1-(4-fluorobenzyl) substituted derivative 9d exhibited the most potent anti-AChE activity with IC50 value of 8.9nM and high AChE/BuChE selectivity (SI>230). Kinetic and molecular modeling studies suggested that compound 9d was mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. Besides, the preliminary structure-activity relationships were discussed. Title: Behavioral and biochemical responses in freshwater fish Carassius auratus exposed to sertraline Xie Z, Lu G, Li S, Nie Y, Ma B, Liu J Ref: Chemosphere, 135:146, 2015 : PubMed ESTHER: Xie_2015_Chemosphere_135_146 PubMedSearch: Xie 2015 Chemosphere 135 146 PubMedID: 25950408 Abstract Sertraline is one of the most commonly prescribed selective serotonin reuptake inhibitors and is frequently detected in the aquatic environment. However, knowledge regarding relationships among molecular or biochemical endpoints involved in modes of action (MOAs) of sertraline and ecologically important behavioral responses of fish is insufficient. The present study aimed to investigate the bioconcentration and possible adverse outcomes pathways (AOPs) in crucian carp (Carassius auratus) exposed to various concentrations of sertraline (4.36, 21.3 and 116mugL-1) for 7d. Bioconcentration factor values were in the range of 19.5-626 in liver, 6.94-285 in brain, 4.01-146 in gill and 0.625-43.1 in muscle during the entire period of exposure. Liver superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) activities and brain acetylcholinesterase (AChE) activity were selected as biochemical endpoints associated with MOAs. Swimming activity, shoaling, feeding rate and food consumption were determined to assess behavioral responses. Fish plasma levels of sertraline exceeding human therapeutic doses were also predicted from external exposure concentrations. Significant enhancements in CAT, GPx, AChE and swimming activities and decreases in shoaling tendency, feeding rate and food consumption were observed when fish plasma levels exceeded human therapeutic thresholds. Shoaling, feeding rate and food consumption were correlated with the activities of SOD, CAT and GST. A significant positive correlation between swimming activity and AChE activity was also observed. As such, our study provides important AOPs linking biochemical responses with ultimate ecologically relevant behavioral endpoints. Title: The Report of Sustained Low-Efficiency Dialysis (SLED) Treatment in Fifteen Patients of Severe Snakebite Cheng J, Wang D, Hu S, Jiang H, Lu H, Lei Q, Liu J, Yuan F, Chen R Ref: Cell Biochem Biophys, 69:71, 2014 : PubMed ESTHER: Cheng_2014_Cell.Biochem.Biophys_69_71 PubMedSearch: Cheng 2014 Cell.Biochem.Biophys 69 71 PubMedID: 24068524 Abstract To investigate the therapeutic efficacy of sustained low-efficiency dialysis (SLED) in severe snakebite patients. Fifteen patients of severe snakebite was treated with SLED from July 2005 to August 2009 were included in the study. Central venous access was established in all patients. SLED was administered using Dialog(+) dialyzer (B. Braun, Germany). SLED sessions were 6-12 h in duration at a blood flow rate of 200 ml/min and a dialysate flow rate of 300 ml/min. Heparin or low molecular weight heparin was used as anticoagulant. Biochemical indicators, APACHE II scores before and after SLED, and clinical outcomes were evaluated. The levels of serum creatinine, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, creatine kinase isozyme MB, and creatine kinase were significantly lower than the level before SLED (P < 0.05); the level of cholinesterase was significantly higher after SLED (P < 0.01); the APACHE II score before SLED was 14.1 +/- 3.8, but decreased significantly to 7.9 +/- 1.4, 6.2 +/- 1.1, and 4.2 +/- 0.8 on days 1, 2, and 7 after SLED, respectively (P < 0.01). Three patients died on days 1, 3, and 4 after SLED, respectively. The remaining twelve patients were either cured or showed improvement at the time of discharge. The survival rate was 80 % where as mortality was 20 %. SLED may be an effective treatment option in severe snakebite patients. It can reduce mortality, thereby, resulting in increased survival rates. Title: Ginsenoside Rg5 improves cognitive dysfunction and beta-amyloid deposition in STZ-induced memory impaired rats via attenuating neuroinflammatory responses Chu S, Gu J, Feng L, Liu J, Zhang M, Jia X, Liu M, Yao D Ref: Int Immunopharmacol, 19:317, 2014 : PubMed ESTHER: Chu_2014_Int.Immunopharmacol_19_317 PubMedSearch: Chu 2014 Int.Immunopharmacol 19 317 PubMedID: 24503167 Abstract Neuroinflammatory responses play a crucial role in the pathogenesis of Alzheimer's disease (AD). Ginsenoside Rg5 (Rg5), an abundant natural compound in Panax ginseng, has been found to be beneficial in treating AD. In the present study, we demonstrated that Rg5 improved cognitive dysfunction and attenuated neuroinflammatory responses in streptozotocin (STZ)-induced memory impaired rats. Cognitive deficits were ameliorated with Rg5 (5, 10 and 20mg/kg) treatment in a dose-dependent manner together with decreased levels of inflammatory cytokines TNF-alpha and IL-1beta (P<0.05) in brains of STZ rats. Acetylcholinesterase (AChE) activity was also significantly reduced by Rg5 whereas choline acetyltransferase (ChAT) activity was remarkably increased in the cortex and hippocampus of STZ-induced AD rats (P<0.05). In addition, Congo red and immunohistochemistry staining results showed that Rg5 alleviated Abeta deposition but enhanced the expressions of insulin-like growth factors 1 (IGF-1) and brain derived neurophic factor (BDNF) in the hippocampus and cerebral cortex (P<0.05). Western blot analysis also demonstrated that Rg5 increased remarkably BDNF and IGF-1 expressions whereas decreased significantly Abeta deposits (P<0.05). Furthermore, it was observed that the expressions of COX-2 and iNOS were significantly up-regulated in STZ-induced AD rats and down-regulated strongly (P<0.05) by Rg5 compared with control rats. These data demonstrated that STZ-induced learning and memory impairments in rats could be improved by Rg5, which was associated with attenuating neuroinflammatory responses. Our findings suggested that Rg5 could be a beneficial agent for the treatment of AD. Title: Investigation of a new acetogen isolated from an enrichment of the tammar wallaby forestomach Gagen EJ, Wang J, Padmanabha J, Liu J, de Carvalho IP, Webb RI, Al Jassim R, Morrison M, Denman SE, McSweeney CS Ref: BMC Microbiol, 14:314, 2014 : PubMed ESTHER: Gagen_2014_BMC.Microbiol_14_314 PubMedSearch: Gagen 2014 BMC.Microbiol 14 314 PubMedID: 25495654 Gene_locus related to this paper: 9firm-a0a0d0sh39 Abstract BACKGROUND: Forestomach fermentation in Australian marsupials such as wallabies and kangaroos, though analogous to rumen fermentation, results in lower methane emissions. Insights into hydrogenotrophy in these systems could help in devising strategies to reduce ruminal methanogenesis. Reductive acetogenesis may be a significant hydrogen sink in these systems and previous molecular analyses have revealed a novel diversity of putative acetogens in the tammar wallaby forestomach. Title: Identification of a marine bacillus strain c5 and parathion-methyl degradation characteristics of the extracellular esterase b1 Hao J, Liu J, Sun M Ref: Biomed Res Int, 2014:863094, 2014 : PubMed ESTHER: Hao_2014_Biomed.Res.Int_2014_863094 PubMedSearch: Hao 2014 Biomed.Res.Int 2014 863094 PubMedID: 25580438 Abstract A bacterial strain C5 that can produce new type of marine esterase was isolated and screened from marine sludge. According to 16S rRNA sequence analysis and physiological and biochemical experiments, the strain was identified as Bacillus subtilis. A single isozyme with a molecular weight of 86 kDa was observed by SDS-PAGE and native-PAGE. On this basis, the mechanism of esterase B1 secreted by strain C5 degrading parathion-methyl was explored, and the effects of temperature and pH on the degradation rate were investigated. From the results, p-nitrophenol was one of the degradation products of B1 degrading parathion-methyl, and the best degradation effect could be achieved at the temperature of 40 degrees C and the neutral pH value. Title: A multi-biomarker assessment of single and combined effects of norfloxacin and sulfamethoxazole on male goldfish (Carassius auratus) Liu J, Lu G, Wu D, Yan Z Ref: Ecotoxicology & Environmental Safety, 102:12, 2014 : PubMed ESTHER: Liu_2014_Ecotoxicol.Environ.Saf_102_12 PubMedSearch: Liu 2014 Ecotoxicol.Environ.Saf 102 12 PubMedID: 24580816 Abstract In the present study, the sublethal effects of norfloxacin alone and in combination with sulfamethoxazole in goldfish (Carassius auratus) were investigated, the biomarkers including acetylcholinesterase (AChE) in brain, 7-ethoxyresorufin O-deethylase (EROD), glutathione S-transferase (GST), and superoxides dismutase (SOD) activities in liver, vitellogenin (Vtg) in serum and DNA damage in gonad were determined after 1, 2, 4 and 7 days of exposure. Brain AChE activity was significantly inhibited by norfloxacin (>/=0.4mg/L) after 4 and 7 days and the mixtures with sulfamethoxazole (>/=0.24mg/L) after 4 days of exposure, and significant concentration-response relationships were obtained. Liver EROD, GST and SOD activities were significantly increased by the individual and mixed pharmaceuticals in most cases and exhibited analogously bell-shaped concentration-response curves. Serum Vtg was increased by the highest concentration of norfloxacin and two higher concentrations of the mixtures. Higher concentrations of the test antibiotics induced significant DNA damage in a concentration- and time-dependent manner. The results indicated that selected antibiotics possesses cytotoxic and genotoxic potential against the non-target organism C. auratus. Title: Bioconcentration, metabolism, and biomarker responses in freshwater fish Carassius auratus exposed to roxithromycin Liu J, Lu G, Wang Y, Yan Z, Yang X, Ding J, Jiang Z Ref: Chemosphere, 99:102, 2014 : PubMed ESTHER: Liu_2014_Chemosphere_99_102 PubMedSearch: Liu 2014 Chemosphere 99 102 PubMedID: 24210552 Abstract To investigate the distribution, bioconcentration, metabolism, and biomarker responses of macrolide antibiotic roxithromycin (ROX) in fish, crucian carp (Carassius auratus) were exposed to various concentrations of ROX (4, 20, and 100mugL(-1)) for 20d. The ROX content in different tissues was quantified using UPLC/MS/MS. The liver exhibited the highest ROX concentration followed by the bile, gills, and muscle tissues. After 15d of exposure to different concentrations of ROX, the bioconcentration factors were 2.15-38.0 in the liver, 0.950-20.7 in the bile, 0.0506-19.7 in the gill, and 0.0439-13.8 in the muscle; these results were comparable to the estimated BCF values. The metabolites formed in the bile were identified based on metabolic identification in human bile. Additionally, the biomarkers, including acetylcholinesterase in the brain, as well as 7-ethoxyresorufin O-deethylase and superoxide dismutase in the liver changed significantly after 5, 10, 15, and 20d of exposure (P<0.05). Our results suggest that ROX can accumulate and be metabolized in fish; therefore, interactions between ROX or its metabolites and the biological systems may induce biochemical disturbances in fish. Title: Tissue distribution, bioconcentration, metabolism, and effects of erythromycin in crucian carp (Carassius auratus) Liu J, Lu G, Ding J, Zhang Z, Wang Y Ref: Sci Total Environ, 490C:914, 2014 : PubMed ESTHER: Liu_2014_Sci.Total.Environ_490C_914 PubMedSearch: Liu 2014 Sci.Total.Environ 490C 914 PubMedID: 24911771 Abstract In this study, the tissue distribution, bioconcentration, metabolism and biological effects of the macrolide antibiotic erythromycin (ERY) were investigated in fish using crucian carp (Carassius auratus) as a model. Crucian carp were exposed to various concentrations of ERY (4, 20, and 100mug/L) for 28days. The UPLC/MS/MS analysis of both water and tissue provided the bioconcentration of ERY and its metabolites in the fish body. The results from tissue samples showed that a maximum tissue concentration occurred in the muscle and that the bioconcentration factor (BCF) of 72.2 was lower than the theoretical BCF of 90.4 calculated from the octanol-water coefficient of ERY. A significant portion of the absorbed ERY was metabolized via demethylation and dehydration and observed in the form of descladinose in fish. In addition, the relevant biomarkers, including acetylcholinesterase in the brain, as well as 7-ethoxyresorufin O-deethylase and superoxide dismutase in the liver, changed significantly during 28days of exposure (P<0.05). These results clearly indicated that ERY accumulated in fish and that similar metabolites as those observed in mammals were produced, resulting in the biochemical disturbance of biological systems. Title: Synthesis and characterization of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for treatment of Alzheimer's disease Liu J, Qiu J, Wang M, Wang L, Su L, Gao J, Gu Q, Xu J, Huang SL and Li D <2 more author(s)> Liu J, Qiu J, Wang M, Wang L, Su L, Gao J, Gu Q, Xu J, Huang SL, Gu LQ, Huang ZS, Li D (- 2) Ref: Biochimica & Biophysica Acta, 1840:2886, 2014 : PubMed ESTHER: Liu_2014_Biochim.Biophys.Acta_1840_2886 PubMedSearch: Liu 2014 Biochim.Biophys.Acta 1840 2886 PubMedID: 24821011 Abstract BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that is characterized by dementia, cognitive impairment, and memory loss. Diverse factors are related to the development of AD, such as increased level of beta-amyloid (Abeta), acetylcholine, metal ion deregulation, hyperphosphorylated tau protein, and oxidative stress. Title: SET-mediated NDRG1 inhibition is involved in acquisition of epithelial-to-mesenchymal transition phenotype and cisplatin resistance in human lung cancer cell Liu H, Gu Y, Yin J, Zheng G, Wang C, Zhang Z, Deng M, Liu J, Jia X, He Z Ref: Cell Signal, 26:2710, 2014 : PubMed ESTHER: Liu_2014_Cell.Signal_26_2710 PubMedSearch: Liu 2014 Cell.Signal 26 2710 PubMedID: 25152373 Abstract Development of resistance to therapy continues to be a serious clinical problem in lung cancer management. Cancer cells undergoing epithelial-to-mesenchymal transition (EMT) have been shown to play roles in resistance to chemotherapy. Here, we utilized a proteomics-based method and identified a significant downregulation of the metastasis suppressor NDRG1 in drug resistant lung cancer cells. We showed that downregulation of DNRG1 constitutes a mechanism for acquisition of EMT phenotype and endows lung cancer cells with an increased resistance to cisplatin. We also identified a signal cascade, namely, SET--- PP2A---| c-myc---| NDRG1, in which upregulation of SET is critical for inhibition of NDRG1. We also found that blockade of SET (or reactivation of PP2A) by FTY720 reverted EMT, restored drug sensitivity, and inhibited invasiveness and growth of lung tumor xenografts. Together, our results indicated a functional link between SET-mediated NDRG1 regulation and acquisition of EMT phenotype and drug resistance, and provided an evidence that blockade of SET-driven EMT can overcome drug resistance and inhibit tumor progression. Title: The cannabinoid receptor antagonist AM251 increases paraoxon and chlorpyrifos oxon toxicity in rats Liu J, Pope C Ref: Neurotoxicology, 46C:12, 2014 : PubMed ESTHER: Liu_2014_Neurotoxicol_46C_12 PubMedSearch: Liu 2014 Neurotoxicol 46C 12 PubMedID: 25447325 Abstract Organophosphorus anticholinesterases (OPs) elicit acute toxicity by inhibiting acetylcholinesterase (AChE), leading to acetylcholine accumulation and overstimulation of cholinergic receptors. Endocannabinoids (eCBs, e.g., arachidonoyl ethanolamide [AEA] and 2-arachidonoyl glycerol [2-AG]) are neuromodulators that regulate neurotransmission by reducing neurotransmitter release. The eCBs are degraded by the enzymes fatty acid amide hydrolase (FAAH, primarily involved in hydrolysis of AEA) and monoacylglycerol lipase (MAGL, primarily responsible for metabolism of 2-AG). We previously reported that the cannabinoid receptor agonist WIN 55,212-2 reduced cholinergic toxicity after paraoxon exposure. This study compared the effects of the cannabinoid receptor antagonist AM251 on acute toxicity following either paraoxon (PO) or chlorpyrifos oxon (CPO). CPO was more potent in vitro than PO at inhibiting AChE ( approximately 2 fold), FAAH ( approximately 8 fold), and MAGL ( approximately 19 fold). Rats were treated with vehicle, PO (0.3 and 0.6mg/kg, sc) or CPO (6 and 12mg/kg, sc) and subsets treated with AM251 (3mg/kg, ip; 30min after OP). Signs of toxicity were recorded for 4h and rats were then sacrificed. OP-treated rats showed dose-related involuntary movements, with AM251 increasing signs of toxicity with the lower dosages. PO and CPO elicited excessive secretions, but AM251 had no apparent effect with either OP. Lethality was increased by AM251 with the higher dosage of PO, but no lethality was noted with either dosage of CPO, with or without AM251. Both OPs caused extensive inhibition of hippocampal AChE and FAAH (>80-90%), but only CPO inhibited MAGL (37-50%). These results provide further evidence that eCB signaling can influence acute OP toxicity. The selective in vivo inhibition of MAGL by CPO may be important in the differential lethality noted between PO and CPO with AM251 co-administration. Title: Establishment of a selective evaluation method for DPP4 inhibitors based on recombinant human DPP8 and DPP9 proteins Liu J, Huan Y, Li C, Liu M, Shen Z Ref: Acta Pharm Sin B, 4:135, 2014 : PubMed ESTHER: Liu_2014_Acta.Pharm.Sin.B_4_135 PubMedSearch: Liu 2014 Acta.Pharm.Sin.B 4 135 PubMedID: 26579375 Abstract Dipeptidyl peptidase 4 (DPP4) is recognised as an attractive anti-diabetic drug target, and several DPP4 inhibitors are already on the market. As members of the same gene family, dipeptidyl peptidase 8 (DPP8) and dipeptidyl peptidase 9 (DPP9) share high sequence and structural homology as well as functional activity with DPP4. However, the inhibition of their activities was reported to cause severe toxicities. Thus, the development of DPP4 inhibitors that do not have DPP8 and DPP9 inhibitory activity is critical for safe anti-diabetic therapy. To achieve this goal, we established a selective evaluation method for DPP4 inhibitors based on recombinant human DPP8 and DPP9 proteins expressed by Rosetta cells. In this method, we used purified recombinant 120 kDa DPP8 or DPP9 protein from the Rosetta expression system. The optimum concentrations of the recombinant DPP8 and DPP9 proteins were 30 ng/mL and 20 ng/mL, respectively, and the corresponding concentrations of their substrates were both 0.2 mmol/L. This method was highly reproducible and reliable for the evaluation of the DPP8 and DPP9 selectivity for DPP4 inhibitor candidates, which would provide valuable guidance in the development of safe DPP4 inhibitors. Title: The structural basis of the Tle4-Tli4 complex reveals the self-protection mechanism of H2-T6SS in Pseudomonas aeruginosa Lu D, Zheng Y, Liao N, Wei L, Xu B, Liu X, Liu J Ref: Acta Crystallographica D Biol Crystallogr, 70:3233, 2014 : PubMed ESTHER: Lu_2014_Acta.Crystallogr.D.Biol.Crystallogr_70_3233 PubMedSearch: Lu 2014 Acta.Crystallogr.D.Biol.Crystallogr 70 3233 PubMedID: 25478841 Gene_locus related to this paper: pseae-PA1510 Abstract The type VI secretion system (T6SS) has recently been demonstrated to mediate interbacterial competition and to discriminate between self and nonself. T6SS+ bacteria employ toxic effectors to inhibit rival cells and concurrently use effector cognate immunity proteins to protect their sibling cells. The effector and immunity pairs (E-I pairs) endow the bacteria with a great advantage in niche competition. Tle4-Tli4 (PA1510-PA1509) is a newly identified E-I pair that is controlled by H2-T6SS in Pseudomonas aeruginosa. Tle4 exhibits phospholipase activity, which destroys the cell membrane of rival cells, and the periplasm-located Tli4 in donor cells eliminates this toxic effect of Tle4. In this paper, the structure of the Tle4-Tli4 complex is reported at 1.75 A resolution. Tle4 consists of two domains: a conserved alpha/beta-hydrolase domain and an unusual cap domain in which two lid regions (lid1 and lid2) display a closed conformation that buries the catalytic triad in a deep funnel. Tli4 also displays a two-domain structure, in which a large lobe and a small lobe form a crab claw-like conformation. Tli4 uses this crab claw to grasp the cap domain of Tle4, especially the lid2 region, which prevents the interfacial activation of Tle4 and thus causes enzymatic dysfunction of Tle4 in sister cells. Title: Pyridostigmine prevents peripheral vascular endothelial dysfunction in rats with myocardial infarction Qin F, Lu Y, He X, Zhao M, Bi X, Yu X, Liu J, Zang W Ref: Clinical & Experimental Pharmacology & Physiology, 41:202, 2014 : PubMed ESTHER: Qin_2014_Clin.Exp.Pharmacol.Physiol_41_202 PubMedSearch: Qin 2014 Clin.Exp.Pharmacol.Physiol 41 202 PubMedID: 24471445 Inhibitor(s) related to this paper: Pyridostigmine Abstract Myocardial infarction (MI) is characterized by the withdrawal of vagal activity and increased sympathetic activity. We have shown previously that pyridostigmine (PYR), an acetylcholinesterase inhibitor, was able to improve vagal activity and ameliorate cardiac dysfunction following MI. However, the effect of PYR on endothelial dysfunction in peripheral arteries after MI remains unclear. In the present study, MI was induced by coronary artery ligation in adult Sprague-Dawley rats. Rats were treated intragastrically with saline or PYR (approximately 31 mg/kg per day) for 2 weeks, at which time haemodynamic and parasympathetic parameters and the vascular reactivity of isolated mesenteric arteries were measured and the ultrastructure of the endothelium evaluated. Compared with the MI group, PYR not only improved cardiac function, vagal nerve activity and endothelial impairment, but also reduced intravascular superoxide anion and malondialdehyde. In addition, in the PYR-treated MI group, nitric oxide (NO) bioavailability was increased and attenuated endothelium-dependent relaxations were improved, whereas restored vasodilator responses were inhibited by N(G) -nitro-l-arginine methyl ester. Based on our results, PYR is able to attenuate the impairment of peripheral endothelial function and maintain endothelial ultrastructural integrity in MI rats by inhibiting reactive oxygen species production, enhancing NO bioavailability and improving vagal activity. Title: Whole-genome sequencing of cultivated and wild peppers provides insights into Capsicum domestication and specialization Qin C, Yu C, Shen Y, Fang X, Chen L, Min J, Cheng J, Zhao S, Xu M and Zhang Z <58 more author(s)> Qin C, Yu C, Shen Y, Fang X, Chen L, Min J, Cheng J, Zhao S, Xu M, Luo Y, Yang Y, Wu Z, Mao L, Wu H, Ling-Hu C, Zhou H, Lin H, Gonzalez-Morales S, Trejo-Saavedra DL, Tian H, Tang X, Zhao M, Huang Z, Zhou A, Yao X, Cui J, Li W, Chen Z, Feng Y, Niu Y, Bi S, Yang X, Cai H, Luo X, Montes-Hernandez S, Leyva-Gonzalez MA, Xiong Z, He X, Bai L, Tan S, Liu D, Liu J, Zhang S, Chen M, Zhang L, Zhang Y, Liao W, Wang M, Lv X, Wen B, Liu H, Luan H, Yang S, Wang X, Xu J, Li X, Li S, Wang J, Palloix A, Bosland PW, Li Y, Krogh A, Rivera-Bustamante RF, Herrera-Estrella L, Yin Y, Yu J, Hu K, Zhang Z (- 58) Ref: Proc Natl Acad Sci U S A, 111:5135, 2014 : PubMed ESTHER: Qin_2014_Proc.Natl.Acad.Sci.U.S.A_111_5135 PubMedSearch: Qin 2014 Proc.Natl.Acad.Sci.U.S.A 111 5135 PubMedID: 24591624 Gene_locus related to this paper: capch-q75qh4, capan-a0a1u8fuf5, capan-a0a1u8gmz3, capan-a0a1u8f879, capan-a0a1u8ftr2, capan-a0a1u8g8s6 Abstract As an economic crop, pepper satisfies people's spicy taste and has medicinal uses worldwide. To gain a better understanding of Capsicum evolution, domestication, and specialization, we present here the genome sequence of the cultivated pepper Zunla-1 (C. annuum L.) and its wild progenitor Chiltepin (C. annuum var. glabriusculum). We estimate that the pepper genome expanded approximately 0.3 Mya (with respect to the genome of other Solanaceae) by a rapid amplification of retrotransposons elements, resulting in a genome comprised of approximately 81% repetitive sequences. Approximately 79% of 3.48-Gb scaffolds containing 34,476 protein-coding genes were anchored to chromosomes by a high-density genetic map. Comparison of cultivated and wild pepper genomes with 20 resequencing accessions revealed molecular footprints of artificial selection, providing us with a list of candidate domestication genes. We also found that dosage compensation effect of tandem duplication genes probably contributed to the pungent diversification in pepper. The Capsicum reference genome provides crucial information for the study of not only the evolution of the pepper genome but also, the Solanaceae family, and it will facilitate the establishment of more effective pepper breeding programs. Title: Direct mass spectrometry analysis of biofluid samples using slug-flow microextraction nano-electrospray ionization Ren Y, McLuckey MN, Liu J, Ouyang Z Ref: Angew Chem Int Ed Engl, 53:14124, 2014 : PubMed ESTHER: Ren_2014_Angew.Chem.Int.Ed.Engl_53_14124 PubMedSearch: Ren 2014 Angew.Chem.Int.Ed.Engl 53 14124 PubMedID: 25284028 Abstract Direct mass spectrometry (MS) analysis of biofluids with simple procedures represents a key step in the translation of MS techniques to clinical and point-of-care applications. The current study reports the development of a single-step method using slug-flow microextraction and nano-electrospray ionization for MS analysis of organic compounds in blood and urine. High sensitivity and quantitation precision have been achieved in the analysis of therapeutic and illicit drugs in 5 muL samples. Real-time chemical derivatization has been incorporated for analyzing anabolic steroids. The monitoring of enzymatic functions has also been demonstrated with cholinesterase in wet blood. The reported study encourages the future development of disposable cartridges, which function with simple operation to replace the traditional complex laboratory procedures for MS analysis of biological samples. Title: Association between copy number variation losses and alcohol dependence across African American and European American ethnic groups Ulloa AE, Chen J, Vergara VM, Calhoun V, Liu J Ref: Alcohol Clin Exp Res, 38:1266, 2014 : PubMed ESTHER: Ulloa_2014_Alcohol.Clin.Exp.Res_38_1266 PubMedSearch: Ulloa 2014 Alcohol.Clin.Exp.Res 38 1266 PubMedID: 24512105 Abstract BACKGROUND: Copy number variations (CNVs) are structural genetic mutations consisting of segmental gains or losses in DNA sequence. Although CNVs contribute substantially to genomic variation, few genetic and imaging studies report association of CNVs with alcohol dependence (AD). Our purpose is to find evidence of this association across ethnic populations and genders. This work is the first AD-CNV study across ethnic groups and the first to include the African American (AA) population. Title: Complete Genome Sequence of Magnetospirillum gryphiswaldense MSR-1 Wang X, Wang Q, Zhang W, Wang Y, Li L, Wen T, Zhang T, Zhang Y, Xu J and Li J <9 more author(s)> Wang X, Wang Q, Zhang W, Wang Y, Li L, Wen T, Zhang T, Zhang Y, Xu J, Hu J, Li S, Liu L, Liu J, Jiang W, Tian J, Li Y, Schuler D, Wang L, Li J (- 9) Ref: Genome Announc, 2:, 2014 : PubMed ESTHER: Wang_2014_Genome.Announc_2_e00171 PubMedSearch: Wang 2014 Genome.Announc 2 e00171 PubMedID: 24625872 Gene_locus related to this paper: maggm-v6ezc0 Abstract We report the complete genomic sequence of Magnetospirillum gryphiswaldense MSR-1 (DSM 6361), a type strain of the genus Magnetospirillum belonging to the Alphaproteobacteria. Compared to the reported draft sequence, extensive rearrangements and differences were found, indicating high genomic flexibility and "domestication" by accelerated evolution of the strain upon repeated passaging. Title: An eco-friendly, simple, and sensitive fluorescence biosensor for the detection of choline and acetylcholine based on C-dots and the Fenton reaction Wei J, Ren J, Liu J, Meng X, Ren X, Chen Z, Tang F Ref: Biosensors & Bioelectronics, 52:304, 2014 : PubMed ESTHER: Wei_2014_Biosens.Bioelectron_52_304 PubMedSearch: Wei 2014 Biosens.Bioelectron 52 304 PubMedID: 24080209 Abstract A simple and novel method is proposed for the preparation of Carbon dots (C-dots) with excellent properties. We firstly demonstrated that the fluorescence of C-dots decreased apparently in the presence of H2O2 and Fe(2+). Based on the this finding, C-dots are successfully adopted as probes for the detection of H2O2. After the experimental conditions are optimized, the limit of detection (LOD) for H2O2 is found to be 0.1 muM. Furthermore, we established an eco-friendly, simple and sensitive biosensor for the detection of choline and acetylcholine (ACh) based on the detection of H2O2 using C-dots as probes. The detection limit for choline is 0.1 muM and the linear range is 0.1-40 muM. The detection limit for ACh is found to be 0.5 muM and the linear range is 0.5-60 muM. The excellent performance of the proposed biosensor shows that this method possesses the potential for practical application. Title: Identification of tanshinone IIA as a natural monoacylglycerol lipase inhibitor by combined in silico and in vitro approach Yang R, Lu Y, Liu J Ref: Med Chem Commun, 5:1528, 2014 : PubMed ESTHER: Yang_2014_Med.Chem.Commun_5_1528 PubMedSearch: Yang 2014 Med.Chem.Commun 5 1528 Inhibitor(s) related to this paper: Tanshinone-IIA Abstract Monoacylglycerol lipase (MAGL) was proposed as a novel target for the treatment of Alzheimer's disease (AD). In this paper, in silico screening of a focused library was implemented to dock natural products against MAGL to evaluate the calculated binding affinities of ligands with the receptor. Five hits were experimentally tested to determine their inhibitory effects on MAGL in vitro. Finally, tanshinone IIA (1) was successfully identified as a natural MAGL inhibitor in a concentration dependent manner with an IC50 value of 48 M. Considering being used as long-term treatment of cardiovascular diseases in China, tanshinone IIA has the potential to be developed as a good candidate for the treatment of AD and other MAGL-associated diseases. Title: A highly efficient cocaine-detoxifying enzyme obtained by computational design Zheng F, Xue L, Hou S, Liu J, Zhan M, Yang W, Zhan CG Ref: Nat Commun, 5:3457, 2014 : PubMed ESTHER: Zheng_2014_Nat.Commun_5_3457 PubMedSearch: Zheng 2014 Nat.Commun 5 3457 PubMedID: 24643289 Gene_locus related to this paper: human-BCHE Inhibitor(s) related to this paper: Cocaine Abstract Compared with naturally occurring enzymes, computationally designed enzymes are usually much less efficient, with their catalytic activities being more than six orders of magnitude below the diffusion limit. Here we use a two-step computational design approach, combined with experimental work, to design a highly efficient cocaine hydrolysing enzyme. We engineer E30-6 from human butyrylcholinesterase (BChE), which is specific for cocaine hydrolysis, and obtain a much higher catalytic efficiency for cocaine conversion than for conversion of the natural BChE substrate, acetylcholine (ACh). The catalytic efficiency of E30-6 for cocaine hydrolysis is comparable to that of the most efficient known naturally occurring hydrolytic enzyme, acetylcholinesterase, the catalytic activity of which approaches the diffusion limit. We further show that E30-6 can protect mice from a subsequently administered lethal dose of cocaine, suggesting the enzyme may have therapeutic potential in the setting of cocaine detoxification or cocaine abuse. Title: Genome sequence of the date palm Phoenix dactylifera L Al-Mssallem IS, Hu S, Zhang X, Lin Q, Liu W, Tan J, Yu X, Liu J, Pan L and Yu J <34 more author(s)> Al-Mssallem IS, Hu S, Zhang X, Lin Q, Liu W, Tan J, Yu X, Liu J, Pan L, Zhang T, Yin Y, Xin C, Wu H, Zhang G, Ba Abdullah MM, Huang D, Fang Y, Alnakhli YO, Jia S, Yin A, Alhuzimi EM, Alsaihati BA, Al-Owayyed SA, Zhao D, Zhang S, Al-Otaibi NA, Sun G, Majrashi MA, Li F, Tala, Wang J, Yun Q, Alnassar NA, Wang L, Yang M, Al-Jelaify RF, Liu K, Gao S, Chen K, Alkhaldi SR, Liu G, Zhang M, Guo H, Yu J (- 34) Ref: Nat Commun, 4:2274, 2013 : PubMed ESTHER: Al-Mssallem_2013_Nat.Commun_4_2274 PubMedSearch: Al-Mssallem 2013 Nat.Commun 4 2274 PubMedID: 23917264 Gene_locus related to this paper: phodc-a0a2h3y3d5, phodc-a0a2h3z529, phodc-a0a2h3y147, phodc-a0a2h3xrz4, phodc-a0a3q0ic37, phodc-a0a2h3yxf0, phodc-a0a2h3zh01, phodc-a0a3q0hs32 Abstract Date palm (Phoenix dactylifera L.) is a cultivated woody plant species with agricultural and economic importance. Here we report a genome assembly for an elite variety (Khalas), which is 605.4 Mb in size and covers >90% of the genome (~671 Mb) and >96% of its genes (~41,660 genes). Genomic sequence analysis demonstrates that P. dactylifera experienced a clear genome-wide duplication after either ancient whole genome duplications or massive segmental duplications. Genetic diversity analysis indicates that its stress resistance and sugar metabolism-related genes tend to be enriched in the chromosomal regions where the density of single-nucleotide polymorphisms is relatively low. Using transcriptomic data, we also illustrate the date palm's unique sugar metabolism that underlies fruit development and ripening. Our large-scale genomic and transcriptomic data pave the way for further genomic studies not only on P. dactylifera but also other Arecaceae plants. Title: Whole-genome sequencing of Oryza brachyantha reveals mechanisms underlying Oryza genome evolution Chen J, Huang Q, Gao D, Wang J, Lang Y, Liu T, Li B, Bai Z, Luis Goicoechea J and Chen M <30 more author(s)> Chen J, Huang Q, Gao D, Wang J, Lang Y, Liu T, Li B, Bai Z, Luis Goicoechea J, Liang C, Chen C, Zhang W, Sun S, Liao Y, Zhang X, Yang L, Song C, Wang M, Shi J, Liu G, Liu J, Zhou H, Zhou W, Yu Q, An N, Chen Y, Cai Q, Wang B, Liu B, Min J, Huang Y, Wu H, Li Z, Zhang Y, Yin Y, Song W, Jiang J, Jackson SA, Wing RA, Chen M (- 30) Ref: Nat Commun, 4:1595, 2013 : PubMed ESTHER: Chen_2013_Nat.Commun_4_1595 PubMedSearch: Chen 2013 Nat.Commun 4 1595 PubMedID: 23481403 Gene_locus related to this paper: orysa-Q6ZDG3, orysa-q6h415, orysj-q6yse8, orysa-q33aq0, orybr-j3l7k2, orybr-j3m138, orybr-j3l6m8, orybr-j3m3b3, orybr-j3l8d1, orybr-j3kza5, orybr-j3mnb5, orybr-j3n4p4, orybr-j3lg73, orybr-j3l342, orybr-j3msi2, orybr-j3nb83, orybr-j3mpc5 Abstract The wild species of the genus Oryza contain a largely untapped reservoir of agronomically important genes for rice improvement. Here we report the 261-Mb de novo assembled genome sequence of Oryza brachyantha. Low activity of long-terminal repeat retrotransposons and massive internal deletions of ancient long-terminal repeat elements lead to the compact genome of Oryza brachyantha. We model 32,038 protein-coding genes in the Oryza brachyantha genome, of which only 70% are located in collinear positions in comparison with the rice genome. Analysing breakpoints of non-collinear genes suggests that double-strand break repair through non-homologous end joining has an important role in gene movement and erosion of collinearity in the Oryza genomes. Transition of euchromatin to heterochromatin in the rice genome is accompanied by segmental and tandem duplications, further expanded by transposable element insertions. The high-quality reference genome sequence of Oryza brachyantha provides an important resource for functional and evolutionary studies in the genus Oryza. Title: Does preconception paternal exposure to a physiologically relevant level of bisphenol A alter spatial memory in an adult rat? Fan Y, Ding S, Ye X, Manyande A, He D, Zhao N, Yang H, Jin X, Liu J and Ying C <2 more author(s)> Fan Y, Ding S, Ye X, Manyande A, He D, Zhao N, Yang H, Jin X, Liu J, Tian C, Xu S, Ying C (- 2) Ref: Horm Behav, 64:598, 2013 : PubMed ESTHER: Fan_2013_Horm.Behav_64_598 PubMedSearch: Fan 2013 Horm.Behav 64 598 PubMedID: 24005185 Abstract Bisphenol A (BPA) is a ubiquitous environmental endocrine disrupting compound (EDC); public health concerns have been fueled by findings that maternal BPA exposure can change sex differences in the brain and in some behaviors. We investigated whether a physiologically relevant dose of BPA ingested by male rats before conception would affect spatial memory and hippocampal acetylcholinesterase (AchE) in their adult offspring. Twenty-two 60-day-old male rats (F0) received either a BPA diet (50mug/kg/day) or vehicle alone for 10weeks before being mated with non-exposed females. The paternal rats and their forty adult offspring's (F1) behaviors were then examined in the Morris Water Maze (MWM) and their AchE activities in the hippocampus were evaluated. BPA exposure led to spatial memory deficits along with decreased AchE activities in the hippocampus (p=0.01) in adult F0 rats. This paternal exposure also induced impairment in spatial memory acquisition in both sexes while retention only in females in F1 rats, as well as abolished sex differences in the hippocampus AchE. Overall, these data provide new evidence that paternal BPA exposure, at a "safe" dose, may induce transgenerational alterations in spatial memory in a sex-specific manner. Title: The effect of lipid nanoparticle PEGylation on neuroinflammatory response in mouse brain Huang JY, Lu YM, Wang H, Liu J, Liao MH, Hong LJ, Tao RR, Ahmed MM, Liu P and Han F <3 more author(s)> Huang JY, Lu YM, Wang H, Liu J, Liao MH, Hong LJ, Tao RR, Ahmed MM, Liu P, Liu SS, Fukunaga K, Du YZ, Han F (- 3) Ref: Biomaterials, 34:7960, 2013 : PubMed ESTHER: Huang_2013_Biomaterials_34_7960 PubMedSearch: Huang 2013 Biomaterials 34 7960 PubMedID: 23880338 Abstract Nanocarrier-based drug delivery systems have attracted wide interest for the treatment of brain disease. However, neurotoxicity of nanoparticle has limited their therapeutic application. Here we demonstrated that lipid nanoparticles (LNs) accumulated in the brain parenchyma within 3 h of intravenous injection to mice and persisted for more than 24 weeks, coinciding with a dramatic activation of brain microglia. Morphological characteristic of microglial activation also observed in LNs-treated Cx3cr1(GFP/+) mice. In vivo study with two-photon confocal microscopy revealed abnormal Ca(2+) waves in microglia following LNs injection. The correlated activation of caspase-1, IL-1beta and neurovascular damage following LNs injection was attenuated in P2X7(-/-) mice. PEGylation of LNs reduced correlated nanoparticles aggregation. Moreover, PEGylation of LNs ameliorated the P2X7/caspase-1/IL-1beta signalling-dependent microglia activation and neurovascular damage. In conclusion, PEGylation of LNs is a promising biomaterial for brain-targeted therapy that inhibits P2X7-dependent neuroinflammatory response. Title: A novel chemical screening strategy in zebrafish identifies common pathways in embryogenesis and rhabdomyosarcoma development Le X, Pugach EK, Hettmer S, Storer NY, Liu J, Wills AA, DiBiase A, Chen EY, Ignatius MS and Zon LI <3 more author(s)> Le X, Pugach EK, Hettmer S, Storer NY, Liu J, Wills AA, DiBiase A, Chen EY, Ignatius MS, Poss KD, Wagers AJ, Langenau DM, Zon LI (- 3) Ref: Development, 140:2354, 2013 : PubMed ESTHER: Le_2013_Development_140_2354 PubMedSearch: Le 2013 Development 140 2354 PubMedID: 23615277 Abstract The zebrafish is a powerful genetic model that has only recently been used to dissect developmental pathways involved in oncogenesis. We hypothesized that operative pathways during embryogenesis would also be used for oncogenesis. In an effort to define RAS target genes during embryogenesis, gene expression was evaluated in Tg(hsp70-HRAS(G12V)) zebrafish embryos subjected to heat shock. dusp6 was activated by RAS, and this was used as the basis for a chemical genetic screen to identify small molecules that interfere with RAS signaling during embryogenesis. A KRAS(G12D)-induced zebrafish embryonal rhabdomyosarcoma was then used to assess the therapeutic effects of the small molecules. Two of these inhibitors, PD98059 and TPCK, had anti-tumor activity as single agents in both zebrafish embryonal rhabdomyosarcoma and a human cell line of rhabdomyosarcoma that harbored activated mutations in NRAS. PD98059 inhibited MEK1 whereas TPCK suppressed S6K1 activity; however, the combined treatment completely suppressed eIF4B phosphorylation and decreased translation initiation. Our work demonstrates that the activated pathways in RAS induction during embryogenesis are also important in oncogenesis and that inhibition of these pathways suppresses tumor growth. Title: Draft genome of the wheat A-genome progenitor Triticum urartu Ling HQ, Zhao S, Liu D, Wang J, Sun H, Zhang C, Fan H, Li D, Dong L and Zhang A <39 more author(s)> Ling HQ, Zhao S, Liu D, Wang J, Sun H, Zhang C, Fan H, Li D, Dong L, Tao Y, Gao C, Wu H, Li Y, Cui Y, Guo X, Zheng S, Wang B, Yu K, Liang Q, Yang W, Lou X, Chen J, Feng M, Jian J, Zhang X, Luo G, Jiang Y, Liu J, Wang Z, Sha Y, Zhang B, Tang D, Shen Q, Xue P, Zou S, Wang X, Liu X, Wang F, Yang Y, An X, Dong Z, Zhang K, Luo MC, Dvorak J, Tong Y, Yang H, Li Z, Wang D, Zhang A (- 39) Ref: Nature, 496:87, 2013 : PubMed ESTHER: Ling_2013_Nature_496_87 PubMedSearch: Ling 2013 Nature 496 87 PubMedID: 23535596 Gene_locus related to this paper: triua-m8a764, triua-m8ag96, triua-m7zp69, wheat-w5d1z6, wheat-w5d232, wheat-w5bnf5, triua-t1nm05, wheat-w5cae4, triua-m7ytf7, wheat-w5f1j8, triua-m8ad49, wheat-a0a077s1q2, wheat-a0a3b6c2m6, triua-m7zi26, wheat-a0a3b6at77 Abstract Bread wheat (Triticum aestivum, AABBDD) is one of the most widely cultivated and consumed food crops in the world. However, the complex polyploid nature of its genome makes genetic and functional analyses extremely challenging. The A genome, as a basic genome of bread wheat and other polyploid wheats, for example, T. turgidum (AABB), T. timopheevii (AAGG) and T. zhukovskyi (AAGGA(m)A(m)), is central to wheat evolution, domestication and genetic improvement. The progenitor species of the A genome is the diploid wild einkorn wheat T. urartu, which resembles cultivated wheat more extensively than do Aegilops speltoides (the ancestor of the B genome) and Ae. tauschii (the donor of the D genome), especially in the morphology and development of spike and seed. Here we present the generation, assembly and analysis of a whole-genome shotgun draft sequence of the T. urartu genome. We identified protein-coding gene models, performed genome structure analyses and assessed its utility for analysing agronomically important genes and for developing molecular markers. Our T. urartu genome assembly provides a diploid reference for analysis of polyploid wheat genomes and is a valuable resource for the genetic improvement of wheat. Title: Enhanced enantioselectivity of a carboxyl esterase from Rhodobacter sphaeroides by directed evolution Ma J, Wu L, Guo F, Gu J, Tang X, Jiang L, Liu J, Zhou J, Yu H Ref: Applied Microbiology & Biotechnology, 97:4897, 2013 : PubMed ESTHER: Ma_2013_Appl.Microbiol.Biotechnol_97_4897 PubMedSearch: Ma 2013 Appl.Microbiol.Biotechnol 97 4897 PubMedID: 22987200 Gene_locus related to this paper: rhos4-q3j2v1 Abstract The present work created an esterase variant from Rhodobacter sphaeroides (RspE) with enhanced selectivity in hydrolytic kinetic resolutions by directed evolution. A "model" substrate, methyl mandelate, was introduced in the high-throughput screening procedure. E values of a variant CH (Asn62Cys/Leu145His) for six different esters were 10-83, which were a relative improvement compared to 2-20 for the wild type. Our subsequent crystal structure interpretation and molecular dynamics simulations helped shed light on the source of enantioselectivity modified by directed evolution. Though mutations displayed no "direct" interaction with the substrate, they were hypothesized to strengthen the intramolecular interaction in the catalytic cavity of variant. Conformation analysis revealed that the enhanced enantioselectivity of variant CH for the seven substrates applied in this study was derived from the decrease in size of the substrate binding pocket. Title: Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the clavicipitaceae reveals dynamics of alkaloid loci Schardl CL, Young CA, Hesse U, Amyotte SG, Andreeva K, Calie PJ, Fleetwood DJ, Haws DC, Moore N and Zeng Z <44 more author(s)> Schardl CL, Young CA, Hesse U, Amyotte SG, Andreeva K, Calie PJ, Fleetwood DJ, Haws DC, Moore N, Oeser B, Panaccione DG, Schweri KK, Voisey CR, Farman ML, Jaromczyk JW, Roe BA, O'Sullivan DM, Scott B, Tudzynski P, An Z, Arnaoudova EG, Bullock CT, Charlton ND, Chen L, Cox M, Dinkins RD, Florea S, Glenn AE, Gordon A, Guldener U, Harris DR, Hollin W, Jaromczyk J, Johnson RD, Khan AK, Leistner E, Leuchtmann A, Li C, Liu J, Liu M, Mace W, Machado C, Nagabhyru P, Pan J, Schmid J, Sugawara K, Steiner U, Takach JE, Tanaka E, Webb JS, Wilson EV, Wiseman JL, Yoshida R, Zeng Z (- 44) Ref: PLoS Genet, 9:e1003323, 2013 : PubMed ESTHER: Schardl_2013_PLoS.Genet_9_E1003323 PubMedSearch: Schardl 2013 PLoS.Genet 9 E1003323 PubMedID: 23468653 Gene_locus related to this paper: clap2-m1w2a8, clap2-m1w555, clap2-m1wa31, clap2-m1whd2, clap2-m1weh2, clap2-m1w5y7, clap2-m1wh11, clap2-m1vyn7 Abstract The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (Epichloe and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some-including the infamous ergot alkaloids-have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the epichloae, their protective roles as symbionts, and their associations with the highly speciose and ecologically diverse cool-season grasses. Title: Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking Stephens SH, Hartz SM, Hoft NR, Saccone NL, Corley RC, Hewitt JK, Hopfer CJ, Breslau N, Coon H and Ehringer MA <116 more author(s)> Stephens SH, Hartz SM, Hoft NR, Saccone NL, Corley RC, Hewitt JK, Hopfer CJ, Breslau N, Coon H, Chen X, Ducci F, Dueker N, Franceschini N, Frank J, Han Y, Hansel NN, Jiang C, Korhonen T, Lind PA, Liu J, Lyytikainen LP, Michel M, Shaffer JR, Short SE, Sun J, Teumer A, Thompson JR, Vogelzangs N, Vink JM, Wenzlaff A, Wheeler W, Yang BZ, Aggen SH, Balmforth AJ, Baumeister SE, Beaty TH, Benjamin DJ, Bergen AW, Broms U, Cesarini D, Chatterjee N, Chen J, Cheng YC, Cichon S, Couper D, Cucca F, Dick D, Foroud T, Furberg H, Giegling I, Gillespie NA, Gu F, Hall AS, Hallfors J, Han S, Hartmann AM, Heikkila K, Hickie IB, Hottenga JJ, Jousilahti P, Kaakinen M, Kahonen M, Koellinger PD, Kittner S, Konte B, Landi MT, Laatikainen T, Leppert M, Levy SM, Mathias RA, McNeil DW, Medland SE, Montgomery GW, Murray T, Nauck M, North KE, Pare PD, Pergadia M, Ruczinski I, Salomaa V, Viikari J, Willemsen G, Barnes KC, Boerwinkle E, Boomsma DI, Caporaso N, Edenberg HJ, Francks C, Gelernter J, Grabe HJ, Hops H, Jarvelin MR, Johannesson M, Kendler KS, Lehtimaki T, Magnusson PK, Marazita ML, Marchini J, Mitchell BD, Nothen MM, Penninx BW, Raitakari O, Rietschel M, Rujescu D, Samani NJ, Schwartz AG, Shete S, Spitz M, Swan GE, Volzke H, Veijola J, Wei Q, Amos C, Cannon DS, Grucza R, Hatsukami D, Heath A, Johnson EO, Kaprio J, Madden P, Martin NG, Stevens VL, Weiss RB, Kraft P, Bierut LJ, Ehringer MA (- 116) Ref: Genet Epidemiol, 37:846, 2013 : PubMed ESTHER: Stephens_2013_Genet.Epidemiol_37_846 PubMedSearch: Stephens 2013 Genet.Epidemiol 37 846 PubMedID: 24186853 Abstract Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype. Title: Cell debris self-immobilized thermophilic lipase: a biocatalyst for synthesizing aliphatic polyesters Sun Y, Yang Y, Wang C, Liu J, Shi W, Zhu X, Lu L, Li Q Ref: Appl Biochem Biotechnol, 170:399, 2013 : PubMed ESTHER: Sun_2013_Appl.Biochem.Biotechnol_170_399 PubMedSearch: Sun 2013 Appl.Biochem.Biotechnol 170 399 PubMedID: 23536248 Abstract The paper explored the catalytic activity of a cell debris self-immobilized thermophilic lipase for polyester synthesis, using the ring-opening polymerization of sigma-caprolactone as model. Effects of biocatalyst concentration, temperature, and reaction medium on monomer conversion and product molecular weight were systematically evaluated. The biocatalyst displayed high catalytic activity at high temperatures (70-90 degreesC), with 100 % monomer conversion. High monomer conversion values (>90 %) were achieved in both hydrophobic and hydrophilic solvents, and also in solvent-free system, with the exception of dichloromethane. Poly(sigma-caprolactone) was obtained in 100 % monomer conversion, with a number-average molecular weight of 1,680 g/mol and a polydispersity index of 1.35 in cyclohexane at 70 degreesC for 72 h. Furthermore, the biocatalyst exhibited excellent operational stability, with monomer conversion values exceeding 90 % over the course of 15 batch reactions. Title: The draft genomes of soft-shell turtle and green sea turtle yield insights into the development and evolution of the turtle-specific body plan Wang Z, Pascual-Anaya J, Zadissa A, Li W, Niimura Y, Huang Z, Li C, White S, Xiong Z and Irie N <22 more author(s)> Wang Z, Pascual-Anaya J, Zadissa A, Li W, Niimura Y, Huang Z, Li C, White S, Xiong Z, Fang D, Wang B, Ming Y, Chen Y, Zheng Y, Kuraku S, Pignatelli M, Herrero J, Beal K, Nozawa M, Li Q, Wang J, Zhang H, Yu L, Shigenobu S, Liu J, Flicek P, Searle S, Kuratani S, Yin Y, Aken B, Zhang G, Irie N (- 22) Ref: Nat Genet, 45:701, 2013 : PubMed ESTHER: Wang_2013_Nat.Genet_45_701 PubMedSearch: Wang 2013 Nat.Genet 45 701 PubMedID: 23624526 Gene_locus related to this paper: chemy-m7c042, chemy-m7bp40, chemy-m7cgq9, chemy-m7bs15, chemy-m7c0b2, chemy-m7bkv2, chemy-m7bnk5, chemy-m7bzy6 Abstract The unique anatomical features of turtles have raised unanswered questions about the origin of their unique body plan. We generated and analyzed draft genomes of the soft-shell turtle (Pelodiscus sinensis) and the green sea turtle (Chelonia mydas); our results indicated the close relationship of the turtles to the bird-crocodilian lineage, from which they split approximately 267.9-248.3 million years ago (Upper Permian to Triassic). We also found extensive expansion of olfactory receptor genes in these turtles. Embryonic gene expression analysis identified an hourglass-like divergence of turtle and chicken embryogenesis, with maximal conservation around the vertebrate phylotypic period, rather than at later stages that show the amniote-common pattern. Wnt5a expression was found in the growth zone of the dorsal shell, supporting the possible co-option of limb-associated Wnt signaling in the acquisition of this turtle-specific novelty. Our results suggest that turtle evolution was accompanied by an unexpectedly conservative vertebrate phylotypic period, followed by turtle-specific repatterning of development to yield the novel structure of the shell. Title: Draft Genome Sequence of Shewanella decolorationis S12, a Dye-Degrading Bacterium Isolated from a Wastewater Treatment Plant Xu M, Fang Y, Liu J, Chen X, Sun G, Guo J, Hua Z, Tu Q, Wu L and Liu X <1 more author(s)> Xu M, Fang Y, Liu J, Chen X, Sun G, Guo J, Hua Z, Tu Q, Wu L, Zhou J, Liu X (- 1) Ref: Genome Announc, 1:, 2013 : PubMed ESTHER: Xu_2013_Genome.Announc_1_e00993 PubMedSearch: Xu 2013 Genome.Announc 1 e00993 PubMedID: 24309738 Gene_locus related to this paper: 9gamm-v1dg58, 9gamm-v1daq6 Abstract Shewanella decolorationis is a valuable microorganism for degrading diverse synthetic textile dyes. Here, we present an annotated draft genome sequence of S. decolorationis S12, which contains 4,219 protein-coding genes and 86 structural RNAs. This information regarding the genetic basis of this bacterium can greatly advance our understanding of the physiology of this species. Title: The genome of the hydatid tapeworm Echinococcus granulosus Zheng H, Zhang W, Zhang L, Zhang Z, Li J, Lu G, Zhu Y, Wang Y, Huang Y and Wang S <21 more author(s)> Zheng H, Zhang W, Zhang L, Zhang Z, Li J, Lu G, Zhu Y, Wang Y, Huang Y, Liu J, Kang H, Chen J, Wang L, Chen A, Yu S, Gao Z, Jin L, Gu W, Wang Z, Zhao L, Shi B, Wen H, Lin R, Jones MK, Brejova B, Vinar T, Zhao G, McManus DP, Chen Z, Zhou Y, Wang S (- 21) Ref: Nat Genet, 45:1168, 2013 : PubMed ESTHER: Zheng_2013_Nat.Genet_45_1168 PubMedSearch: Zheng 2013 Nat.Genet 45 1168 PubMedID: 24013640 Gene_locus related to this paper: echgr-k4epc5, echmu-u6hbw4, echgr-w6ugl0, echgr-w6u7y4, echgr-w6vaq5, echgr-a0a068wxj3, echgr-a0a068wgw1, echgr-a0a068wl60 Abstract Cystic echinococcosis (hydatid disease), caused by the tapeworm E. granulosus, is responsible for considerable human morbidity and mortality. This cosmopolitan disease is difficult to diagnose, treat and control. We present a draft genomic sequence for the worm comprising 151.6 Mb encoding 11,325 genes. Comparisons with the genome sequences from other taxa show that E. granulosus has acquired a spectrum of genes, including the EgAgB family, whose products are secreted by the parasite to interact and redirect host immune responses. We also find that genes in bile salt pathways may control the bidirectional development of E. granulosus, and sequence differences in the calcium channel subunit EgCavbeta1 may be associated with praziquantel sensitivity. Our study offers insights into host interaction, nutrient acquisition, strobilization, reproduction, immune evasion and maturation in the parasite and provides a platform to facilitate the development of new, effective treatments and interventions for echinococcosis control. Title: Fo Shou San, an ancient Chinese herbal decoction, protects endothelial function through increasing endothelial nitric oxide synthase activity Bi CWC, Xu L, Tian XY, Liu J, Zheng KY, Lau CW, Lau DT, Choi RC, Dong TTX and Tsim KWK <1 more author(s)> Bi CWC, Xu L, Tian XY, Liu J, Zheng KY, Lau CW, Lau DT, Choi RC, Dong TTX, Huang Y, Tsim KWK (- 1) Ref: PLoS ONE, 7:e51670, 2012 : PubMed ESTHER: Bi_2012_PLoS.One_7_e51670 PubMedSearch: Bi 2012 PLoS.One 7 e51670 PubMedID: 23284736 Abstract Fo Shou San (FSS) is an ancient herbal decoction comprised of Chuanxiong Rhizoma (CR; Chuanxiong) and Angelicae Sinensis Radix (ASR; Danggui) in a ratio of 2:3. Previous studies indicate that FSS promotes blood circulation and dissipates blood stasis, thus which is being used widely to treat vascular diseases. Here, we aim to determine the cellular mechanism for the vascular benefit of FSS. The treatment of FSS reversed homocysteine-induced impairment of acetylcholine (ACh)-evoked endothelium-dependent relaxation in aortic rings, isolated from rats. Like radical oxygen species (ROS) scavenger tempol, FSS attenuated homocysteine-stimulated ROS generation in cultured human umbilical vein endothelial cells (HUVECs), and it also stimulated the production of nitric oxide (NO) as measured by fluorescence dye and biochemical assay. In addition, the phosphorylation levels of both Akt kinase and endothelial NO synthases (eNOS) were markedly increased by FSS treatment, which was abolished by an Akt inhibitor triciribine. Likewise, triciribine reversed FSS-induced NO production in HUVECs. Finally, FSS elevated intracellular Ca(2+) levels in HUVECs, and the Ca(2+) chelator BAPTA-AM inhibited the FSS-stimulated eNOS phosphorylation. The present results show that this ancient herbal decoction benefits endothelial function through increased activity of Akt kinase and eNOS; this effect is causally via a rise of intracellular Ca(2+) and a reduction of ROS. Title: Reaction pathway and free energy profiles for butyrylcholinesterase-catalyzed hydrolysis of acetylthiocholine Chen X, Fang L, Liu J, Zhan CG Ref: Biochemistry, 51:1297, 2012 : PubMed ESTHER: Chen_2012_Biochemistry_51_1297 PubMedSearch: Chen 2012 Biochemistry 51 1297 PubMedID: 22304234 Abstract The catalytic mechanism for butyrylcholineserase (BChE)-catalyzed hydrolysis of acetylthiocholine (ATCh) has been studied by performing pseudobond first-principles quantum mechanical/molecular mechanical-free energy (QM/MM-FE) calculations on both acylation and deacylation of BChE. Additional quantum mechanical (QM) calculations have been carried out, along with the QM/MM-FE calculations, to understand the known substrate activation effect on the enzymatic hydrolysis of ATCh. It has been shown that the acylation of BChE with ATCh consists of two reaction steps including the nucleophilic attack on the carbonyl carbon of ATCh and the dissociation of thiocholine ester. The deacylation stage includes nucleophilic attack of a water molecule on the carboxyl carbon of substrate and dissociation between the carboxyl carbon of substrate and hydroxyl oxygen of Ser198 side chain. QM/MM-FE calculation results reveal that the acylation of BChE is rate-determining. It has also been demonstrated that an additional substrate molecule binding to the peripheral anionic site (PAS) of BChE is responsible for the substrate activation effect. In the presence of this additional substrate molecule at PAS, the calculated free energy barrier for the acylation stage (rate-determining step) is decreased by ~1.7 kcal/mol. All of our computational predictions are consistent with available experimental kinetic data. The overall free energy barriers calculated for BChE-catalyzed hydrolysis of ATCh at regular hydrolysis phase and substrate activation phase are ~13.6 and ~11.9 kcal/mol, respectively, which are in reasonable agreement with the corresponding experimentally derived activation free energies of 14.0 kcal/mol (for regular hydrolysis phase) and 13.5 kcal/mol (for substrate activation phase). Title: Reaction Pathway and Free Energy Profile for Cocaine Hydrolase-Catalyzed Hydrolysis of (-)-Cocaine Liu J, Zhan CG Ref: J Chem Theory Comput, 8:1426, 2012 : PubMed ESTHER: Liu_2012_J.Chem.Theory.Comput_8_1426 PubMedSearch: Liu 2012 J.Chem.Theory.Comput 8 1426 PubMedID: 23066354 Abstract Reaction pathway of cocaine hydrolysis catalyzed by our recently discovered most efficient cocaine hydrolase which is the A199S/F227A/S287G/A328W/Y332G mutant of human butyrylcholinesterase BChE and the corresponding free energy profile have been studied by performing first-principles pseudobond quantum mechanical/molecular mechanical QM/MM)-free energy FE calculations Based on the QM/MM-FE results the catalytic hydrolysis process consists of four major reaction steps including the nucleophilic attack on carbonyl carbon of cocaine benzoyl ester by hydroxyl group of S198 dissociation of cocaine benzoyl ester nucleophilic attack on carbonyl carbon of cocaine benzoyl ester by water and finally the dissociation between cocaine benzoyl group and S198 of the enzyme The second reaction step is rate-determining The calculated free energy barrier associated with the transition state for the rate-determining step is 15.0 kcal/mol which is in excellent agreement with the experimentally-derived activation free energy of 14.7 kcal/mol The mechanistic insights obtained from the present study will be valuable for rational design of more active cocaine hydrolase against cocaine In particular future efforts aiming at further increasing the catalytic activity of the enzyme against cocaine should focus on stabilization of the transition state for the second reaction step in which the benzoyl ester of cocaine dissociates. Title: Changes of calcium channel mRNA, protein and current in NG108-15 cells after cell differentiation Liu J, Tu H, Zhang D, Li YL Ref: Biochemical & Biophysical Research Communications, 423:55, 2012 : PubMed ESTHER: Liu_2012_Biochem.Biophys.Res.Commun_423_55 PubMedSearch: Liu 2012 Biochem.Biophys.Res.Commun 423 55 PubMedID: 22627136 Abstract Based on the characteristics of differentiated NG108-15 cells (cell membrane excitability, acetylcholine release, and activities of choline acetyltransferase and acetylcholinesterase), NG108-15 cells are extensively used to explore neuronal functions as a cholinergic cell line. In the present study, differentiation-induced alterations of voltage-gated Ca(2+) channel mRNA, protein, and current were investigated in the NG108-15 cells. Real-time PCR, Western blot, and whole-cell patch-clamp data showed that differentiation caused mRNA, protein, and ion current changes of all Ca(2+) channel subunits. However, the changes of mRNA, protein, and ion current are inconsistent in all Ca(2+) channel subunits. Especially, P/Q- and R-type Ca(2+) channel proteins do not form the functional P/Q- and R-type Ca(2+) channels even if the mRNA and protein of P/Q- and R-type Ca(2+) channels can be detected in NG108-15 cells. These results indicate that differentiation can modulate gene transcription, protein translation, and post-translation of the Ca(2+) channels to induce the alteration of the Ca(2+) ion currents in NG108-15 cells. From these data, we understand that combining real-time PCR, Western blot, and patch-clamp techniques can comprehensively unveil the modulation of the Ca(2+) channels. Title: Induction of histiocytic sarcoma in mouse skeletal muscle Liu J, Hettmer S, Milsom MD, Hofmann I, Hua F, Miller C, Bronson RT, Wagers AJ Ref: PLoS ONE, 7:e44044, 2012 : PubMed ESTHER: Liu_2012_PLoS.One_7_e44044 PubMedSearch: Liu 2012 PLoS.One 7 e44044 PubMedID: 22952867 Abstract Myeloid sarcomas are extramedullary accumulations of immature myeloid cells that may present with or without evidence of pathologic involvement of the bone marrow or peripheral blood, and often coincide with or precede a diagnosis of acute myeloid leukemia (AML). A dearth of experimental models has hampered the study of myeloid sarcomas and led us to establish a new system in which tumor induction can be evaluated in an easily accessible non-hematopoietic tissue compartment. Using ex-vivo transduction of oncogenic Kras(G12V) into p16/p19(-/-) bone marrow cells, we generated transplantable leukemia-initiating cells that rapidly induced tumor formation in the skeletal muscle of immunocompromised NOD.SCID mice. In this model, murine histiocytic sarcomas, equivalent to human myeloid sarcomas, emerged at the injection site 30-50 days after cell implantation and consisted of tightly packed monotypic cells that were CD48+, CD47+ and Mac1+, with low or absent expression of other hematopoietic lineage markers. Tumor cells also infiltrated the bone marrow, spleen and other non-hematopoietic organs of tumor-bearing animals, leading to systemic illness (leukemia) within two weeks of tumor detection. P16/p19(-/-); Kras(G12V) myeloid sarcomas were multi-clonal, with dominant clones selected during secondary transplantation. The systemic leukemic phenotypes exhibited by histiocytic sarcoma-bearing mice were nearly identical to those of animals in which leukemia was introduced by intravenous transplantation of the same donor cells. Moreover, murine histiocytic sarcoma could be similarly induced by intramuscular injection of MLL-AF9 leukemia cells. This study establishes a novel, transplantable model of murine histiocytic/myeloid sarcoma that recapitulates the natural progression of these malignancies to systemic disease and indicates a cell autonomous leukemogenic mechanism. Title: The yak genome and adaptation to life at high altitude Qiu Q, Zhang G, Ma T, Qian W, Wang J, Ye Z, Cao C, Hu Q, Kim J and Liu J <35 more author(s)> Qiu Q, Zhang G, Ma T, Qian W, Wang J, Ye Z, Cao C, Hu Q, Kim J, Larkin DM, Auvil L, Capitanu B, Ma J, Lewin HA, Qian X, Lang Y, Zhou R, Wang L, Wang K, Xia J, Liao S, Pan S, Lu X, Hou H, Wang Y, Zang X, Yin Y, Ma H, Zhang J, Wang Z, Zhang Y, Zhang D, Yonezawa T, Hasegawa M, Zhong Y, Liu W, Huang Z, Zhang S, Long R, Yang H, Lenstra JA, Cooper DN, Wu Y, Shi P, Liu J (- 35) Ref: Nat Genet, 44:946, 2012 : PubMed ESTHER: Qiu_2012_Nat.Genet_44_946 PubMedSearch: Qiu 2012 Nat.Genet 44 946 PubMedID: 22751099 Gene_locus related to this paper: bosmu-l8ic43, bovin-2neur, bovin-balip, bovin-BCHE, bovin-e1bbv2, bovin-e1bn79, bovin-est8, bovin-f1mi11, bovin-f1n385, bovin-g3mxp5, bovin-lipli, bovin-lipr2, bovin-q2kj30, bovin-q3sz79, bovin-q3t0r6, bovin-ABHDA, bovin-q08dw9, bovin-ABHD16B, bovin-SPG21, bovin-TEX30, 9ceta-l8iwv2, 9ceta-l8idy3, 9ceta-l8hsi3, bovin-e1bjq9, bovin-f1mc21, 9ceta-l8hyl8, bovin-LIPG, bovin-a0a3q1nm09, bovin-f1n2i5 Abstract Domestic yaks (Bos grunniens) provide meat and other necessities for Tibetans living at high altitude on the Qinghai-Tibetan Plateau and in adjacent regions. Comparison between yak and the closely related low-altitude cattle (Bos taurus) is informative in studying animal adaptation to high altitude. Here, we present the draft genome sequence of a female domestic yak generated using Illumina-based technology at 65-fold coverage. Genomic comparisons between yak and cattle identify an expansion in yak of gene families related to sensory perception and energy metabolism, as well as an enrichment of protein domains involved in sensing the extracellular environment and hypoxic stress. Positively selected and rapidly evolving genes in the yak lineage are also found to be significantly enriched in functional categories and pathways related to hypoxia and nutrition metabolism. These findings may have important implications for understanding adaptation to high altitude in other animal species and for hypoxia-related diseases in humans. Title: Enhanced activity of Rhizomucor miehei lipase by directed evolution with simultaneous evolution of the propeptide Wang J, Wang D, Wang B, Mei ZH, Liu J, Yu HW Ref: Applied Microbiology & Biotechnology, 96:443, 2012 : PubMed ESTHER: Wang_2012_Appl.Microbiol.Biotechnol_96_443 PubMedSearch: Wang 2012 Appl.Microbiol.Biotechnol 96 443 PubMedID: 22584429 Gene_locus related to this paper: rhimi-lipas Abstract Propeptides are short sequences that facilitate the folding of their associated proteins. The present study found that the propeptide of Rhizomucor miehei lipase (RML) was not proteolytically removed in Escherichia coli. Moreover, RML was not expressed if the propeptide was removed artificially during the cloning process in E. coli. This behavior in E. coli permitted the application of directed evolution to full-length RML, which included both propeptide and catalytic domain, to explore the role played by the propeptide in governing enzyme activity. The catalytic rate constant, k (cat), of the most active mutant RML protein (Q5) was increased from 10.63 +/- 0.80 to 71.44 +/- 3.20 min(-1) after four rounds of screening. Sequence analysis of the mutant displayed three mutations in the propeptide (L57V, S65A, and V67A) and two mutations in the functional region (I111T and S168P). This result showed that improved activity was obtained with essential involvement by mutations in the propeptide, meaning that the majority of mutants with enhanced activity had simultaneous mutations in propeptide and catalytic domains. This observation leads to the hypothesis that directed evolution has simultaneous and synergistic effects on both functional and propeptide domains that arise from the role played by the propeptide in the folding and maturation of the enzyme. We suggest that directed evolution of full-length proteins including their propeptides is a strategy with general validity for extending the range of conformations available to proteins, leading to the enhancement of the catalytic rates of the enzymes. Title: Crystal structure of a mono- and diacylglycerol lipase from Malassezia globosa reveals a novel lid conformation and insights into the substrate specificity Xu T, Liu L, Hou S, Xu J, Yang B, Wang Y, Liu J Ref: J Struct Biol, 178:363, 2012 : PubMed ESTHER: Xu_2012_J.Struct.Biol_178_363 PubMedSearch: Xu 2012 J.Struct.Biol 178 363 PubMedID: 22484238 Gene_locus related to this paper: malgo-a8puy1 Abstract Most lipases contain a lid domain to shield the hydrophobic binding site from the water environment. The lid, mostly in helical form, can undergo a conformational change to expose the active cleft during the interfacial activation. Here we report the crystal structures of Malassezia globosa LIP1 (SMG1) at 1.45 and 2.60 resolution in two crystal forms. The structures present SMG1 in its closed form, with a novel lid in loop conformation. SMG1 is one of the few members in the fungal lipase family that has been found to be strictly specific for mono- and diacylglycerol. To date, the mechanism for this substrate specificity remains largely unknown. To investigate the substrate binding properties, we built a model of SMG1 in open conformation. Based on this model, we found that the two bulky hydrophobic residues adjacent to the catalytic site and the N-terminal hinge region of the lid both may act as steric hindrances for triacylglycerols binding. These unique structural features of SMG1 will provide a better understanding on the substrate specificity of mono- and diacylglycerol lipases and a platform for further functional study of this enzyme. Title: Why Does the G117H Mutation Considerably Improve the Activity of Human Butyrylcholinesterase against Sarin? Insights from Quantum Mechanical/Molecular Mechanical Free Energy Calculations Yao Y, Liu J, Zhan CG Ref: Biochemistry, 51:8980, 2012 : PubMed ESTHER: Yao_2012_Biochemistry_51_8980 PubMedSearch: Yao 2012 Biochemistry 51 8980 PubMedID: 23092211 Abstract Human butyrylcholinesterase (BChE) is recognized as the most promising bioscavenger for organophosphorus (OP) warfare nerve agents. The G117H mutant of human BChE has been identified as a potential catalytic bioscavenger with a remarkably improved activity against OP nerve agents such as sarin, but it still does not satisfy the clinical use. For further design of the higher-activity mutants against OP nerve agents, it is essential to understand how the G117H mutation improves the activity. The reaction mechanisms and the free energy profiles for spontaneous reactivation of wild-type BChE and its G117H mutant phosphorylated by sarin have been explored, in this study, by performing first-principles quantum mechanical/molecular mechanical free energy calculations, and the remarkable role of the G117H mutation on the activity has been elucidated. For both the wild-type and G117H mutant enzymes, H438 acts as a general base to initiate the spontaneous reactivation that consists of two reaction steps: the nucleophilic attack at the phosphorus by a water molecule and decomposition of the pentacoordinated phosphorus intermediate. The calculated overall free energy barriers, i.e., 30.2 and 23.9 kcal/mol for the wild type and G117H mutant, respectively, are in good agreement with available experimental kinetic data. On the basis of the calculated results, the mutated residue (H117 in the G117H mutant) cannot initiate the spontaneous reactivation as a general base. Instead, it skews the oxyanion hole and makes the phosphorus more open to the nucleophilic water molecule, resulting in a remarkable change in the rate-determining step and significantly improved catalytic activity of human BChE. Title: The oyster genome reveals stress adaptation and complexity of shell formation Zhang G, Fang X, Guo X, Li L, Luo R, Xu F, Yang P, Zhang L, Wang X and Yin Y <66 more author(s)> Zhang G, Fang X, Guo X, Li L, Luo R, Xu F, Yang P, Zhang L, Wang X, Qi H, Xiong Z, Que H, Xie Y, Holland PW, Paps J, Zhu Y, Wu F, Chen Y, Wang J, Peng C, Meng J, Yang L, Liu J, Wen B, Zhang N, Huang Z, Zhu Q, Feng Y, Mount A, Hedgecock D, Xu Z, Liu Y, Domazet-Loso T, Du Y, Sun X, Zhang S, Liu B, Cheng P, Jiang X, Li J, Fan D, Wang W, Fu W, Wang T, Wang B, Zhang J, Peng Z, Li Y, Li N, Chen M, He Y, Tan F, Song X, Zheng Q, Huang R, Yang H, Du X, Chen L, Yang M, Gaffney PM, Wang S, Luo L, She Z, Ming Y, Huang W, Huang B, Zhang Y, Qu T, Ni P, Miao G, Wang Q, Steinberg CE, Wang H, Qian L, Liu X, Yin Y (- 66) Ref: Nature, 490:49, 2012 : PubMed ESTHER: Zhang_2012_Nature_490_49 PubMedSearch: Zhang 2012 Nature 490 49 PubMedID: 22992520 Gene_locus related to this paper: cragi-k1qzk7, cragi-k1rad0, cragi-k1p6v9, cragi-k1pa46, cragi-k1pga2, cragi-k1pp63, cragi-k1pwa8, cragi-k1q0b1.1, cragi-k1q0b1.2, cragi-k1q1h2, cragi-k1q2z6, cragi-k1qaj8, cragi-k1qaw5, cragi-k1qhl5, cragi-k1qly1, cragi-k1qqb1.1, cragi-k1qqb1.2, cragi-k1qs61, cragi-k1qs99, cragi-k1qwl6, cragi-k1r068, cragi-k1r0n3.1, cragi-k1r0n3.2, cragi-k1r0r4, cragi-k1r1i9, cragi-k1r8q9, cragi-k1rgi1, cragi-k1rig4, cragi-k1s0a7.1, cragi-k1s0a7.2, cragi-k1s0a7.3, cragi-k1q6q0, cragi-k1rru1, cragi-k1qfi4, cragi-k1qvm5, cragi-k1qq58, cragi-k1qdc0, cragi-k1r754, cragi-k1pje5, cragi-k1qca6, cragi-k1qdt5, cragi-k1qkz7, cragi-k1rgd2, cragi-k1puh6, cragi-k1raz4, cragi-k1qqj4, cragi-k1rbs1 Abstract The Pacific oyster Crassostrea gigas belongs to one of the most species-rich but genomically poorly explored phyla, the Mollusca. Here we report the sequencing and assembly of the oyster genome using short reads and a fosmid-pooling strategy, along with transcriptomes of development and stress response and the proteome of the shell. The oyster genome is highly polymorphic and rich in repetitive sequences, with some transposable elements still actively shaping variation. Transcriptome studies reveal an extensive set of genes responding to environmental stress. The expansion of genes coding for heat shock protein 70 and inhibitors of apoptosis is probably central to the oyster's adaptation to sessile life in the highly stressful intertidal zone. Our analyses also show that shell formation in molluscs is more complex than currently understood and involves extensive participation of cells and their exosomes. The oyster genome sequence fills a void in our understanding of the Lophotrochozoa. Title: Comparative effects of chlorpyrifos in wild type and cannabinoid Cb1 receptor knockout mice Baireddy P, Liu J, Hinsdale M, Pope C Ref: Toxicol Appl Pharmacol, 256:324, 2011 : PubMed ESTHER: Baireddy_2011_Toxicol.Appl.Pharmacol_256_324 PubMedSearch: Baireddy 2011 Toxicol.Appl.Pharmacol 256 324 PubMedID: 21672545 Abstract Endocannabinoids (eCBs) modulate neurotransmission by inhibiting the release of a variety of neurotransmitters. The cannabinoid receptor agonist WIN 55.212-2 (WIN) can modulate organophosphorus (OP) anticholinesterase toxicity in rats, presumably by inhibiting acetylcholine (ACh) release. Some OP anticholinesterases also inhibit eCB-degrading enzymes. We studied the effects of the OP insecticide chlorpyrifos (CPF) on cholinergic signs of toxicity, cholinesterase activity and ACh release in tissues from wild type (+/+) and cannabinoid CB1 receptor knockout (-/-) mice. Mice of both genotypes (n=5-6/treatment group) were challenged with CPF (300 mg/kg, 2 ml/kg in peanut oil, sc) and evaluated for functional and neurochemical changes. Both genotypes exhibited similar cholinergic signs and cholinesterase inhibition (82-95% at 48h after dosing) in cortex, cerebellum and heart. WIN reduced depolarization-induced ACh release in vitro in hippocampal slices from wild type mice, but had no effect in hippocampal slices from knockouts or in striatal slices from either genotype. Chlorpyrifos oxon (CPO, 100 muM) reduced release in hippocampal slices from both genotypes in vitro, but with a greater reduction in tissues from wild types (21% vs 12%). CPO had no significant in vitro effect on ACh release in striatum. CPF reduced ACh release in hippocampus from both genotypes ex vivo, but reduction was again significantly greater in tissues from wild types (52% vs 36%). In striatum, CPF led to a similar reduction (20-23%) in tissues from both genotypes. Thus, while CB1 deletion in mice had little influence on the expression of acute toxicity following CPF, CPF- or CPO-induced changes in ACh release appeared sensitive to modulation by CB1-mediated eCB signaling in a brain-regional manner. Title: Genome of alkaliphilic Bacillus pseudofirmus OF4 reveals adaptations that support the ability to grow in an external pH range from 7.5 to 11.4 Janto B, Ahmed A, Ito M, Liu J, Hicks DB, Pagni S, Fackelmayer OJ, Smith TA, Earl J and Krulwich TA <12 more author(s)> Janto B, Ahmed A, Ito M, Liu J, Hicks DB, Pagni S, Fackelmayer OJ, Smith TA, Earl J, Elbourne LD, Hassan K, Paulsen IT, Kolsto AB, Tourasse NJ, Ehrlich GD, Boissy R, Ivey DM, Li G, Xue Y, Ma Y, Hu FZ, Krulwich TA (- 12) Ref: Environ Microbiol, 13:3289, 2011 : PubMed ESTHER: Janto_2011_Environ.Microbiol_13_3289 PubMedSearch: Janto 2011 Environ.Microbiol 13 3289 PubMedID: 21951522 Gene_locus related to this paper: alkpo-d3fst0 Abstract Bacillus pseudofirmus OF4 is an extreme but facultative alkaliphile that grows non-fermentatively in a pH range from 7.5 to above 11.4 and can withstand large sudden increases in external pH. It is a model organism for studies of bioenergetics at high pH, at which energy demands are higher than at neutral pH because both cytoplasmic pH homeostasis and ATP synthesis require more energy. The alkaliphile also tolerates a cytoplasmic pH>9.0 at external pH values at which the pH homeostasis capacity is exceeded, and manages other stresses that are exacerbated at alkaline pH, e.g. sodium, oxidative and cell wall stresses. The genome of B.pseudofirmus OF4 includes two plasmids that are lost from some mutants without viability loss. The plasmids may provide a reservoir of mobile elements that promote adaptive chromosomal rearrangements under particular environmental conditions. The genome also reveals a more acidic pI profile for proteins exposed on the outer surface than found in neutralophiles. A large array of transporters and regulatory genes are predicted to protect the alkaliphile from its overlapping stresses. In addition, unanticipated metabolic versatility was observed, which could ensure requisite energy for alkaliphily under diverse conditions. Title: The MDGA1 gene confers risk to schizophrenia and bipolar disorder Li J, Liu J, Feng G, Li T, Zhao Q, Li Y, Hu Z, Zheng L, Zeng Z and Shi Y <2 more author(s)> Li J, Liu J, Feng G, Li T, Zhao Q, Li Y, Hu Z, Zheng L, Zeng Z, He L, Wang T, Shi Y (- 2) Ref: Schizophr Res, 125:194, 2011 : PubMed ESTHER: Li_2011_Schizophr.Res_125_194 PubMedSearch: Li 2011 Schizophr.Res 125 194 PubMedID: 21146959 Abstract OBJECTIVE: The structural, cytoarchitectural and functional brain abnormalities reported in patients with mental disorders may be due to aberrant neuronal migration influenced by cell adhesion molecules. MDGA1, like Ig-containing cell adhesion molecules, has several cell adhesion molecule-like domains. Moreover, Kahler et al. (2008) reported that the MDGA1 gene was a schizophrenia susceptibility gene in Scandinavian population. To further investigate whether the MDGA1 gene is a shared risk factor of schizophrenia, bipolar disorder and major depressive disorder in Chinese Han population, we conducted this study. Title: Discovery of isoxazole analogues of sazetidine-A as selective alpha4beta2-nicotinic acetylcholine receptor partial agonists for the treatment of depression Liu J, Yu LF, Eaton JB, Caldarone B, Cavino K, Ruiz C, Terry M, Fedolak A, Wang D and Kozikowski AP <4 more author(s)> Liu J, Yu LF, Eaton JB, Caldarone B, Cavino K, Ruiz C, Terry M, Fedolak A, Wang D, Ghavami A, Lowe DA, Brunner D, Lukas RJ, Kozikowski AP (- 4) Ref: Journal of Medicinal Chemistry, 54:7280, 2011 : PubMed ESTHER: Liu_2011_J.Med.Chem_54_7280 PubMedSearch: Liu 2011 J.Med.Chem 54 7280 PubMedID: 21905669 Abstract Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment, targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenaline, is not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogues that interact with alpha4beta2 nicotinic acetylcholine receptors (nAChRs) as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the alpha4beta2 subtype of nAChR over alpha3beta4-nAChRs are partial agonists at the alpha4beta2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450-related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline. Title: Complete genome sequence of the industrial strain Ketogulonicigenium vulgare WSH-001 Liu L, Li Y, Zhang J, Zhou Z, Liu J, Li X, Zhou J, Du G, Wang L, Chen J Ref: Journal of Bacteriology, 193:6108, 2011 : PubMed ESTHER: Liu_2011_J.Bacteriol_193_6108 PubMedSearch: Liu 2011 J.Bacteriol 193 6108 PubMedID: 21994934 Gene_locus related to this paper: ketvy-e3f614, ketvw-f9yby2 Abstract Ketogulonicigenium vulgare is an industrial organism commonly used in the vitamin C industry. Here, we report the finished, annotated, and compared 3.28-Mbp high-quality genome sequence of Ketogulonicigenium vulgare WSH-001, a 2-keto-l-gulonic acid-producing industrial strain stocked in our laboratory. Title: Complete genome sequence of the industrial strain Bacillus megaterium WSH-002 Liu L, Li Y, Zhang J, Zou W, Zhou Z, Liu J, Li X, Wang L, Chen J Ref: Journal of Bacteriology, 193:6389, 2011 : PubMed ESTHER: Liu_2011_J.Bacteriol_193_6389 PubMedSearch: Liu 2011 J.Bacteriol 193 6389 PubMedID: 22038958 Gene_locus related to this paper: bacmd-d5dhr4, bacmd-d5dlu4, bacmd-d5dna5, bacme-g2rqm9, bacme-g2rsv7, bacme-g9bex6 Abstract Bacillus megaterium, an industrial strain, has been widely used in protein production and the vitamin C industry. Here we reported a finished, annotated, and compared 4.14-Mbp high-quality genome sequence of B. megaterium WSH-002, which is the companion strain for Ketogulonicigenium vulgare in the vitamin C industry and is stocked in our laboratory. Title: Reaction mechanism for cocaine esterase-catalyzed hydrolyses of (+)- and (-)-cocaine: unexpected common rate-determining step Liu J, Zhao X, Yang W, Zhan CG Ref: J Phys Chem B, 115:5017, 2011 : PubMed ESTHER: Liu_2011_J.Phys.Chem.B_115_5017 PubMedSearch: Liu 2011 J.Phys.Chem.B 115 5017 PubMedID: 21486046 Abstract First-principles quantum mechanical/molecular mechanical free energy calculations have been performed to examine the catalytic mechanism for cocaine esterase (CocE)-catalyzed hydrolysis of (+)-cocaine in comparison with CocE-catalyzed hydrolysis of (-)-cocaine. It has been shown that the acylation of (+)-cocaine consists of nucleophilic attack of the hydroxyl group of Ser117 on the carbonyl carbon of (+)-cocaine benzoyl ester and the dissociation of (+)-cocaine benzoyl ester. The first reaction step of deacylation of (+)-cocaine, which is identical to that of (-)-cocaine, is rate-determining, indicating that CocE-catalyzed hydrolyses of (+)- and (-)-cocaine have a common rate-determining step. The computational results predict that the catalytic rate constant of CocE against (+)-cocaine should be the same as that of CocE against (-)-cocaine, in contrast with the remarkable difference between human butyrylcholinesterase-catalyzed hydrolyses of (+)- and (-)-cocaine. The prediction has been confirmed by experimental kinetic analysis on CocE-catalyzed hydrolysis of (+)-cocaine in comparison with CocE-catalyzed hydrolysis of (-)-cocaine. The determined common rate-determining step indicates that rational design of a high-activity mutant of CocE should be focused on the first reaction step of the deacylation. Furthermore, the obtained mechanistic insights into the detailed differences in the acylation between the (+)- and (-)-cocaine hydrolyses provide indirect clues for rational design of amino acid mutations that could more favorably stabilize the rate-determining transition state in the deacylation and, thus, improve the catalytic activity of CocE. This study provides a valuable mechanistic base for rational design of an improved esterase for therapeutic treatment of cocaine abuse. Title: Benzofurans from Styrax agrestis as acetylcholinesterase inhibitors: structure-activity relationships and molecular modeling studies Liu J, Dumontet V, Simonin AL, Iorga BI, Guerineau V, Litaudon M, Nguyen VH, Gueritte F Ref: Journal of Natural Products, 74:2081, 2011 : PubMed ESTHER: Liu_2011_J.Nat.Prod_74_2081 PubMedSearch: Liu 2011 J.Nat.Prod 74 2081 PubMedID: 21939219 Abstract An extract of Styrax agrestis fruits, collected in Vietnam, significantly inhibited acetylcholinesterase (AChE) in vitro. Bioassay-guided fractionation revealed three new egonol-type benzofurans: egonol-9(Z),12(Z) linoleate (1), 7-demethoxyegonol-9(Z),12(Z) linoleate (2), and 7-demethoxyegonol oleate (4). Ten known egonol-type benzofurans were also isolated (3, 5, 6-13). In order to better understand structure-activity relationships in this series, egonol derivatives 14-19 were prepared by chemical modifications and evaluated for their inhibition of AChE, butyrylcholinesterase (BChE), and AChE-induced Abeta aggregation. Compounds 1-4 were the most potent inhibitors of the series, which exhibited inhibitory activity against AChE (IC50 1.4-3.1 muM) and, for 1, Abeta aggregation (77.6%). Molecular docking studies were also performed to investigate interaction of these compounds with the active site of AChE. Title: High throughput enzyme inhibitor screening by functionalized magnetic carbonaceous microspheres and graphene oxide-based MALDI-TOF-MS Liu Y, Li Y, Liu J, Deng C, Zhang X Ref: J Am Soc Mass Spectrom, 22:2188, 2011 : PubMed ESTHER: Liu_2011_J.Am.Soc.Mass.Spectrom_22_2188 PubMedSearch: Liu 2011 J.Am.Soc.Mass.Spectrom 22 2188 PubMedID: 21952774 Abstract In this work, a high throughput methodology for screening enzyme inhibitors has been demonstrated by combining enzyme immobilized magnetic carbonaceous microspheres and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with grapheme oxide as matrix. First, model enzyme acetylcholinesterase (AChE) was immobilized onto the 3-glycidoxypropyltrimethoxysilane (GLYMO)-modified magnetic carbonaceous (MC) microspheres, displaying a high enzyme activity and stability, and also facilitating the separation of enzyme from substrate and product. The efficiency of immobilized AChE was monitored by biochemical assay, which was carried out by mixing enzyme-immobilized MC microspheres with model substrate acetylcholine (ACh), and subsequent quantitative determination of substrate ACh and product choline using graphene oxide-based MALDI-TOF-MS with no background inference. The limit of detection (LOD) for ACh was 0.25 fmol/muL, and excellent linearity (R(2)=0.9998) was maintained over the range of 0.5 and 250 fmol/muL. Choline was quantified over the range of 0.05 and 15 pmol/muL, also with excellent linearity (R(2)=0.9994) and low LOD (0.15 fmol/muL). Good accuracy and precision were obtained for all concentrations within the range of the standard curves. All together, eight compounds (four known AChE inhibitors and four control chemical compounds with no AChE inhibit effect) were tested with our promoted methodology, and the obtained results demonstrated that our high throughput screening methodology could be a great help to the routine enzyme inhibitor screening. Title: Complete genome sequence of Haloarcula hispanica, a Model Haloarchaeon for studying genetics, metabolism, and virus-host interaction Liu H, Wu Z, Li M, Zhang F, Zheng H, Han J, Liu J, Zhou J, Wang S, Xiang H Ref: Journal of Bacteriology, 193:6086, 2011 : PubMed ESTHER: Liu_2011_J.Bacteriol_193_6086 PubMedSearch: Liu 2011 J.Bacteriol 193 6086 PubMedID: 21994921 Gene_locus related to this paper: halma-q5uym0 Abstract Haloarcula hispanica is an extremely halophilic archaeon that has an unusually low restriction barrier and is therefore significant for studying archaeal genetics, metabolism, and virus-host interactions. Here we report the complete genome sequence (3,890,005 bp) of H. hispanica strain CGMCC 1.2049, consisting of two chromosomes and one megaplasmid. Title: Whole-genome sequences of four Mycobacterium bovis BCG vaccine strains Pan Y, Yang X, Duan J, Lu N, Leung AS, Tran V, Hu Y, Wu N, Liu D and Zhu B <6 more author(s)> Pan Y, Yang X, Duan J, Lu N, Leung AS, Tran V, Hu Y, Wu N, Liu D, Wang Z, Yu X, Chen C, Zhang Y, Wan K, Liu J, Zhu B (- 6) Ref: Journal of Bacteriology, 193:3152, 2011 : PubMed ESTHER: Pan_2011_J.Bacteriol_193_3152 PubMedSearch: Pan 2011 J.Bacteriol 193 3152 PubMedID: 21478353 Gene_locus related to this paper: myctu-RV1215C Abstract Mycobacterium bovis Bacille Calmette-Guerin (BCG) is the only vaccine available against tuberculosis (TB). A number of BCG strains are in use, and they exhibit biochemical and genetic differences. We report the genome sequences of four BCG strains representing different lineages, which will help to design more effective TB vaccines. Title: The HindIII polymorphism in the lipoprotein lipase gene predicts type 2 diabetes risk among Chinese adults Qi Y, Liu J, Wang W, Wang M, Sun JY, Li Y, Wu ZS, Zhao D Ref: Clinica Chimica Acta, 412:1229, 2011 : PubMed ESTHER: Qi_2011_Clin.Chim.Acta_412_1229 PubMedSearch: Qi 2011 Clin.Chim.Acta 412 1229 PubMedID: 21419757 Abstract OBJECTIVE: We aimed to investigate the polymorphism HindIII of the lipoprotein lipase (LPL) gene to explore whether it had a potential role in susceptibility to type 2 diabetes mellitus (T2DM) among Han Chinese, and whether this effect was influenced by regulating LPL or other risk factors. METHODS: Overall, 654 Han Chinese adults were selected from a community-based cross-sectional study using a stratified cluster random sampling. Genotyping was performed using the PCR-RFLP technique, and the metabolic variables were measured using standard methods. RESULTS: Individuals with the HindIII H-/H- genotype tended to have higher pre-heparin LPL (PrLPL) and lower triglyceride levels but an unexpected higher prevalence of T2DM compared with the H+/H+ genotype carriers. The association between the H-/H- genotype and T2DM risk remained unchanged across all subgroups of lipids/glucose-related RF. In a recessive model, the H-/H- genotype conferred a 2.12-fold increased risk [odds ratio (OR): 3.12; 95% confidence interval (CI): 1.18-8.27] for T2DM after controlling for age and sex, and increased further after additionally adjusting for traditional RFs, and PrLPL (OR=4.45; 95% CI=1.51-13.07). CONCLUSIONS: This study indicated that Chinese adults with the LPL gene HindIII H-/H- genotype had a significantly increased risk of T2DM, even if they had favorable lipid profiles. Title: Phytotoxicity of fusaric acid and analogs to cotton Stipanovic RD, Puckhaber LS, Liu J, Bell AA Ref: Toxicon, 57:176, 2011 : PubMed ESTHER: Stipanovic_2011_Toxicon_57_176 PubMedSearch: Stipanovic 2011 Toxicon 57 176 PubMedID: 20955724 Gene_locus related to this paper: gibf5-fub4, gibf5-fub5 Abstract We developed a cotton cotyledonary leaf bioassay to test the phytotoxicity of fusaric acid (5-butylpicolinic acid), picolinic acid and related analogs. The compounds were dissolved in aqueous Tween 80, and 20 microL of the test solution was placed at three positions on the leaf, and a needle was used to puncture the leaf through each drop; the results were evaluated after 48 h. In contrast to previous studies, we found the carboxylic acid group is essential for phytotoxicity. Nicotinic acid was considerably less phytotoxic than picolinic acid and conversion of picolinic acid to the amide or N-oxide decreased phytotoxicity. Increasing the alkyl chain length at the 5-position on picolinic acid from two up to five carbons atoms increased phytotoxicity. Fusaric acid methyl ester, the most phytotoxic compound tested, is a naturally occurring compound; as such it has potential as a herbicide in organic farming. Title: Unique regulation of adipose triglyceride lipase (ATGL) by perilipin 5, a lipid droplet-associated protein Wang H, Bell M, Sreenivasan U, Hu H, Liu J, Dalen K, Londos C, Yamaguchi T, Rizzo MA and Sztalryd C <3 more author(s)> Wang H, Bell M, Sreenivasan U, Hu H, Liu J, Dalen K, Londos C, Yamaguchi T, Rizzo MA, Coleman R, Gong D, Brasaemle D, Sztalryd C (- 3) Ref: Journal of Biological Chemistry, 286:15707, 2011 : PubMed ESTHER: Wang_2011_J.Biol.Chem_286_15707 PubMedSearch: Wang 2011 J.Biol.Chem 286 15707 PubMedID: 21393244 Abstract Lipolysis is a critical metabolic pathway contributing to energy homeostasis through degradation of triacylglycerides stored in lipid droplets (LDs), releasing fatty acids. Neutral lipid lipases act at the oil/water interface. In mammalian cells, LD surfaces are coated with one or more members of the perilipin protein family, which serve important functions in regulating lipolysis. We investigated mechanisms by which three perilipin proteins control lipolysis by adipocyte triglyceride lipase (ATGL), a key lipase in adipocytes and non-adipose cells. Using a cell culture model, we examined interactions of ATGL and its co-lipase CGI-58 with perilipin 1 (perilipin A), perilipin 2 (adipose differentiation-related protein), and perilipin 5 (LSDP5) using multiple techniques as follows: anisotropy Forster resonance energy transfer, co-immunoprecipitation, [(32)P]orthophosphate radiolabeling, and measurement of lipolysis. The results show that ATGL interacts with CGI-58 and perilipin 5; the latter is selectively expressed in oxidative tissues. Both proteins independently recruited ATGL to the LD surface, but with opposite effects; interaction of ATGL with CGI-58 increased lipolysis, whereas interaction of ATGL with perilipin 5 decreased lipolysis. In contrast, neither perilipin 1 nor 2 interacted directly with ATGL. Activation of protein kinase A (PKA) increased [(32)P]orthophosphate incorporation into perilipin 5 by 2-fold, whereas neither ATGL nor CGI-58 was labeled under the incubation conditions. Cells expressing both ectopic perilipin 5 and ATGL showed a 3-fold increase in lipolysis following activation of PKA. Our studies establish perilipin 5 as a novel ATGL partner and provide evidence that the protein composition of perilipins at the LD surface regulates lipolytic activity of ATGL. Title: Integrated transcriptional and proteomic analysis with in vitro biochemical assay reveal the important role of CYP3A46 in T-2 toxin hydroxylation in porcine primary hepatocytes Wang J, Jiang J, Zhang H, Cai H, Li C, Li K, Liu J, Guo X, Zou G and Dai J <2 more author(s)> Wang J, Jiang J, Zhang H, Cai H, Li C, Li K, Liu J, Guo X, Zou G, Wang D, Deng Y, Dai J (- 2) Ref: Mol Cell Proteomics, 10:M111 008748, 2011 : PubMed ESTHER: Wang_2011_Mol.Cell.Proteomics_10_M111 008748 PubMedSearch: Wang 2011 Mol.Cell.Proteomics 10 M111 008748 PubMedID: 21685020 Abstract Both T-2 toxin and its metabolites are highly potent mycotoxins that can cause severe human and animal diseases upon exposure. Understanding the toxic mechanism and biotransformation process of T-2 toxin at a cellular level is essential for the development of counter-measures. We investigated the effect of T-2 toxin in porcine primary hepatocytes using porcine genome array and two-dimensional difference gel electrophoresis with matrix-assisted laser desorption/ionization tandem time of flight mass spectrometry. Integrated transcriptional and proteomic analysis demonstrated that T-2 toxin adversely affected porcine hepatocytes by initiating lipid metabolism disorder, oxidative stress response, and apoptosis. In addition, xenobiotic metabolism genes, including cytochrome P450 3As (CYP3A46 and CYP3A39), carboxylesterase 1Cs (CES1C4 and CES1C5), and epoxide hydrolase (EPHX1), increased in T-2 toxin treatment cells. Using HepG2 cells to over-express the recombinant xenobiotic metabolism genes above and rapid resolution liquid chromatography/tandem mass spectrometry to detect metabolites of T-2 toxin, we determined that porcine CYP3A46 mainly catalyzed T-2 to form 3'-hydroxy-T-2, which was further confirmed by purified CYP3A46 protein. However, recombinant porcine CES1C5 and EPHX1 did not enhance hydrolysis and de-epoxidation of T-2 implying that other esterases and epoxide hydrolases may play dominant roles in those reactions. Title: [The changes of blood neurotransmitter levels in workers occupationally exposed to ethylbenzene] Wang YR, Yang DY, Zhang M, Wang Q, Liu J, Li JG Ref: Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi, 29:125, 2011 : PubMed ESTHER: Wang_2011_Zhonghua.Lao.Dong.Wei.Sheng.Zhi.Ye.Bing.Za.Zhi_29_125 PubMedSearch: Wang 2011 Zhonghua.Lao.Dong.Wei.Sheng.Zhi.Ye.Bing.Za.Zhi 29 125 PubMedID: 21619842 Abstract OBJECTIVE: To explore the effects of occupational ethylbenzene exposure on blood neurotransmitter levels in population. METHODS: The exposure group consisted of 246 workers occupationally exposed to ethylbenzene and the control group was composed of 122 staffs from the offices. The basic information on ethylbenzene exposure was collected by the questionnaire. The mandelic acid (MA) and phenylglyoxylic acid (PGA) in the post-working urine were measured using the high performance liquid chromatography. The levels of gamma-aminobutyric acid (GABA), dopamine (DA) and acetylcholinesterase (AchE) activity were detected by reversed phase high performance liquid chromatography, spectrofluorometry and DTNB method, respectively. The blood biochemical indexes: alanine transaminase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin (ALB), alkaline phosphatase (ALP), total bilirubin (TBIL) were examined. Also the hematologic indexes: red blood cell (RBC), white blood cell (WBC), hemoglobin (HGB) and platelet (PLT) were determined. RESULTS: The levels of MA, PGA and MA+PGA of urine in the exposed group were significantly higher than those in the control group (P < 0.05). There were no significant differences of the biochemical indexes (AST, ALT, TP, ALB, BUN, Cr, ALP and TBIL), hematologic indexes (WBC, RBC, Hb and PLT) and serum GABA between the exposure group and the control group (P > 0.05). But the serum DA [(0.21 +/- 0.011) mg/L] and AChE levels [(0.321 +/- 0.066) U/L] in the exposure group were significantly lower than those in the control group [(0.25 +/- 0.015) mg/L, (0.583 +/- 0.125) U/L], respectively (P < 0.05). CONCLUSION: MA and PGA in urine can serve as the biomarkers of internal exposure dose. Before the obvious changes of biochemical indexes and hematologic indexes appear, the exposure to ethylbenzene can influence the blood neurotransmitter levels in workers exposed to ethylbenzene. Title: Biochemical effects of acute phoxim administration on antioxidant system and acetylcholinesterase in Oxya chinensis (Thunberg) (Orthoptera: Acrididae) Wu H, Liu J, Zhang R, Zhang J, Guo Y, Ma E Ref: Pesticide Biochemistry and Physiology, 100:23, 2011 : PubMed ESTHER: Wu_2011_Pestic.Biochem.Physiol_100_23 PubMedSearch: Wu 2011 Pestic.Biochem.Physiol 100 23 Abstract The study was undertaken to evaluate the effects of different concentrations of phoxim on acetylcholinesterase (AChE) and esterase (EST) activities, and antioxidant system after topical application to Oxya chinensis. The results showed that phoxim inhibited AChE activity, and did not cause significant changes in the EST activity and the levels of malondialdehyde (MDA) and reduced glutathione (GSH). After phoxim administration, superoxide (SOD) and catalase (CAT) activities showed a biphasic response with an initial increase followed by a decline in their activities. Glutathione reductase (GR) and glutathione peroxidase (GPx) activities were inhibited in comparison with the control. Glutathione S-transferase (GST) activity showed irregular changes. Its activity increased significantly at the concentrations of 0.06 and 0.12 ug/uL and decreased at the concentrations of 0.09 and 0.24 ug/uL compared with the control. Changes in SOD, CAT, GST, GPx, and GR activities indicated that phoxim caused oxidative damage in O. chinensis. However, no significant changes in MDA content suggested that these enzymes played important roles in scavenging the oxidative free radicals induced by phoxim in O. chinensis. The formation of oxygen free radicals might be a factor in the toxicity of phoxim. Title: Design, preparation, and characterization of high-activity mutants of human butyrylcholinesterase specific for detoxification of cocaine Xue L, Ko MC, Tong M, Yang W, Hou S, Fang L, Liu J, Zheng F, Woods JH and Zhan CG <1 more author(s)> Xue L, Ko MC, Tong M, Yang W, Hou S, Fang L, Liu J, Zheng F, Woods JH, Tai HH, Zhan CG (- 1) Ref: Molecular Pharmacology, 79:290, 2011 : PubMed ESTHER: Xue_2011_Mol.Pharmacol_79_290 PubMedSearch: Xue 2011 Mol.Pharmacol 79 290 PubMedID: 20971807 Abstract Cocaine is a widely abused drug without a U.S. Food and Drug Administration-approved medication. There is a recognized, promising anticocaine medication to accelerate cocaine metabolism, producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway [i.e., cocaine hydrolysis catalyzed by butyrylcholinesterase (BChE) in plasma]. An ideal, therapeutically valuable mutant of human BChE should have not only a significantly improved catalytic activity against (-)-cocaine but also certain selectivity for (-)-cocaine over neurotransmitter acetylcholine (ACh), such that one would not expect systemic administration of the BChE mutant to interrupt cholinergic transmission. The present study accounting for the mutation-caused changes of the catalytic activities of BChE against both (-)-cocaine and ACh by means of molecular modeling and site-directed mutagenesis has led to identification of three BChE mutants that have not only a considerably improved catalytic efficiency against (-)-cocaine but also the desirable selectivity for (-)-cocaine over ACh. Two representative BChE mutants have been confirmed to be potent in actual protection of mice from acute toxicity (convulsion and lethality) of a lethal dose of cocaine (180 mg/kg). Pretreatment with the BChE mutant (i.e., 1 min before cocaine administration) dose-dependently protected mice against cocaine-induced convulsions and lethality. In particular, all mice pretreated with the mutant (e.g., 0.02 mg or more of A199S/F227A/S287G/A328W/E441D BChE) survived. The in vivo data reveal the primary factor (i.e., the relative catalytic efficiency), determining the efficacy in practical protection of mice from the acute cocaine toxicity and future direction for further improving the efficacy of the enzyme in the cocaine overdose treatment. Title: Complete genome sequences of Mycobacterium tuberculosis strains CCDC5079 and CCDC5080, which belong to the Beijing family Zhang Y, Chen C, Liu J, Deng H, Pan A, Zhang L, Zhao X, Huang M, Lu B and Wan K <3 more author(s)> Zhang Y, Chen C, Liu J, Deng H, Pan A, Zhang L, Zhao X, Huang M, Lu B, Dong H, Du P, Chen W, Wan K (- 3) Ref: Journal of Bacteriology, 193:5591, 2011 : PubMed ESTHER: Zhang_2011_J.Bacteriol_193_5591 PubMedSearch: Zhang 2011 J.Bacteriol 193 5591 PubMedID: 21914894 Gene_locus related to this paper: myctu-cut3, myctu-cutas1, myctu-cutas2, myctu-Rv0160c, myctu-Rv1069c, myctu-RV1215C, myctu-Rv2045c, myctu-RV3452, myctu-RV3724, myctu-Rv3802c, myctu-y0571 Abstract Mycobacterium tuberculosis is one of most prevalent pathogens in the world. Drug-resistant strains of this pathogen caused by the excessive use of antibiotics have long posed serious threats to public health worldwide. A broader picture of drug resistance mechanisms at the genomic level can be obtained only with large-scale comparative genomic methodology. Two closely related Beijing family isolates, one resistant to four first-line drugs (CCDC5180) and one sensitive to them (CCDC5079), were completely sequenced. These sequences will serve as valuable references for further drug resistance site identification studies and could be of great importance for developing drugs targeting these sites. Title: Development and validation of a sample stabilization strategy and a UPLC-MS/MS method for the simultaneous quantitation of acetylcholine (ACh), histamine (HA), and its metabolites in rat cerebrospinal fluid (CSF) Zhang Y, Tingley FD, 3rd, Tseng E, Tella M, Yang X, Groeber E, Liu J, Li W, Schmidt CJ, Steenwyk R Ref: Journal of Chromatography B Analyt Technol Biomed Life Sciences, 879:2023, 2011 : PubMed ESTHER: Zhang_2011_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_879_2023 PubMedSearch: Zhang 2011 J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci 879 2023 PubMedID: 21684223 Abstract A UPLC-MS/M |
