Author Report for: Zhang DNo contact information in database for Zhang D
Guo C, Wang T, Zhang D, Ge X, Li J Ref: Biochemical & Biophysical Research Communications, 654:102, 2023 : PubMed ESTHER: Guo_2023_Biochem.Biophys.Res.Commun_654_102 PubMedSearch: Guo 2023 Biochem.Biophys.Res.Commun 654 102 PubMedID: 36905760 Abstract Alzheimer's disease (AD) is the most common neurodegenerative disorder in the world. The aggregation of both amyloid beta (Abeta) peptides extracellularly and Tau proteins intracellularly plays key roles in the pathological consequences of AD, which lead to cholinergic neurodegeneration and eventually death. Currently, there are no effective methods to stop the progression of AD. Using ex vivo, in vivo and clinical approaches, we investigated the functional effects of plasminogen on the widely used FAD, Abeta42 oligomer or Tau intracranial injection-induced AD mouse model and explored its therapeutic effects on patients with AD. The results show that intravenously injected plasminogen rapidly crosses the bloodbrain barrier (BBB); increases plasmin activity in the brain; colocalizes with and effectively promotes the clearance of Abeta42 peptide and Tau protein deposits ex vivo and in vivo; increases the choline acetyltransferase (ChAT) level and decreases the acetylcholinesterase (AChE) activity; and improves the memory functions. Clinically, when GMP-level plasminogen was administered to 6 AD patients for 1-2 weeks, their average scores on the Minimum Mental State Examination (MMSE), which is a standard scoring system used to measure the memory loss and cognitive deficits, were extremely significantly improved by 4.2 +/- 2.23 points, e.g., an average increase from 15.5 +/- 8.22 before treatment to 19.7 +/- 7.09 after treatment. The preclinical study and pilot clinical study suggest that plasminogen is effective in treating AD and may be a promising drug candidate. Title: Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia: randomized trials and multiomics analysis Guo LK, Su Y, Zhang YY, Yu H, Lu Z, Li WQ, Yang YF, Xiao X, Yan H and Yue WH <17 more author(s)> Guo LK, Su Y, Zhang YY, Yu H, Lu Z, Li WQ, Yang YF, Xiao X, Yan H, Lu TL, Li J, Liao YD, Kang ZW, Wang LF, Li Y, Li M, Liu B, Huang HL, Lv LX, Yao Y, Tan YL, Breen G, Everall I, Wang HX, Huang Z, Zhang D, Yue WH (- 17) Ref: Mil Med Res, 10:24, 2023 : PubMed ESTHER: Guo_2023_Mil.Med.Res_10_24 PubMedSearch: Guo 2023 Mil.Med.Res 10 24 PubMedID: 37269009 Abstract BACKGROUND: Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers. Previous studies have indicated the association between treatment response and genetic and epigenetic factors, but no effective biomarkers have been identified. Hence, further research is imperative to enhance precision medicine in SCZ treatment. METHODS: Participants with SCZ were recruited from two randomized trials. The discovery cohort was recruited from the CAPOC trial (n = 2307) involved 6 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone, and Haloperidol/Perphenazine (subsequently equally assigned to one or the other) groups. The external validation cohort was recruited from the CAPEC trial (n = 1379), which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, and Aripiprazole groups. Additionally, healthy controls (n = 275) from the local community were utilized as a genetic/epigenetic reference. The genetic and epigenetic (DNA methylation) risks of SCZ were assessed using the polygenic risk score (PRS) and polymethylation score, respectively. The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis, methylation quantitative trait loci, colocalization, and promoter-anchored chromatin interaction. Machine learning was used to develop a prediction model for treatment response, which was evaluated for accuracy and clinical benefit using the area under curve (AUC) for classification, R(2) for regression, and decision curve analysis. RESULTS: Six risk genes for SCZ (LINC01795, DDHD2, SBNO1, KCNG2, SEMA7A, and RUFY1) involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response. The developed and externally validated prediction model, which incorporated clinical information, PRS, genetic risk score (GRS), and proxy methylation level (proxyDNAm), demonstrated positive benefits for a wide range of patients receiving different APDs, regardless of sex [discovery cohort: AUC = 0.874 (95% CI 0.867-0.881), R(2) = 0.478; external validation cohort: AUC = 0.851 (95% CI 0.841-0.861), R(2) = 0.507]. CONCLUSIONS: This study presents a promising precision medicine approach to evaluate treatment response, which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ. Trial registration Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ ), 18. Aug 2009 retrospectively registered: CAPOC-ChiCTR-RNC-09000521 ( https://www.chictr.org.cn/showproj.aspx?proj=9014 ), CAPEC-ChiCTR-RNC-09000522 ( https://www.chictr.org.cn/showproj.aspx?proj=9013 ). Title: A novel skeleton alkaloid from Portulaca oleracea L. and its bioactivities Lan X, Guo S, Zhao Y, Zhang M, Zhang D, Leng A, Ying X Ref: Fitoterapia, :105608, 2023 : PubMed ESTHER: Lan_2023_Fitoterapia__105608 PubMedSearch: Lan 2023 Fitoterapia 105608 PubMedID: 37453700 Abstract A novel skeleton alkaloid was obtained from Portulaca oleracea L., which was identified as 10,11-dihydroxybenzo[5',6'] pentaleno[1',2':3,4]pyrrolo[2,1-b]oxazol-7(11bH)-one, named oleracone M, and its structure was determined using UHPLC-ESI-QTOF/MS, 1D NMR and 2D NMR spectroscopy, and circular dichroism. Then the bioactivities of the compound were investigated including the anti-inflammatory, anti-acetylcholinesterase and antioxidant activities. The results showed that the novel skeleton alkaloid exhibited the potent effect on inhibiting the secretion of IL-1beta at 10 microM, anticholinesterase activity with IC(50) value of 49.58 microM, and antioxidant activity with IC(50) value of 66.43 microM. Title: Molecular identification of carboxylesterase genes and their potential roles in the insecticides susceptibility of Grapholita molesta Li J, Jia Y, Zhang D, Li Z, Zhang S, Liu X Ref: Insect Molecular Biology, :, 2023 : PubMed ESTHER: Li_2023_Insect.Mol.Biol__ PubMedSearch: Li 2023 Insect.Mol.Biol PubMedID: 36661850 Abstract Grapholita molesta is one of the most damaging pests worldwide in stone and pome fruits. Application of chemical pesticides is still the main method to control this pest, and results in resistance to several types of insecticides. Carboxylesterase (CarE) is one kind of the important enzymes involved in the detoxification metabolism and tolerance of xenobiotics and insecticides. However, the roles of CarEs in insecticides susceptibility of G. molesta are still unclear. In the present study, the enzyme activity of CarEs and mRNA expression of six CarE genes were consistently elevated after treatment with three insecticides (emamectin benzoate, lambda-cyhalothrin, and chlorantraniliprole). According to spatio-temporal expression profiles, 6 CarE genes expressed differently in different developmental stages, and highly expressed in some detoxification metabolic organs. RNAi-mediated knockdown of these six CarE genes indicated that the susceptibility of G. molesta to all these three insecticides were obviously raised after GmCarE9, GmCarE14, GmCarE16, and GmCarE22 knockdown, respectively. Overall, these results demonstrated that GmCarE9, GmCarE14, GmCarE16, and GmCarE22 play a role in the susceptibility of G. molesta to emamectin benzoate, lambda-cyhalothrin, and chlorantraniliprole treatment. This study expands our understanding of CarEs in insects, that the same CarE gene could participate in the susceptibility of different insecticides. This article is protected by copyright. All rights reserved. Title: Inhibition of Caspase-11-Mediated Pyroptosis Alleviates Acute Kidney Injury Associated with Severe Acute Pancreatitis in Rats Shao Y, Li C, Jiang Y, Li H, Tang X, Gao Z, Zhang D Ref: J Invest Surg, 36:1, 2023 : PubMed ESTHER: Shao_2023_J.Invest.Surg_36_1 PubMedSearch: Shao 2023 J.Invest.Surg 36 1 PubMedID: 36350036 Abstract Background: Acute kidney injury (AKI) is a common complication in patients with severe acute pancreatitis (SAP). Caspase-11-mediated pyroptosis is essential for the progression of multiple diseases, but its role in SAP-induced AKI remains unknown.Aims: This research investigated whether caspase-11-mediated pyroptosis is involved in SAP-induced AKI and whether inhibiting caspase-11-mediated pyroptosis improves SAP-induced AKI.Methods: A rat model of SAP with AKI was established by slowly injecting 5% sodium taurocholate into the biliopancreatic duct, then wedelolactone (25 or 50 mg/kg), an inhibitor of caspase-11, was injected through the intra-peritoneum 1 and 6 h after SAP induction. Serum biochemical indexes, including serum amylase, lipase, interleukin (IL)-6, blood urea nitrogen (BUN), tumor necrosis factor (TNF)-alpha, and creatinine (Cr) in rats, were evaluated using biochemical test kits. Caspase-11 and gasdermin D (GSDMD) expression in the kidney tissues was evaluated by western blotting and immunohistochemical staining. IL-1 and IL-18 levels in kidney tissues were detected by ELISA kits. Furthermore, histopathological alterations of pancreas and kidney were assessed by H&E staining.Results: The serum biochemical indexes and pyroptosis-related proteins in kidney tissues were significantly increased after SAP induction. Furthermore, wedelolactone decreased the expression of pyroptosis-linked proteins in kidney tissues, reduced serum lipase, amylase, IL-6, TNF-alpha, BUN, and Cr, and ameliorated the renal and pancreatic histological damage in SAP rats.Conclusion: Caspase-11-mediated pyroptosis contributes to SAP-induced AKI, and targeting caspase-11-mediated pyroptosis might be a novel treatment strategy for SAP-induced AKI. Title: New advances in clinical application of neostigmine: no longer focusing solely on increasing skeletal muscle strength Si S, Zhao X, Su F, Lu H, Zhang D, Sun L, Wang F, Xu L Ref: Front Pharmacol, 14:1227496, 2023 : PubMed ESTHER: Si_2023_Front.Pharmacol_14_1227496 PubMedSearch: Si 2023 Front.Pharmacol 14 1227496 PubMedID: 37601044 Abstract Neostigmine is a clinical cholinesterase inhibitor, that is, commonly used to enhance the function of the cholinergic neuromuscular junction. Recent studies have shown that neostigmine regulates the immune-inflammatory response through the cholinergic anti-inflammatory pathway, affecting perioperative neurocognitive function. This article reviews the relevant research evidence over the past 20 years, intending to provide new perspectives and strategies for the clinical application of neostigmine. Title: Transcriptome reveals the toxicity difference of dimethyl disulfide by contact and fumigation on Meloidogyne incognita through calcium channel-mediated oxidative phosphorylation Wang Q, Wang X, Zhang D, Fang W, Li Y, Cao A, Yan D Ref: J Hazard Mater, 460:132268, 2023 : PubMed ESTHER: Wang_2023_J.Hazard.Mater_460_132268 PubMedSearch: Wang 2023 J.Hazard.Mater 460 132268 PubMedID: 37619272 Abstract The prevention and control of root-knot nematode disease has been posing a severe challenge worldwide. Fumigant dimethyl disulfide (DMDS) has excellent biological activity against nematodes. However, DMDS displays significant differences in contact and fumigation toxicity on nematodes. The specific regulatory mechanisms of DMDS on nematodes were investigated by characterizing the ultrastructure of nematodes, examining the physiological and biochemical indicators, and conducting transcriptome high-throughput sequencing. As indicated by the results, DMDS fumigation exhibited the biological activity of against M. incognita 121 times higher than DMDS contact. DMDS contact destroyed nematode body wall cells. Besides, DMDS fumigation destroyed the structure of pseudocoelom. DMDS treatment expedited the oxygen consumption of nematode while inhibiting acetylcholinesterase activity. As indicated by the analysis of vital signaling pathways based on transcriptome, DMDS based on the contact mode penetrated directly into the nematode through the body wall and subsequently affected calcium channels in the body wall and muscle, disrupting their structure; it serves as an uncoupling agent to interfere with ATP synthase. Moreover, DMDS based on the fumigation mode entered the body through the respiratory pathway of olfactory perception-oxygen exchange and subsequently affected calcium channels in the nerve; eventually, DMDS acted on complex IV or complex I. Title: Uncovering the interactions between PME and PMEI at the gene and protein levels: Implications for the design of specific PMEI Wang Y, Zhang D, Huang L, Zhang Z, Shi Q, Hu J, He G, Guo X, Shi H, Liang L Ref: J Mol Model, 29:286, 2023 : PubMed ESTHER: Wang_2023_J.Mol.Model_29_286 PubMedSearch: Wang 2023 J.Mol.Model 29 286 PubMedID: 37610510 Abstract CONTEXT: Pectin methylesterase inhibitor (PMEI) can specifically bind and inhibit the activity of pectin methylesterase (PME), which has been widely used in fruit and vegetable juice processing. However, the limited three-dimensional structure, unclear action mechanism, low thermal stability and biological activity of PMEI severely limited its application. In this work, molecular recognition and conformational changes of PME and PMEI were analyzed by various molecular simulation methods. Then suggestions were proposed for improving thermal stability and affinity maturation of PMEI through semi-rational design. METHODS: Phylogenetic trees of PME and PMEI were established using the Maximum likelihood (ML) method. The results show that PME and PMEI have good sequence and structure conservation in various plants, and the simulated data can be widely adopted. In this work, MD simulations were performed using AMBER20 package and ff14SB force field. Protein interaction analysis indicates that H-bonds, van der Waals forces, and the salt bridge formed of K224 with ID116 are the main driving forces for mutual molecular recognition of PME and PMEI. According to the analyses of free energy landscape (FEL), conformational cluster, and motion, the association with PMEI greatly disrupts PME's dispersed functional motion mode and biological function. By monitoring the changes of residue contact number and binding free energy, (I)G35M/ (I)G35R: (I)T93F and (I)T113W/ (I)T113W: (I)D116W mutations contribute to thermal stability and affinity maturation of the PME-PMEI complex system, respectively. This work reveals the interaction between PME and PMEI at the gene and protein levels and provides options for modifying specific PMEI. Title: Toxicity and Physiological Effects of Nine Lamiaceae Essential Oils and Their Major Compounds on Reticulitermes dabieshanensis Yang X, Jin C, Wu Z, Han H, Zhang Z, Xie Y, Zhang D Ref: Molecules, 28:, 2023 : PubMed ESTHER: Yang_2023_Molecules_28_ PubMedSearch: Yang 2023 Molecules 28 PubMedID: 36903258 Abstract The volatile metabolites of Salvia sclarea, Rosmarinus officinalis, Thymus serpyllum, Mentha spicata, Melissa officinalis, Origanum majorana, Mentha piperita, Ocimum basilicum and Lavandula angustifolia were determined by gas chromatography-mass spectrometry. The vapor insecticidal properties of the analyzed essential oils and their compounds were screened using Reticulitermes dabieshanensis workers. The most effective oils were S. sclarea (major constituent linalyl acetate, 65.93%), R. officinalis (1,8-cineole, 45.56%), T. serpyllum (thymol, 33.59%), M. spicata (carvone, 58.68%), M. officinalis (citronellal, 36.99%), O. majorana (1,8-cineole, 62.29%), M. piperita (menthol, 46.04%), O. basilicum (eugenol, 71.08%) and L. angustifolia (linalool, 39.58%), which exhibited LC(50) values ranging from 0.036 to 1.670 microL/L. The lowest LC(50) values were recorded for eugenol (0.060 microL/L), followed by thymol (0.062 microL/L), carvone (0.074 microL/L), menthol (0.242 microL/L), linalool (0.250 microL/L), citronellal (0.330 microL/L), linalyl acetate (0.712 microL/L) and 1,8-cineole (1.478 microL/L). The increased activity of esterases (ESTs) and glutathione S-transferase (GST) were observed but only alongside the decreased activity of acetylcholinesterase (AChE) in eight main components. Our results indicate that S. sclarea, R. officinalis, T. serpyllum, M. spicata, M. officinalis, O. marjorana, M. piperita, O. basilicum and L. angustifolia essential oils (EOs) and their compounds, linalyl acetate, 1,8-cineole, thymol, carvone, citronellal, menthol, eugenol and linalool could be developed as control agents against termites. Title: Single and Combined Effects of Chlorpyrifos and Glyphosate on the Brain of Common Carp: Based on Biochemical and Molecular Perspective Zhang D, Ding W, Liu W, Li L, Zhu G, Ma J Ref: Int J Mol Sci, 24:, 2023 : PubMed ESTHER: Zhang_2023_Int.J.Mol.Sci_24_ PubMedSearch: Zhang 2023 Int.J.Mol.Sci 24 PubMedID: 37629125 Abstract Chlorpyrifos (CPF) and glyphosate (GLY) are the most widely used organophosphate insecticide and herbicide worldwide, respectively; co-occurrence of CPF and GLY in aquatic environments occurs where they inevitably have potential hazards to fish. However, the potential mechanisms of CPF and GLY to induce toxicity have not been fully explored. To identify the adverse impacts of CPF and GLY on fish, either alone or in combination (MIX), CPF (25 microg/L) and GLY (3.5 mg/L) were set up according to an environmentally relevant concentration to expose to common carp for 21 days. After exposure, CPF and GLY decreased the activities of acetylcholinesterase and Na(+)/K(+)-ATPase, altered monoamine oxidase levels, decreased antioxidant enzyme activities (superoxide dismutase, catalase, glutathione S-transferase and glutamic reductase), and induced the accumulation of malondialdehyde in the carp brain. The parameters in the MIX groups had a greater impact compared to that in the CPF or GLY group, suggesting that both single and combined exposure could affect neurological signaling systems and cause oxidative stress and lipid peroxidation damage in carp brains, and that MIX exposure increases the impact of each pollutant. RNA-seq results showed that single or combined exposure to CPF and GLY induced global transcriptomic changes in fish brains, and the number of differentially expressed genes in MIX-treated carp brains were globally increased compared to either the CPF or GLY groups, suggesting that the effects of co-exposure were greater than single exposure. Further analysis results revealed that the global transcriptomic changes participated in oxidative stress, immune dysfunction, and apoptosis of fish brains, and identified that the P13k-Akt signaling pathway participates in both single and combined exposure of CPF- and GLY-induced toxicity. Taken together, our results demonstrated that the interaction of CPF and GLY might be synergic and provided novel insights into the molecular mechanisms of fish brains coping with CPF and GLY. Title: Analysis of the Structure and Activity of Dipeptidyl Peptidase IV (DPP-IV) Inhibitory Oligopeptides from Sorghum Kafirin Dai L, Kong L, Cai X, Jiang P, Liu N, Zhang D, Li Z Ref: Journal of Agricultural and Food Chemistry, :, 2022 : PubMed ESTHER: Dai_2022_J.Agric.Food.Chem__ PubMedSearch: Dai 2022 J.Agric.Food.Chem PubMedID: 35130437 Abstract Potential dipeptidyl peptidase IV (DPP-IV) inhibitory oligopeptides from sorghum kafirin were developed using in silico and in vitro methodologies for the management of diabetes. Twenty-eight peptides with 5-10 residues were identified from the papain hydrolysates of sorghum kafirin. Sixteen nontoxic DPP-IV inhibitory peptides were screened with a computer method based on molecular docking. Molecular docking revealed that LPFYPQ (LP6), GPVTPPILG (GP9), and LPFYPQGV (LP8) effectively inactivated DPP-IV by binding to its active sites with a low interaction energy. An in silico analysis of these three inhibitory oligopeptides indicated that they were all bound to the S1 and S2 active pockets of DPP-IV through hydrogen bonds and hydrophobic interactions. The in vitro inhibitory activity was also verified. The DPP-IV inhibitory activities of LP6 and LP8 decreased after gastric digestion and remained stable after intestinal digestion, and the GP9 inhibitory activity remained stable after gastrointestinal digestion. Experimental results from Caco-2 cells showed further inhibitory effects of oligopeptides on DPP-IV. The results are relevant to the exploration of biofunctional DPP-IV inhibitory peptides from sorghum as a treatment for patients with diabetes or in medical research. Title: Structure-Guided Regulation in the Enantioselectivity of an Epoxide Hydrolase to Produce Enantiomeric Monosubstituted Epoxides and Vicinal Diols via Kinetic Resolution Hu D, Hu BC, Hou XD, Zhang D, Lei YQ, Rao YJ, Wu MC Ref: Org Lett, :, 2022 : PubMed ESTHER: Hu_2022_Org.Lett__ PubMedSearch: Hu 2022 Org.Lett PubMedID: 35229602 Gene_locus related to this paper: aspng-q1ktb5 Abstract Structure-guided microtuning of an Aspergillus usamii epoxide hydrolase was executed. One mutant, A214C/A250I, displayed a 12.6-fold enhanced enantiomeric ratio (E = 202) toward rac-styrene oxide, achieving its nearly perfect kinetic resolution at 0.8 M in pure water or 1.6 M in n-hexanol/water. Several other beneficial mutants also displayed significantly improved E values, offering promising biocatalysts to access 19 structurally diverse chiral monosubstituted epoxides (97.1 - <= 99% ee(s)) and vicinal diols (56.2-98.0% ee(p)) with high yields. Title: Synthesis, insecticidal activity, and mode of action of novel imidazopyridine mesoionic derivatives containing an amido group Liu Z, Song R, Zhang D, Wu R, Liu T, Wu Z, Zhang J, Hu D Ref: Pest Manag Sci, :, 2022 : PubMed ESTHER: Liu_2022_Pest.Manag.Sci__ PubMedSearch: Liu 2022 Pest.Manag.Sci PubMedID: 36054072 Abstract BACKGROUND: In our previous work, we applied a new synthetic strategy to design and synthesize a series of imidazopyridine mesoionic derivatives with an ester group. The newly synthesized compounds had excellent insecticidal activity against aphids; however, insecticidal activity against planthoppers was less than satisfactory. In the present study, we designed and synthesized a series of novel imidazopyridine mesoionic compounds, containing an amido group, and these compounds were found to have improved insecticidal activity against planthoppers. RESULTS: The bioassay results demonstrated that most of the target compounds had moderate-to-good insecticidal activity against Sogatella furcifera, and some exhibited good-to-excellent insecticidal activity against Aphis craccivora. Among them, compound C6 had the highest insecticidal activity against S. furcifera and A. craccivora, with LC(50) values of 10.5 and 2.09 microg mL(-1) , respectively. Proteomic results suggested that the differentially expressed proteins mainly were enriched in the nervous system-related pathways after compound C6 treatment. Enzymatic assay results showed that compound C6 and triflumezopyrim had a certain inhibitory effect on acetylcholinesterase. Molecular docking and real-time quantitative PCR results indicated that compound C6 not only may act on the nicotinic acetylcholine receptor, but also may interact with the alpha4 and beta1 subunits of this receptor. CONCLUSION: The results reported here contribute to the development of new mesoionic insecticides and further our understanding of the mode-of-action of imidazopyridine mesoionic derivatives. 2022 Society of Chemical Industry. Title: Impact of AADAC gene expression on prognosis in patients with Borrmann type III advanced gastric cancer Wang Y, Fang T, Yin X, Zhang L, Zhang X, Zhang D, Zhang Y, Wang X, Wang H, Xue Y Ref: BMC Cancer, 22:635, 2022 : PubMed ESTHER: Wang_2022_BMC.Cancer_22_635 PubMedSearch: Wang 2022 BMC.Cancer 22 635 PubMedID: 35681154 Gene_locus related to this paper: human-AADAC Abstract BACKGROUND: The prognosis of Borrmann type III advanced gastric cancer (AGC) is known to vary significantly among patients. This study aimed to determine which differentially expressed genes (DEGs) are directly related to the survival time of Borrmann type III AGC patients and to construct a prognostic model. METHODS: We selected 25 patients with Borrmann type III AGC who underwent radical gastrectomy. According to the difference in overall survival (OS), the patients were divided into group A (OS<1 year, n=11) and group B (OS>3 years, n=14). DEGs related to survival time in patients with Borrmann type III AGC were determined by mRNA sequencing. The prognosis and functional differences of DEGs in different populations were determined by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) public databases. The expression of mRNA and protein in cell lines was detected by quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot (WB). Immunohistochemical (IHC) staining was used to detect protein expression in the paraffin-embedded tissues of 152 patients with Borrmann type III AGC who underwent radical gastrectomy. After survival analysis, nomograms were constructed to predict the prognosis of patients with Borrmann type III AGC. RESULTS: Arylacetamide deacetylase (AADAC) is a survival-related DEG in patients with Borrmann type III AGC. The higher the expression level of its mRNA and protein is, the better the prognosis of patients. Bioinformatics analysis found that AADAC showed significant differences in prognosis and function in European and American populations and Asian populations. In addition, the mRNA and protein expression levels of AADAC were high in differentiated gastric cancer (GC) cells. We also found that AADAC was an independent prognostic factor for patients with Borrmann type III AGC, and its high expression was significantly correlated with better OS and disease-free survival (DFS). Nomogram models of AADAC expression level combined with clinicopathological features can be used to predict the OS and DFS of Borrmann type III AGC. CONCLUSION: AADAC can be used as a biomarker to predict the prognosis of Borrmann type III AGC and has the potential to become a new therapeutic target for GC. Title: Gram-Scale Synthesis of (R)-P-Chlorophenyl-1,2-Ethanediol at High Concentration by a Pair of Epoxide Hydrolases Zhang D, Lei Y, Wang T, Lin W, Chen X, Wu M Ref: Front Bioeng Biotechnol, 10:824300, 2022 : PubMed ESTHER: Zhang_2022_Front.Bioeng.Biotechnol_10_824300 PubMedSearch: Zhang 2022 Front.Bioeng.Biotechnol 10 824300 PubMedID: 35295651 Abstract (R)-p-chlorophenyl-1,2-ethanediol (pCPED) is an important intermediate for the synthesis of (R)-eliprodil that is widely applied in the treatment of ischemic stroke. To prepare (R)-pCPED with high enantiomeric excess (ee (p)) and yield via the enantioconvergent hydrolysis of racemic styrene oxide (rac-pCSO) at high concentration, the bi-enzymatic catalysis was designed and investigated by a pair of epoxide hydrolases, a mutant (PvEH1(Z4X4-59)) of Phaseolus vulgaris EH1 and a mutant (RpEH(F361V)) of Rhodotorula paludigena RpEH. Firstly, the maximum allowable concentration of rac-pCSO was confirmed. Subsequently, the addition mode and the weight ratio of two Escherichia coli cells were optimized. Finally, under the optimized reaction conditions-the cell weight ratio 20:1 of E. coli/pveh1(z4x4-59) to E. coli/rpeh (F361V), a simultaneous addition mode, and reaction temperature at 25 degreesC-300 mM rac-pCSO in the 100 ml 4% (v/v) Tween-20/phosphate buffer system (100 mM, pH 7.0) was completely hydrolyzed within 5 h, affording (R)-pCPED with 87.8% ee (p), 93.4% yield, and 8.63 g/L/h space-time yield (STY). This work would be an efficient technical strategy for the preparation of chiral vicinal diols at industrial scale. Title: Fine mapping of powdery mildew resistance gene MlWE74 derived from wild emmer wheat (Triticum turgidum ssp. dicoccoides) in an NBS-LRR gene cluster Zhu K, Li M, Wu H, Zhang D, Dong L, Wu Q, Chen Y, Xie J, Lu P and Hua W <13 more author(s)> Zhu K, Li M, Wu H, Zhang D, Dong L, Wu Q, Chen Y, Xie J, Lu P, Guo G, Zhang H, Zhang P, Li B, Li W, Wang Q, Zhu J, Hu W, Guo L, Wang R, Yuan C, Li H, Liu Z, Hua W (- 13) Ref: Theor Appl Genet, :, 2022 : PubMed ESTHER: Zhu_2022_Theor.Appl.Genet__ PubMedSearch: Zhu 2022 Theor.Appl.Genet PubMedID: 35006335 Abstract Powdery mildew resistance gene MlWE74, originated from wild emmer wheat accession G-748-M, was mapped in an NBS-LRR gene cluster of chromosome 2BS. Wheat powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a globally devastating disease. Wild emmer wheat (Triticum turgidum var. dicoccoides) is a valuable genetic resource for improving disease resistance in common wheat. A powdery mildew resistance gene was transferred to hexaploid wheat line WE74 from wild emmer accession G-748-M. Genetic analysis revealed that the powdery mildew resistance in WE74 is controlled by a single dominant gene, herein temporarily designated MlWE74. Bulked segregant analysis (BSA) and molecular mapping delimited MlWE74 to the terminal region of chromosome 2BS flanking by markers WGGBD412 and WGGBH346 within a genetic interval of 0.25 cM and corresponding to 799.9 kb genomic region in the Zavitan reference sequence. Sequence annotation revealed two phosphoglycerate mutase-like genes, an alpha/beta-hydrolases gene, and five NBS-LRR disease resistance genes that could serve as candidates for map-based cloning of MlWE74. The geographical location analysis indicated that MlWE74 is mainly distributed in Rosh Pinna and Amirim regions, in the northern part of Israel, where environmental conditions are favorable to the occurrence of powdery mildew. Moreover, the co-segregated marker WGGBD425 is helpful in marker-assisted transfer of MlWE74 into elite cultivars. Title: Nearly perfect kinetic resolution of racemic o-nitrostyrene oxide by AuEH2, a microsomal epoxide hydrolase from Aspergillus usamii, with high enantio- and regio-selectivity Hu D, Hu BC, Wen Z, Zhang D, Liu YY, Zang J, Wu MC Ref: Int J Biol Macromol, 169:1, 2021 : PubMed ESTHER: Hu_2021_Int.J.Biol.Macromol_169_1 PubMedSearch: Hu 2021 Int.J.Biol.Macromol 169 1 PubMedID: 33316339 Gene_locus related to this paper: aspng-q1ktb5 Abstract Only a few known epoxide hydrolases (EHs) displayed activity towards o-nitrostyrene oxide (4a), presumably owing to the large steric hindrance caused by o-nitro substituent. Therefore, excavating EHs with high activity and enantio- and/or regio-selectivity towards racemic (rac-) 4a is essential but challenging. Here, AuEH2 from Aspergillus usamii was expressed in E. coli BL21(DE3). E. coli/Aueh2, an E. coli transformant expressing AuEH2, possessed EH activities of 16.2-184 U/g wet cell towards rac-styrene oxide (1a) and its derivatives (2a-13a), and the largest enantiomeric ratio of 96 towards rac-4a. The regioselectivity coefficients, beta(R) and beta(S), of AuEH2 were determined to be 99.2% and 98.9%, suggesting that it regiopreferentially attacks the C(beta) in the oxirane rings of (R)- and (S)-4a. Then, the nearly perfect kinetic resolution of 20 mM rac-4a in pure water was carried out using 20 mg/mL wet cells of E. coli/Aueh2 at 25 degreesC for 50 min, retaining (S)-4a with over 99% ee(s) and 48.9% yield(s), while producing (R)-o-nitrophenyl-1,2-ethanediol (4b) with 95.3% ee(p) and 49.8% yield(p). To elucidate the molecular mechanism of AuEH2 with high enantiopreference for (R)-4a, its crystal structure was solved by X-ray diffraction and the molecular docking of AuEH2 with (R)- or (S)-4a was simulated. Title: The novel therapeutic strategy of vilazodone-donepezil chimeras as potent triple-target ligands for the potential treatment of Alzheimer's disease with comorbid depression Li X, Li J, Huang Y, Gong Q, Fu Y, Xu Y, Huang J, You H, Zhang D and Zhang H <3 more author(s)> Li X, Li J, Huang Y, Gong Q, Fu Y, Xu Y, Huang J, You H, Zhang D, Mao F, Zhu J, Wang H, Zhang H (- 3) Ref: Eur Journal of Medicinal Chemistry, 229:114045, 2021 : PubMed ESTHER: Li_2021_Eur.J.Med.Chem_229_114045 PubMedSearch: Li 2021 Eur.J.Med.Chem 229 114045 PubMedID: 34922191 Abstract Depression is one of the most frequent comorbid psychiatric symptoms of Alzheimer's disease (AD), and no efficacious drugs have been approved specifically for this purpose thus far. Herein, we proposed a novel therapeutic strategy that merged the key pharmacophores of the antidepressant vilazodone (5-HT(1A) receptor partial agonist and serotonin transporter inhibitor) and the anti-AD drug donepezil (acetylcholinesterase inhibitor) together to develop a series of multi-target-directed ligands for potential therapy of the comorbidity of AD and depression. Accordingly, 55 vilazodone-donepezil chimeric derivatives were designed and synthesized, and their triple-target activities against acetylcholinesterase, 5-HT(1A) receptor, and serotonin transporter were systematically evaluated. Among them, compound 5 displayed strong triple-target bioactivities in vitro, low hERG potassium channel inhibition and acceptable brain distribution. Importantly, oral intake of 5 mg/kg of the compound 5 dihydrochloride significantly alleviated the depressive symptoms and ameliorated cognitive dysfunction in mouse models. In brief, these results highlight vilazodone-donepezil chimeras as a prospective therapeutic approach for the treatment of the comorbidity of AD and depression. Title: Bile salt-dependent lipase promotes the barrier integrity of Caco-2 cells by activating Wnt/beta-catenin signaling via LRP6 receptor Qiu Y, Zhou J, Zhang D, Song H, Qian L Ref: Cell Tissue Research, 383:1077, 2021 : PubMed ESTHER: Qiu_2021_Cell.Tissue.Res_383_1077 PubMedSearch: Qiu 2021 Cell.Tissue.Res 383 1077 PubMedID: 33245415 Abstract Bile salt-dependent lipase (BSDL) within intestinal lumen can be endocytosed by enterocytes and support the intestinal barrier function. However, the epithelial-supporting effect of this protein has not been verified in a human cell line and neither the direct signaling pathway nor the function of endocytosis in this process has been clearly identified. We sought to investigate the signaling pathway and the membrane receptor through which BSDL might exert these effects using intestinal epithelial cells. Caco-2 cells were treated with recombinant BSDL, and the barrier function, cell proliferation, and activation of the Wnt signaling pathway were assessed. The effect of Wnt signaling activation induced by BSDL and BSDL endocytosis was investigated in LRP6-silenced and non-silenced cells. Moreover, caveolae- and clathrin-dependent endocytosis inhibitors were also applied respectively to analyze their effects on Wnt signaling activation induced by BSDL. BSDL treatment increased the barrier function but not proliferation of Caco-2 cells. It also induced beta-catenin nuclear translocation and activated Wnt target gene transcription. Moreover, in the Wnt pathway, BSDL increased the levels of non-phosphorylated-beta-catenin (Ser33/37/Thr41) and phosphorylated-beta-catenin (Ser552). Notably, the silencing of LRP6 expression impaired BSDL endocytosis and decreased BSDL-induced beta-catenin nuclear translocation. The inhibition of BSDL endocytosis induced by caveolae-mediated endocytosis inhibitor was stronger than that by clathrin-mediated endocytosis inhibitor, and the Wnt signaling activation associated with its endocytosis was also most likely caveolae-dependent. Our findings suggested that LRP6, a canonical Wnt pathway co-receptor, can mediate BSDL endocytosis and then activate Wnt signaling in Caco-2 cells. Title: Structure-guided improvement in the enantioselectivity of an Aspergillus usamii epoxide hydrolase for the gram-scale kinetic resolution of ortho-trifluoromethyl styrene oxide Wen Z, Hu D, Hu BC, Zhang D, Huang JF, Wu MC Ref: Enzyme Microb Technol, 146:109778, 2021 : PubMed ESTHER: Wen_2021_Enzyme.Microb.Technol_146_109778 PubMedSearch: Wen 2021 Enzyme.Microb.Technol 146 109778 PubMedID: 33812566 Gene_locus related to this paper: aspng-q1ktb5 Abstract Microtuning the substrate-binding pocket (SBP) of EHs has emerged as an effective approach to manipulate their enantio- or regio-selectivities and activities towards target substrates. Here, the enantioselectivity (enantiomeric ratio, E) of AuEH2 towards a racemic (rac-) ortho-trifluoromethyl styrene oxide (o-TFMSO) was improved via microtuning its SBP. Based on the analysis on the crystal structure of AuEH2, its specific residues I192, Y216, R322 and L344 lining the SBP in close to the catalytic triad were identified for site-saturation mutagenesis. After screening, five single-site mutants were selected with E values elevated from 8 to 12-25 towards rac-o-TFMSO. To further improve E, four double-site mutants were constructed by combinatorial mutagenesis of AuEH2(R322V) separately with AuEH2(I192V), AuEH2(Y216F), AuEH2(L344A) and AuEH2(L344C). Among all the mutants, AuEH2(R322V/L344C) possessed the largest E of 83 with activity of 67 U/g wet cell. The kinetic resolution of 200 mM rac-o-TFMSO was conducted at 0 degreesC for 5.5 h using 80 mg/mL wet cells of E. coli/Aueh2(R322V/L344C), a transformant expressing AuEH2(R322V/L344C), retaining (S)-o-TFMSO with 98.4 % ee(s) and 49.3 % yield(s). Furthermore, the molecular docking simulation analysis indicated that AuEH2(R322V/L344C) more enantiopreferentially attacks the terminal carbon (C(beta)) in the oxirane ring of (R)-o-TFMSO than AuEH2. Title: Claulansine F-Donepezil Hybrids as Anti-Alzheimer's Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities Zang Y, Liu K, Wang W, Li C, Ma J, Yang J, Chen X, Wang X, Zhang D Ref: Molecules, 26:, 2021 : PubMed ESTHER: Zang_2021_Molecules_26_ PubMedSearch: Zang 2021 Molecules 26 PubMedID: 33671020 Abstract The multifactorial nature of Alzheimer's disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A total of 26 Claulansine F-donepezil hybrids were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetylcholinesterase (AChE) inhibitory activity (half maximal inhibitory concentration (IC(50)) 1.63-4.62 microM). Moreover, (E)-3-(8-(tert-Butyl)-3,3-dimethyl-3,11-dihydropyrano[3,2-a]carbazol-5-yl)-N-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)acrylamide (6bd) exhibited better neuroprotective effects against OGD/R (oxygen-glucose deprivation/reoxygenation) than lead compound Claulansine F. Furthermore, 6bd could cross the blood-brain barrier in vitro. More importantly, compared to edaravone, 6bd had stronger free-radical scavenging activity. Molecular docking studies revealed that 6bd could interact with the catalytic active site of AChE. All of these outstanding in vitro results indicate 6bd as a leading structure worthy of further investigation. Title: Neuroprotective effects of maize tetrapeptide-anchored gold nanoparticles in Alzheimer's disease Zhang J, Liu R, Zhang D, Zhang Z, Zhu J, Xu L, Guo Y Ref: Colloids Surf B Biointerfaces, 200:111584, 2021 : PubMed ESTHER: Zhang_2021_Colloids.Surf.B.Biointerfaces_200_111584 PubMedSearch: Zhang 2021 Colloids.Surf.B.Biointerfaces 200 111584 PubMedID: 33508658 Abstract Nanopeptide assembled from peptide-anchored nanoparticles possess an enormous research potential in the field of cellular medicine and disease treatment. The aim of this study was to explore the neuroprotective effects of maize tetrapeptide anchored gold nanoparticles against l-glutamic acid-induced PC12 cell apoptosis and a murine Alzheimer's disease model induced by aluminum chloride and d-galactose. The results revealed that the nanopeptide antioxidant inhibited intracellular ROS accumulation and promoted cell differentiation than that of maize bioactive tetrapeptide. Compared with untreated Alzheimer's disease model mice, nanopeptide administration shortened the escape latency time in a water maze test and improved the movements in the autonomic activity test. After 16 days of nanopeptide administration, the central cholinergic system function of acetylcholine and cholineacetyltransferase were enhanced, and the level of acetylcholinesterase was reduced. It also increased superoxide dismutase and glutathione peroxidase activity in sera and hypothalami. Moreover, nanopeptide treatment upregulated cerebral nuclear factor erythroid 2-related factor 2 and heme-oxygenase-1 and downregulated kelch-like ECH-associated protein 1 relative to untreated Alzheimer's disease model mice. Thus, the novel nanopeptide is expected to be used as the neuroprotective agent to prevent Alzheimer's disease. Title: Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate Zhou Y, Fu Y, Yin W, Li J, Wang W, Bai F, Xu S, Gong Q, Peng T and Liu H <7 more author(s)> Zhou Y, Fu Y, Yin W, Li J, Wang W, Bai F, Xu S, Gong Q, Peng T, Hong Y, Zhang D, Liu Q, Xu Y, Xu HE, Zhang H, Jiang H, Liu H (- 7) Ref: Journal of Medicinal Chemistry, 64:1844, 2021 : PubMed ESTHER: Zhou_2021_J.Med.Chem_64_1844 PubMedSearch: Zhou 2021 J.Med.Chem 64 1844 PubMedID: 33570950 Gene_locus related to this paper: human-ACHE Inhibitor(s) related to this paper: H0L-7D9O, H1R-7D9Q, H0R-7D9P Abstract The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD. Title: Inhibition of acetylcholinesterase activity and beta-amyloid oligomer formation by 6-bromotryptamine A, a multi-target anti-Alzheimer's molecule Jin X, Wang M, Shentu J, Huang C, Bai Y, Pan H, Zhang D, Yuan Z, Zhang H and Cui W <5 more author(s)> Jin X, Wang M, Shentu J, Huang C, Bai Y, Pan H, Zhang D, Yuan Z, Zhang H, Xiao X, Wu X, Ding L, Wang Q, He S, Cui W (- 5) Ref: Oncol Lett, 19:1593, 2020 : PubMed ESTHER: Jin_2020_Oncol.Lett_19_1593 PubMedSearch: Jin 2020 Oncol.Lett 19 1593 PubMedID: 31966085 Abstract Alzheimer's disease (AD) is a neurodegenerative disorder characterized by learning and memory impairments. Recent studies have suggested that AD can be induced by multiple factors, such as cholinergic system dysfunction and beta-amyloid (Abeta) neurotoxicity. It was reported that 6-bromo-N-propionyltryptamine could treat neurological diseases, including AD. In the present study, 6-bromotryptamine A, a derivative of 6-bromo-N-propionyltryptamine, was synthesized by the condensation of 2-(6-bromo-1H-indol-3-yl)ethan-1-amine and 2-(4-bromophenyl)acetic acid, and was used as a potential anti-AD molecule. Furthermore, scopolamine can induce impairments of learning and memory, and was widely used to establish AD animal models. The results demonstrated that 6-bromotryptamine A significantly prevented scopolamine-induced short-term cognitive impairments, as revealed by various behavioral tests in mice. Furthermore, an acetylcholinesterase (AChE) activity assay revealed that 6-bromotryptamine A directly inhibited AChE activity. Notably, it was observed that 6-bromotryptamine A blocked the formation of Abeta oligomer, as evaluated by the dot blot assay. All these results suggested that 6-bromotryptamine A may be used to prevent impairments in short-term learning and memory ability possibly via the inhibition of AChE and the blockade of Abeta oligomer formation. 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: Donepezil promotes neurogenesis via Src signaling pathway in a rat model of chronic cerebral hypoperfusion Man J, Cui K, Fu X, Zhang D, Lu Z, Gao Y, Yu L, Li N, Wang J Ref: Brain Research, 1736:146782, 2020 : PubMed ESTHER: Man_2020_Brain.Res_1736_146782 PubMedSearch: Man 2020 Brain.Res 1736 146782 PubMedID: 32184165 Abstract Donepezil, a selective acetylcholinesterase (AchE) inhibitor, enhances stroke-induced neurogenesis within subventricular zone (SVZ). Src/Pyk-2 is one of the downstream pathways of acetylcholine receptors (AchRs), and has been shown to participate in the activation of fibroblast growth factor receptor (FGFR)/epidermal growth factor receptor (EGFR) signaling in cancer cells. In this study, we investigated whether donepezil could promote SVZ neurogenesis in chronic cerebral hypoperfusion (CCH) injury via Src signaling pathway. In the bilateral carotid artery occlusion (2VO) rat model, we observed more nestin/5-bromo-2'-deoxyuridine (BrdU)-positive cells and doublecortin (DCX)/BrdU-positive cells in the SVZ than that in the sham group. Further, donepezil obviously improved neurologic function after 2VO, induced the greater number of SVZ proliferative NSCs and neuroblasts, and elevated levels of Src, p-FGFR1, p-EGFR, p-Akt and p-Raf in ipsilateral SVZ. Lastly, Src inhibitor KX-01 abolished the beneficial effects of donepezil in 2VO rats. These results suggest that donepezil could upregulate Src signaling pathway to enhance CCH-induced SVZ neurogenesis. Title: Neuroprotective effects of the aerial parts of Polygala tenuifolia Willd extract on scopolamine-induced learning and memory impairments in mice Wang X, Zhang D, Song W, Cai CF, Zhou Z, Fu Q, Yan X, Cao Y, Fang M Ref: Biomed Rep, 13:37, 2020 : PubMed ESTHER: Wang_2020_Biomed.Rep_13_37 PubMedSearch: Wang 2020 Biomed.Rep 13 37 PubMedID: 32874571 Abstract Alzheimer's disease is a common neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. Aerial parts of Polygala tenuifolia Willd (APT) is a traditional Chinese medicine used for the treatment of amnesia. The present study aimed to investigate the protective effects of APT on scopolamine-induced learning and memory impairments in mice. Scopolamine-induced mice were used to determine the effects of APT on learning and memory impairment. Mice were orally administered with APT (25, 50 and 100 mg/kg) and piracetam (750 mg/kg) for 14 days, and intraperitoneally injected with scopolamine (2 mg/kg) from days 8 to 14. Morris water maze and step-down tests were performed to evaluate learning and memory. Levels of acetylcholine (ACh), choline acetyltransferase (ChAT), acetylcholinesterase (AChE), interleukin (IL)-1beta, IL-10 and brain-derived neurotrophic factor (BDNF) in the hippocampus and frontal cortex were measured by ELISA. Superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) were measured via biochemical detection. The results demonstrated that APT ameliorated learning and memory impairment in scopolamine-induced mice. Correspondingly, APT significantly increased ACh and ChAT levels in the hippocampus and prefrontal cortex of scopolamine-induced mice. Additionally, treatment with APT significantly increased BDNF and IL-10 levels, and decreased IL-1beta and AChE levels in the same mice. Furthermore, APT significantly increased SOD activity and GSH content, and decreased MDA levels in brain tissue. These results indicated that APT may ameliorate learning and memory impairment by regulating cholinergic activity, promoting BDNF and inhibiting neuroinflammation and oxidative stress. Title: Antifungal Effect of Triglycerol Monolaurate Synthesized by Lipozyme 435-Mediated Esterification Zhang S, Xiong J, Lou W, Ning Z, Zhang D, Yang J Ref: J Microbiol Biotechnol, 30:561, 2020 : PubMed ESTHER: Zhang_2020_J.Microbiol.Biotechnol_30_561 PubMedSearch: Zhang 2020 J.Microbiol.Biotechnol 30 561 PubMedID: 31986567 Abstract This study was designed to synthesize triglycerol monolaurate (TGML) with Lipozyme 435 as the catalyst, and explore its effects on the growth of Aspergillus parasiticus (A. parasiticus) and Aspergillus flavus (A. flavus) and the secretion of aflatoxin b1. The highest content of TGML (49.76%) was obtained at a molar ratio of triglycerol to lauric acid of 1.08, a reaction temperature of 84.93 degC, a reaction time of 6 h and an enzyme dosage of 1.32%. After purification by molecular distillation combined with the washes with ethyl acetate and water, the purity of TGML reached 98.3%. Through characterization by electrospray-ionization mass spectrometry, infrared spectrum and nuclear magnetic resonance, the structure of TGML was identified as a linear triglycerol combined with lauroyl at the end. Finally, the inhibitory effects of TGML on the growths of A. parasiticus and A. flavus and the secretion of aflatoxin b1 were evaluated by measuring the colony diameter, the inhibition rate of mycelial growth and the content of mycotoxin in the media. The results indicated that TGML had a stronger inhibitory effects on colony growth and mycelial development of both toxic molds compared to sodium benzoate and potassium sorbate, and the secretions of toxins from A. parasiticus and A. flavus were completely suppressed when adding TGML at 10 and 5 mM, respectively. Based on the above results, TGML may be used as a substitute for traditional antifungal agents in the food industry. Title: The relationship of lipoprotein-associated phospholipase A2 activity with the seriousness of coronary artery disease Zhang H, Gao Y, Wu D, Zhang D Ref: BMC Cardiovasc Disord, 20:295, 2020 : PubMed ESTHER: Zhang_2020_BMC.Cardiovasc.Disord_20_295 PubMedSearch: Zhang 2020 BMC.Cardiovasc.Disord 20 295 PubMedID: 32546193 Abstract BACKGROUND: The level of lipoprotein-associated phospholipase A2 (LP-PLA2) in serum is independently correlated to coronary artery diseases (CAD). The aim of the study was to determine whether LP-PLA2 activity is positively associated with the seriousness of CAD. METHODS: Amount to 1056 patients suspected of having CAD underwent coronary angiography (CAG) to determine the seriousness of CAD. According to the amount of diseased coronary branches, the 1056 patients were split into three groups: single-vessel stenosis group, multiple-vessels stenosis group (> or = 2 diseased coronary branches),and control group (no diseased coronary branches). According to CAG results, electrocardiography, cardiac biomarker, and clinical presentation, all patients were split into four groups: acute myocardial infarction (AMI), unstable angina (UA), stable angina (SA), and control groups (excluding CAD). The activity of LP-PLA2 was compared statistically among the subgroups. Receiver operating characteristic analysis was applied to investigate the role of LP-PLA2 in evaluating the presence and seriousness of CAD. RESULTS: The level of LP-PLA2 increased in line with the number of diseased coronary branches. The levels of LP-PLA2 in the AMI and UA groups were observably higher when compared with the control and SA groups. LP-PLA2 had 75.6% sensitivity and 67.3% specificity for recognizing CAD, and 53.0% sensitivity and 80.3% specificity for recognizing severe coronary artery lesions. CONCLUSION: The activity of LP-PLA2 is positively correlated to the seriousness of CAD. Title: Sequencing of a Wild Apple (Malus baccata) Genome Unravels the Differences Between Cultivated and Wild Apple Species Regarding Disease Resistance and Cold Tolerance Chen X, Li S, Zhang D, Han M, Jin X, Zhao C, Wang S, Xing L, Ma J and An N <1 more author(s)> Chen X, Li S, Zhang D, Han M, Jin X, Zhao C, Wang S, Xing L, Ma J, Ji J, An N (- 1) Ref: G3 (Bethesda), 9:2051, 2019 : PubMed ESTHER: Chen_2019_G3.(Bethesda)_9_2051 PubMedSearch: Chen 2019 G3.(Bethesda) 9 2051 PubMedID: 31126974 Gene_locus related to this paper: malba-a0a540mnd7, malba-a0a540lct9, malba-a0a540lik7, malba-a0a540lik0, malba-a0a540lri2, malba-a0a540lr05 Abstract Malus baccata is one of four wild apple species that can hybridize with the cultivated apple species (Malus domestica). It is widely used in high-latitude apple-producing areas as a rootstock and breeding resource because of its disease resistance, and cold tolerance. A lack of a reference genome has limited the application of M. baccata for apple breeding. We present a draft reference genome for M. baccata The assembled sequence consisting of 665 Mb, with a scaffold N50 value of 452 kb, included transposable elements (413 Mb) and 46,114 high-quality protein-coding genes. According to a genetic map derived from 390 sibling lines, 72% of the assembly and 85% of the putative genes were anchored to 17 linkage groups. Many of the M. baccata genes under positive selection pressure were associated with plant-pathogen interaction pathways. We identified 2,345 Transcription factor-encoding genes in 58 families in the M. baccata genome. Genes related to disease defense and cold tolerance were also identified. A total of 462 putative nucleotide-binding site (NBS)-leucine-rich-repeat (LRR) genes, 177 Receptor-like kinase (RLK) and 51 receptor-like proteins (RLP) genes were identified in this genome assembly. The M. baccata genome contained 3978 cold-regulated genes, and 50% of these gene promoter containing DREB motif which can be induced by CBF gene. We herein present the first M. baccata genome assembly, which may be useful for exploring genetic variations in diverse apple germplasm, and for facilitating marker-assisted breeding of new apple cultivars exhibiting resistance to disease and cold stress. Title: Fascaplysin Derivatives Are Potent Multitarget Agents against Alzheimer's Disease: in Vitro and in Vivo Evidence Pan H, Qiu H, Zhang K, Zhang P, Liang W, Yang M, Mou C, Lin M, He M and Cui W <8 more author(s)> Pan H, Qiu H, Zhang K, Zhang P, Liang W, Yang M, Mou C, Lin M, He M, Xiao X, Zhang D, Wang H, Liu F, Li Y, Jin H, Yan X, Liang H, Cui W (- 8) Ref: ACS Chem Neurosci, 10:4741, 2019 : PubMed ESTHER: Pan_2019_ACS.Chem.Neurosci_10_4741 PubMedSearch: Pan 2019 ACS.Chem.Neurosci 10 4741 PubMedID: 31639294 Abstract Alzheimer's disease (AD) is characterized by progressive neurodegeneration and impaired cognitive functions. Fascaplysin is a beta-carboline alkaloid isolated from marine sponge Fascaplysinopsis bergquist in 1988. Previous studies have shown that fascaplysin might act on acetylcholinesterase and beta-amyloid (Abeta) to produce anti-AD properties. In this study, a series of fascaplysin derivatives were synthesized. The cholinesterase inhibition activities, the neuronal protective effects, and the toxicities of these compounds were evaluated in vitro. Compounds 2a and 2b, the two most powerful compounds in vitro, were further selected to evaluate their cognitive-enhancing effects in animals. Both 2a and 2b could ameliorate cognitive dysfunction induced by scopolamine or Abeta oligomers without affecting locomotor functions in mice. We also found that 2a and 2b could prevent cholinergic dysfunctions, decrease pro-inflammatory cytokine expression, and inhibit Abeta-induced tau hyperphosphorylation in vivo. Most importantly, pharmacodynamics studies suggested that 2b could penetrate the blood-brain barrier and be retained in the central nervous system. All these results suggested that fascaplysin derivatives are potent multitarget agents against AD and might be clinical useful for AD treatment. Title: Macrophage ABHD5 Suppresses NFkappaB-Dependent Matrix Metalloproteinase Expression and Cancer Metastasis Shang S, Ji X, Zhang L, Chen J, Li C, Shi R, Xiang W, Kang X, Zhang D and Miao H <6 more author(s)> Shang S, Ji X, Zhang L, Chen J, Li C, Shi R, Xiang W, Kang X, Zhang D, Yang F, Dai R, Chen P, Chen S, Chen Y, Li Y, Miao H (- 6) Ref: Cancer Research, 79:5513, 2019 : PubMed ESTHER: Shang_2019_Cancer.Res_79_5513 PubMedSearch: Shang 2019 Cancer.Res 79 5513 PubMedID: 31439546 Gene_locus related to this paper: human-ABHD5 Abstract Metabolic reprogramming in tumor-associated macrophages (TAM) is associated with cancer development, however, the role of macrophage triglyceride metabolism in cancer metastasis is unclear. Here, we showed that TAMs exhibited heterogeneous expression of abhydrolase domain containing 5 (ABHD5), an activator of triglyceride hydrolysis, with migratory TAMs expressing lower levels of ABHD5 compared with the nonmigratory TAMs. ABHD5 expression in macrophages inhibited cancer cell migration in vitro in xenograft models and in genetic cancer models. The effects of macrophage ABHD5 on cancer cell migration were dissociated from its metabolic function as neither triglycerides nor ABHD5-regulated metabolites from macrophages affected cancer cell migration. Instead, ABHD5 deficiency in migrating macrophages promoted NFkappaB p65-dependent production of matrix metalloproteinases (MMP). ABHD5 expression negatively correlated with MMP expression in TAMs and was associated with better survival in patients with colorectal cancer. Taken together, our findings show that macrophage ABHD5 suppresses NFkappaB-dependent MMP production and cancer metastasis and may serve as a prognostic marker in colorectal cancer. SIGNIFICANCE: These findings highlight the mechanism by which reduced expression of the metabolic enzyme ABHD5 in macrophages promotes cancer metastasis.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/21/5513/F1.large.jpg. Title: Design, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer's disease Wang D, Hu M, Li X, Zhang D, Chen C, Fu J, Shao S, Shi G, Zhou Y and Zhang T <1 more author(s)> Wang D, Hu M, Li X, Zhang D, Chen C, Fu J, Shao S, Shi G, Zhou Y, Wu S, Zhang T (- 1) Ref: Eur Journal of Medicinal Chemistry, 168:207, 2019 : PubMed ESTHER: Wang_2019_Eur.J.Med.Chem_168_207 PubMedSearch: Wang 2019 Eur.J.Med.Chem 168 207 PubMedID: 30822710 Abstract A series of novel isoflavone analogs were designed, synthesized, and evaluated as multitarget-directed ligands for the treatment of Alzheimer's disease. In vitro evaluations revealed that some ligands had multifunctional profiles, including potent blockage of histamine 3 receptor (H3R), excellent inhibition of acetylcholinesterase (AChE), neuroprotective effects and anti-neuroinflammatory properties. Among these derivatives, compound 9b exhibited the highest ability to block H3R (IC50=0.27muM) and good inhibitory activity against AChE (IC50=0.08muM). Additionally, compound 9b showed obvious neuroprotective effect on SH-SY5Y by preventing copper-induced neuronal damage and potent anti-neuroinflammatory activity by inhibiting the production of inflammatory factors on BV-2cells. A molecular modeling study revealed that 9b acts as a mixed-type inhibitor that interacts simultaneously with H3R and AChE. Moreover, in vivo data revealed that compound 9b did not cause acute toxicity in mice at doses up to 1000mg/kg, and had desirable pharmacokinetic properties, as well as a good blood-brain barrier (BBB) permeability (log BB=1.24+/-0.07). Further studies demonstrated that chronic oral treatment with 9b significantly improved cognitive dysfunction in scopolamine-induced AD mice in the step-down passive avoidance test. Taken together, the present study showed that compound 9b is a promising multifunctional drug candidate for the treatment of Alzheimer's disease. Title: CXCL5, the upregulated chemokine in patients with uterine cervix cancer, in vivo and in vitro contributes to oncogenic potential of Hela uterine cervix cancer cells Feng X, Zhang D, Li X, Ma S, Zhang C, Wang J, Li Y, Liang L, Zhang P and Wang W <7 more author(s)> Feng X, Zhang D, Li X, Ma S, Zhang C, Wang J, Li Y, Liang L, Zhang P, Qu Y, Zhang Z, Yang Z, Xiang Y, Zhang W, Wang S, Shao W, Wang W (- 7) Ref: Biomed Pharmacother, 107:1496, 2018 : PubMed ESTHER: Feng_2018_Biomed.Pharmacother_107_1496 PubMedSearch: Feng 2018 Biomed.Pharmacother 107 1496 PubMedID: 30257367 Abstract CXCL5 is showed a surprisingly elevated profile and implicated in tumorigenesis in several tumors. However, the expression and function of CXCL5 in uterine cervix cancer (UCC) remain largely unknown. The current study aimed to elucidate the expression pattern of CXCL5 in human UCC tissues and Hela cervix cancer cell, as well as its functions in Hela cells. Our data showed that CXCL5 and its receptor CXCR2 were expressed by Hela uterine cervix cancer cells. CXCL5 was upregulated in UCC tissues, and its overexpression was positively correlated with age, but did not correlate with clinical stages and tumor infiltration. Exogenous administration of CXCL5 and CXCL5 overexpression contributed to proliferation and migration activities of Hela cells in vitro, consistent with this, CXCL5 overexpression also promoted growth of Hela cells in a nude mouse xenograft model. At the gene level, CXCL5 overexpression regulated the expression of tumor-related genes including ERK, p-ERK, AKT, p-AKT, DIABOL, NUMB, NDRG3 and CXCR2. Taken together, CXCL5 may contribute to a dominant role in UCC progression and sever as a potential molecular therapeutic target for UCC. Title: Neurological responses of embryo-larval zebrafish to short-term sediment exposure to decabromodiphenylethane Jin MQ, Zhang D, Zhang Y, Zhou SS, Lu XT, Zhao HT Ref: J Zhejiang Univ Sci B, 19:400, 2018 : PubMed ESTHER: Jin_2018_J.Zhejiang.Univ.Sci.B_19_400 PubMedSearch: Jin 2018 J.Zhejiang.Univ.Sci.B 19 400 PubMedID: 29732751 Abstract Decabromodiphenylethane (DBDPE) has been widely used as an alternative flame retardant due to the restriction or phase-out of traditional polybrominated diphenyl ethers (PBDEs), and is of increasing concern regarding its ubiquity, persistence, and potential adverse effects. In the present study, the toxicological effects of DBDPE were evaluated using zebrafish as an in vivo model. Upon being exposed to DBDPE-polluted sediments for a short term, it was found that the mortality and malformation of zebrafish (including edema, bent notochord, and bent tail) were not affected even at the highest concentration tested (1000.0 microg/kg dry sediment). Regarding behavioral responses, it was found that zebrafish larvae of 48 hours post fertilization (hpf) in all groups escaped successfully with a touch to the dorsal fin. However, when exposed to the highest DBDPE concentration, the larvae of 120 hpf exhibited significantly smaller distances as compared to the control. Moreover, the results of the acetylcholinesterase (AChE) activity, the expression levels of two important nerve-related genes, and the cell apoptosis all indicated that DBDPE posed low neurotoxicity in embryo-larval zebrafish. The results in this study shed some light on the potential risks of DBDPE in the real environment and highlight the application of the sediment exposure route in the future. Title: A novel variant associated with HDL-C levels by modifying DAGLB expression levels: An annotation-based genome-wide association study Zhou D, Zhang D, Sun X, Li Z, Ni Y, Shan Z, Li H, Liu C, Zhang S and Lai M <5 more author(s)> Zhou D, Zhang D, Sun X, Li Z, Ni Y, Shan Z, Li H, Liu C, Zhang S, Liu Y, Zheng R, Pan F, Zhu Y, Shi Y, Lai M (- 5) Ref: Eur J Hum Genet, 26:838, 2018 : PubMed ESTHER: Zhou_2018_Eur.J.Hum.Genet_26_838 PubMedSearch: Zhou 2018 Eur.J.Hum.Genet 26 838 PubMedID: 29476167 Abstract Although numbers of genome-wide association studies (GWAS) have been performed for serum lipid levels, limited heritability has been explained. Studies showed that combining data from GWAS and expression quantitative trait loci (eQTLs) signals can both enhance the discovery of trait-associated SNPs and gain a better understanding of the mechanism. We performed an annotation-based, multistage genome-wide screening for serum-lipid-level-associated loci in totally 6863 Han Chinese. A serum high-density lipoprotein cholesterol (HDL-C) associated variant rs1880118 (hg19 chr7:g. 6435220G>C) was replicated (Pcombined = 1.4E-10). rs1880118 was associated with DAGLB (diacylglycerol lipase, beta) expression levels in subcutaneous adipose tissue (P = 5.9E-42) and explained 47.7% of the expression variance. After the replication, an active segment covering variants tagged by rs1880118 near 5' of DAGLB was annotated using histone modification and transcription factor binding signals. The luciferase report assay revealed that the segment containing the minor alleles showed increased transcriptional activity compared with segment contains the major alleles, which was consistent with the eQTL analyses. The expression-trait association tests indicated the association between the DAGLB and serum HDL-C levels using gene-based approaches called "TWAS" (P = 3.0E-8), "SMR" (P = 1.1E-4), and "Sherlock" (P = 1.6E-6). To summarize, we identified a novel HDL-C-associated variant which explained nearly half of the expression variance of DAGLB. Integrated analyses established a genotype-gene-phenotype three-way association and expanded our knowledge of DAGLB in lipid metabolism. Title: Di(2-ethylhexyl) phthalate induces apoptosis through mitochondrial pathway in GC-2spd cells Fu G, Dai J, Zhang D, Zhu L, Tang X, Zhang L, Zhou T, Duan P, Quan C and Shi Y <2 more author(s)> Fu G, Dai J, Zhang D, Zhu L, Tang X, Zhang L, Zhou T, Duan P, Quan C, Zhang Z, Song S, Shi Y (- 2) Ref: Environ Toxicol, 32:1055, 2017 : PubMed ESTHER: Fu_2017_Environ.Toxicol_32_1055 PubMedSearch: Fu 2017 Environ.Toxicol 32 1055 PubMedID: 27416487 Abstract Di(2-ethylhexyl) phthalate (DEHP), a plasticizer of synthetic polymers, is a well-known endocrine disrupting chemical (EDC) and reproductive toxicant. Addressing the unclear mechanism of DEHP-induced reproductive dysfunction, this study used GC-2spd cells to investigate the molecular mechanism involved in the DEHP-induced toxicity in the male reproductive system. The results indicated that the apoptotic cell death was significantly induced by DEHP exposure over 100 muM. Furthermore, DEHP treatment could induce oxidative stress in GC-2spd cells involving in the decrease of superoxide dismutase (SOD) activity (200 muM) and glutathione peroxidase (GSH-Px) activity (50 and 100 muM). In addition, DEHP induction also caused the elevated ratios of Bax/Bcl-2, release of cytochrome c and decomposition of procaspase-3 and procaspase-9 in GC-2spd cells. Taken together, our work provided the evidence that DEHP exposure might induce apoptosis of GC-2spd cells via mitochondria pathway mediated by oxidative stress. Title: Genome sequence of Talaromyces piceus 9-3 provides insights into lignocellulose degradation He R, Bai X, Cai P, Sun C, Zhang D, Chen S Ref: 3 Biotech, 7:368, 2017 : PubMed ESTHER: He_2017_3.Biotech_7_368 PubMedSearch: He 2017 3.Biotech 7 368 PubMedID: 29062678 Gene_locus related to this paper: 9euro-a0a2d2agx5 Abstract Many species of Penicillium have exhibited great potential for lignocellulose hydrolysis. The filamentous fungus Talaromyces piceus 9-3 (anamorph: Penicillium piceum), which was isolated from compost wastes in China, was sequenced in this study. Compared with the cellulase producer T. reesei, T. piceus 9-3 processes a lignocellulolytic enzyme system comprising more diverse enzymatic components, especially hemicellulases. This report will facilitate the use of this strain for biomass degradation. Title: Ameliorative Effect of Ginsenoside Rg1 on Lipopolysaccharide-Induced Cognitive Impairment: Role of Cholinergic System Jin Y, Peng J, Wang X, Zhang D, Wang T Ref: Neurochem Res, 42:1299, 2017 : PubMed ESTHER: Jin_2017_Neurochem.Res_42_1299 PubMedSearch: Jin 2017 Neurochem.Res 42 1299 PubMedID: 28078612 Abstract Bacterial endotoxin lipopolysaccharide (LPS) can induce systemic inflammation, and therefore disrupt learning and memory processes. Ginsenoside Rg1, a major bioactive component of ginseng, is shown to greatly improve cognitive function. The present study was designed to further investigate whether administration of ginsenoside Rg1 can ameliorate LPS-induced cognitive impairment in the Y-maze and Morris water maze (MWM) task, and to explore the underlying mechanisms. Results showed that exposure to LPS (500 mug/kg) significantly impaired working and spatial memory and that repeated treatment with ginsenoside Rg1 (200 mg/kg/day, for 30 days) could effectively alleviate the LPS-induced cognitive decline as indicated by increased working and spatial memory in the Y-maze and MWM tests. Furthermore, ginsenoside Rg1 treatment prevented LPS-induced decrease of acetylcholine (ACh) levels and increase of acetylcholinesterase (AChE) activity. Ginsenoside Rg1 treatment also reverted the decrease of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) protein expression in the prefrontal cortex (PFC) and hippocampus of LPS-treated rats. These findings suggest that ginsenoside Rg1 has protective effect against LPS-induced cognitive deficit and that prevention of LPS-induced changes in cholinergic system is crucial to this ameliorating effect. Title: ChAT-positive neurons participate in subventricular zone neurogenesis after middle cerebral artery occlusion in mice Wang J, Fu X, Zhang D, Yu L, Li N, Lu Z, Gao Y, Wang M, Liu X and Yan B <2 more author(s)> Wang J, Fu X, Zhang D, Yu L, Li N, Lu Z, Gao Y, Wang M, Liu X, Zhou C, Han W, Yan B (- 2) Ref: Behavioural Brain Research, 316:145, 2017 : PubMed ESTHER: Wang_2017_Behav.Brain.Res_316_145 PubMedSearch: Wang 2017 Behav.Brain.Res 316 145 PubMedID: 27609645 Abstract The mechanisms of post-stroke neurogenesis in the subventricular zone (SVZ) are unclear. However, neural stem cell-intrinsic and neurogenic niche mechanisms, as well as neurotransmitters, have been shown to play important roles in SVZ neurogenesis. Recently, a previously unknown population of choline acetyltransferase (ChAT)+ neurons residing in rodent SVZ were identified to have direct control over neural stem cell proliferation by indirectly activating fibroblast growth factor receptor (FGFR). This finding revealed possible neuronal control over SVZ neurogenesis. In this study, we assessed whether these ChAT+ neurons also participate in stroke-induced neurogenesis. We used a permanent middle cerebral artery occlusion (MCAO) model produced by transcranial electrocoagulation in mice, atropine (muscarinic cholinergic receptor [mAchR] antagonist), and donepezil (acetylcholinesterase inhibitor) to investigate the role of ChAT+ neurons in stroke-induced neurogenesis. We found that mAchRs, phosphorylated protein kinase C (p-PKC), and p-38 levels in the SVZ were upregulated in mice on day 7 after MCAO. MCAO also significantly increased the number of BrdU/doublecortin-positive cells and protein levels of phosphorylated-neural cell adhesion molecule and mammalian achaete scute homolog-1. FGFR was activated in the SVZ, and doublecortin-positive cells increased in the peri-infarction region. These post-stroke neurogenic effects were enhanced by donepezil and partially decreased by atropine. Neither atropine nor donepezil affected peri-infarct microglial activation or serum concentrations of TNF-alpha, IFN-gamma, or TGF-beta on day 7 after MCAO. We conclude that ChAT+ neurons in the SVZ may participate in stroke-induced neurogenesis, suggesting a new mechanism for neurogenesis after stroke. Title: Control of secondary cell wall patterning involves xylan deacetylation by a GDSL esterase Zhang B, Zhang L, Li F, Zhang D, Liu X, Wang H, Xu Z, Chu C, Zhou Y Ref: Nat Plants, 3:17017, 2017 : PubMed ESTHER: Zhang_2017_Nat.Plants_3_17017 PubMedSearch: Zhang 2017 Nat.Plants 3 17017 PubMedID: 28260782 Abstract O-acetylation, a ubiquitous modification of cell wall polymers, has striking impacts on plant growth and biomass utilization and needs to be tightly controlled. However, the mechanisms that underpin the control of cell wall acetylation remain elusive. Here, we show a rice brittle leaf sheath1 (bs1) mutant, which contains a lesion in a Golgi-localized GDSL esterase that deacetylates the prominent hemicellulose xylan. Cell wall composition, detailed xylan structure characterization and enzyme kinetics and activity assays on acetylated sugars and xylooligosaccharides demonstrate that BS1 is an esterase that cleaves acetyl moieties from the xylan backbone at O-2 and O-3 positions of xylopyranosyl residues. BS1 thus plays an important role in the maintenance of proper acetylation level on the xylan backbone, which is crucial for secondary wall formation and patterning. Our findings outline a mechanism for how plants modulate wall acetylation and endow a plethora of uncharacterized GDSL esterases with surmisable activities. Title: Cardiomyocyte VEGF Regulates Endothelial Cell GPIHBP1 to Relocate Lipoprotein Lipase to the Coronary Lumen During Diabetes Mellitus Chiu AP, Wan A, Lal N, Zhang D, Wang F, Vlodavsky I, Hussein B, Rodrigues B Ref: Arterioscler Thromb Vasc Biol, 36:145, 2016 : PubMed ESTHER: Chiu_2016_Arterioscler.Thromb.Vasc.Biol_36_145 PubMedSearch: Chiu 2016 Arterioscler.Thromb.Vasc.Biol 36 145 PubMedID: 26586663 Abstract OBJECTIVE: Lipoprotein lipase (LPL)-mediated triglyceride hydrolysis is the major source of fatty acid for cardiac energy. LPL, synthesized in cardiomyocytes, is translocated across endothelial cells (EC) by its transporter glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). Previously, we have reported an augmentation in coronary LPL, which was linked to an increased expression of GPIHBP1 following moderate diabetes mellitus. We examined the potential mechanism by which hyperglycemia amplifies GPIHBP1. APPROACH AND Title: Comparative transcriptome analyses of deltamethrin-susceptible and -resistant Culex pipiens pallens by RNA-seq Lv Y, Wang W, Hong S, Lei Z, Fang F, Guo Q, Hu S, Tian M, Liu B and Zhu C <5 more author(s)> Lv Y, Wang W, Hong S, Lei Z, Fang F, Guo Q, Hu S, Tian M, Liu B, Zhang D, Sun Y, Ma L, Shen B, Zhou D, Zhu C (- 5) Ref: Mol Genet Genomics, 291:309, 2016 : PubMed ESTHER: Lv_2016_Mol.Genet.Genomics_291_309 PubMedSearch: Lv 2016 Mol.Genet.Genomics 291 309 PubMedID: 26377942 Abstract The widespread and improper use of pyrethroid insecticides, such as deltamethrin, has resulted in the evolution of resistance in many mosquito species, including Culex pipiens pallens. With the development of high-throughput sequencing, it is possible to massively screen pyrethroid resistance-associated gene. In this study, we used Illumina-Solexa transcriptome sequencing to identify genes that are expressed differently in deltamethrin-susceptible and -resistant strains of Culex pipiens pallens as a critical knowledge base for further studies. A total of 4,961,197,620 base pairs and 55,124,418 reads were sequenced, mapped to the Culex quinquefasciatus genome and assembled into 17,679 known genes. We recorded 1826 significantly differentially expressed genes (DEGs). Among them, 1078 genes were up-regulated and 748 genes were down-regulated in the deltamethrin-resistant strain compared to -susceptible strain. These DEGs contained cytochrome P450 s, cuticle proteins, UDP-glucuronosyltransferases, lipases, serine proteases, heat shock proteins, esterases and others. Among the 1826 DEGs, we found that the transcriptional levels of CYP6AA9 in the laboratory populations was elevated as the levels of deltamethrin resistance increased. Moreover, the expression levels of the CYP6AA9 were significantly higher in the resistant strains than the susceptible strains in three different field populations. We further confirmed the association between the CYP6AA9 gene and deltamethrin resistance in mosquitoes by RNA interfering (RNAi). Altogether, we explored massive potential pyrethroid resistance-associated genes and demonstrated that CYP6AA9 participated in the pyrethroid resistance in mosquitoes. Title: Complete Genome Sequence of Fish Pathogen Aeromonas hydrophila JBN2301 Yang W, Li N, Li M, Zhang D, An G Ref: Genome Announc, 4:, 2016 : PubMed ESTHER: Yang_2016_Genome.Announc_4_ PubMedSearch: Yang 2016 Genome.Announc 4 PubMedID: 26823580 Gene_locus related to this paper: aerhy-a0a0s3bhm4 Abstract Aeromonas hydrophila is one of the most important fish pathogens in China. Here, we report complete genome sequence of a virulent strain, A. hydrophila JBN2301, which was isolated from diseased crucian carp. Title: alpha/beta-Hydrolase Domain 6 Deletion Induces Adipose Browning and Prevents Obesity and Type 2 Diabetes Zhao S, Mugabo Y, Ballentine G, Attane C, Iglesias J, Poursharifi P, Zhang D, Nguyen TA, Erb H and Prentki M <7 more author(s)> Zhao S, Mugabo Y, Ballentine G, Attane C, Iglesias J, Poursharifi P, Zhang D, Nguyen TA, Erb H, Prentki R, Peyot ML, Joly E, Tobin S, Fulton S, Brown JM, Madiraju SR, Prentki M (- 7) Ref: Cell Rep, 14:2872, 2016 : PubMed ESTHER: Zhao_2016_Cell.Rep_14_2872 PubMedSearch: Zhao 2016 Cell.Rep 14 2872 PubMedID: 26997277 Gene_locus related to this paper: human-ABHD6, mouse-ABHD6 Abstract Suppression of alpha/beta-domain hydrolase-6 (ABHD6), a monoacylglycerol (MAG) hydrolase, promotes glucose-stimulated insulin secretion by pancreatic beta cells. We report here that high-fat-diet-fed ABHD6-KO mice show modestly reduced food intake, decreased body weight gain and glycemia, improved glucose tolerance and insulin sensitivity, and enhanced locomotor activity. ABHD6-KO mice also show increased energy expenditure, cold-induced thermogenesis, brown adipose UCP1 expression, fatty acid oxidation, and white adipose browning. Adipose browning and cold-induced thermogenesis are replicated by the ABHD6 inhibitor WWL70 and by antisense oligonucleotides targeting ABHD6. Our evidence suggests that one mechanism by which the lipolysis derived 1-MAG signals intrinsic and cell-autonomous adipose browning is via PPARalpha and PPARgamma activation, and that ABHD6 regulates adipose browning by controlling signal competent 1-MAG levels. Thus, ABHD6 regulates energy homeostasis, brown adipose function, and white adipose browning and is a potential therapeutic target for obesity and type 2 diabetes. Title: Poster: Striatal cholinergic interneurons regulate L-dopa-induced dyskinesias Bordia T, Xiomara Perez XA, Zhang D, Quik M Ref: Biochemical Pharmacology, 97:630, 2015 : PubMed ESTHER: Bordia_2015_Biochem.Pharmacol_97(4)_630 PubMedSearch: Bordia 2015 Biochem.Pharmacol 97(4) 630 Title: Pigment epithelium-derived factor regulates microvascular permeability through adipose triglyceride lipase in sepsis He T, Hu J, Yan G, Li L, Zhang D, Zhang Q, Chen B, Huang Y Ref: Clinical Science (Lond), 129:49, 2015 : PubMed ESTHER: He_2015_Clin.Sci.(Lond)_129_49 PubMedSearch: He 2015 Clin.Sci.(Lond) 129 49 PubMedID: 25700221 Abstract The integrity of the vascular barrier, which is essential to blood vessel homoeostasis, can be disrupted by a variety of soluble permeability factors during sepsis. Pigment epithelium-derived factor (PEDF), a potent endogenous anti-angiogenic molecule, is significantly increased in sepsis, but its role in endothelial dysfunction has not been defined. To assess the role of PEDF in the vasculature, we evaluated the effects of exogenous PEDF in vivo using a mouse model of cecal ligation and puncture (CLP)-induced sepsis and in vitro using human dermal microvascular endothelial cells (HDMECs). In addition, PEDF was inhibited using a PEDF-monoclonal antibody (PEDF-mAb) or recombinant lentivirus vectors targeting PEDF receptors, including adipose triglyceride lipase (ATGL) and laminin receptor (LR). Our results showed that exogenous PEDF induced vascular hyperpermeability, as measured by extravasation of Evan's Blue (EB), dextran and microspheres in the skin, blood, trachea and cremaster muscle, both in a normal state and under conditions of sepsis. In control and LR-shRNA-treated HDMECs, PEDF alone or in combination with inflammatory mediators resulted in activation of RhoA, which was accompanied by actin rearrangement and disassembly of intercellular junctions, impairing endothelial barrier function. But in ATGL-shRNA-treated HDMECs, PEDF failed to induce the aforementioned alterations, suggesting that PEDF-induced hyperpermeability was mediated through the ATGL receptor. These results reveal a novel role for PEDF as a potential vasoactive substance in septic vascular hyperpermeability. Furthermore, our results suggest that PEDF and ATGL may serve as therapeutic targets for managing vascular hyperpermeability in sepsis. 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: Alpha7 nicotinic receptors as therapeutic targets for Parkinson's disease Quik M, Zhang D, McGregor M, Bordia T Ref: Biochemical Pharmacology, 97:399, 2015 : PubMed ESTHER: Quik_2015_Biochem.Pharmacol_97(4)_399 PubMedSearch: Quik 2015 Biochem.Pharmacol 97(4) 399 PubMedID: 26093062 Abstract Accumulating evidence suggests that CNS alpha7 nicotinic acetylcholine receptors (nAChRs) are important targets for the development of therapeutic approaches for Parkinson's disease. This progressive neurodegenerative disorder is characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines, changes in affect and sleep disturbances. Currently l-dopa is the gold standard treatment for Parkinson's disease motor problems, particularly in the early disease stages. However, it does not improve the other symptoms, nor does it reduce the inevitable disease progression. Novel therapeutic strategies for Parkinson's disease are therefore critical. Extensive pre-clinical work using a wide variety of experimental models shows that nicotine and nAChR agonists protect against damage to nigrostriatal and other neuronal cells. This observation suggests that nicotine and/or nAChR agonists may be useful as disease modifying agents. Additionally, studies in several parkinsonian animal models including nonhuman primates show that nicotine reduces l-dopa-induced dyskinesias, a side effect of l-dopa therapy that may be as incapacitating as Parkinson's disease itself. Work with subtype selective nAChR agonists indicate that alpha7 nAChRs are involved in mediating both the neuroprotective and antidyskinetic effects, thus offering a targeted strategy with optimal beneficial effects and minimal adverse responses. Here, we review studies demonstrating a role for alpha7 nAChRs in protection against neurodegenerative effects and for the reduction of l-dopa-induced dyskinesias. Altogether, this work suggests that alpha7 nAChRs may be useful targets for reducing Parkinson's disease progression and for the management of the dyskinesias that arise with l-dopa therapy. Title: Gender specific effect of LIPC C-514T polymorphism on obesity and relationship with plasma lipid levels in Chinese children Wang H, Zhang D, Ling J, Lu W, Zhang S, Zhu Y, Lai M Ref: J Cell Mol Med, 19:2296, 2015 : PubMed ESTHER: Wang_2015_J.Cell.Mol.Med_19_2296 PubMedSearch: Wang 2015 J.Cell.Mol.Med 19 2296 PubMedID: 26282880 Abstract Hepatic lipase (LIPC) is a key rate-limiting enzyme in lipoprotein catabolism pathways involved in the development of obesity. The C-514T polymorphism in the promoter region is associated with decreased LIPC activity. We performed a case-controlled study (850 obese children and 2119 controls) and evaluated the association between LIPC C-514T polymorphism, obesity and plasma lipid profile in Chinese children and adolescents. Additionally, we conducted a meta-analysis of all results from published studies as well as our own data. A significant association between the polymorphism and obesity is observed in boys (P = 0.042), but not in girls. And we observed a significant relationship of the polymorphism with total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) independent of obesity in boys. The T allele carriers have higher levels of low density lipoprotein cholesterol (LDL-C) in obese boys, and triglyceride (TG), TC and LDL-C in non-obese girls (all P < 0.05). In the meta-analysis, under dominant model the T allele increased body mass index (BMI) level in boys, while it decreased BMI in girls, and increased the levels of TC both in the overall and subgroups, TG and HDL-C in the overall and boys, and LDL-C in the overall (all P < 0.05). Our results suggest that the T allele might carry an increased risk of obesity in Chinese boys. The meta-analysis suggests that T allele acts as a risk allele for higher BMI levels in male childhood, while it is a protective allele in female childhood. And the polymorphism is associated with the levels of plasma lipids, which may be modulated by obesity and gender. Title: Evidence for Association of Cell Adhesion Molecules Pathway and NLGN1 Polymorphisms with Schizophrenia in Chinese Han Population Zhang Z, Yu H, Jiang S, Liao J, Lu T, Wang L, Zhang D, Yue W Ref: PLoS ONE, 10:e0144719, 2015 : PubMed ESTHER: Zhang_2015_PLoS.One_10_e0144719 PubMedSearch: Zhang 2015 PLoS.One 10 e0144719 PubMedID: 26674772 Abstract Multiple risk variants of schizophrenia have been identified by Genome-wide association studies (GWAS). As a complement for GWAS, previous pathway-based analysis has indicated that cell adhesion molecules (CAMs) pathway might be involved in the pathogenesis of schizophrenia. However, less replication studies have been reported. Our objective was to investigate the association between CAMs pathway and schizophrenia in the Chinese Han population. We first performed a pathway analysis utilizing our previous GWAS data. The CAMs pathway (hsa04514) was significantly associated with schizophrenia using hybrid gene set-based test (P = 1.03x10-10) and hypergeometric test (P = 5.04x10-6). Moreover, 12 genes (HLA-A, HLA-C, HLA-DOB, HLA-DPB1, HLA-DQA2, HLA-DRB1, MPZ, CD276, NLGN1, NRCAM, CLDN1 and ICAM3) were modestly significantly associated with schizophrenia (P<0.01). Then, we selected one promising gene neuroligin 1 (NLGN1) to further investigate the association between eight significant SNPs and schizophrenia in an independent sample (1814 schizophrenia cases and 1487 healthy controls). Our study showed that seven SNPs of NLGN1 and two haplotype blocks were significantly associated with schizophrenia. This association was confirmed by the results of combined analysis. Among them, SNP rs9835385 had the most significant association with schizophrenia (P = 2.83x10-7). Furthermore, in silico analysis we demonstrated that NLGN1 is preferentially expressed in human brain and SNP rs1488547 was related to the expression level. We validated the association of CAMs pathway with schizophrenia in pathway-level and identified one susceptibility gene NLGN1. Further investigation of the roles of CAMs pathway in the pathogenesis of schizophrenia is warranted. Title: Complete Genome Sequence of Rhodococcus sp. B7740, a Carotenoid-Producing Bacterium Isolated from the Arctic Sea Zhang D, Li L, Zhu S, Zhang N, Yang J, Ma X, Chen J Ref: Genome Announc, 3:, 2015 : PubMed ESTHER: Zhang_2015_Genome.Announc_3_e00333 PubMedSearch: Zhang 2015 Genome.Announc 3 e00333 PubMedID: 25931596 Gene_locus related to this paper: 9noca-a0a0d5a5c6, 9noca-a0a0d5abf5, 9noca-a0a0d5ae28, 9noca-a0a0d5ahw4 Abstract Rhodococcus sp. B7740 was isolated from Arctic seawater and selected for its capacity to synthesize carotenoids. Here, we report the complete genome sequence of Rhodococcus sp. B7740 to provide the genetic basis for a better understanding of its carotenoid-accumulating capabilities, and we describe the major features of the genome. Title: Operon for biosynthesis of lipstatin, the Beta-lactone inhibitor of human pancreatic lipase Bai T, Zhang D, Lin S, Long Q, Wang Y, Ou H, Kang Q, Deng Z, Liu W, Tao M Ref: Applied Environmental Microbiology, 80:7473, 2014 : PubMed ESTHER: Bai_2014_Appl.Environ.Microbiol_80_7473 PubMedSearch: Bai 2014 Appl.Environ.Microbiol 80 7473 PubMedID: 25239907 Inhibitor(s) related to this paper: Lipstatin Abstract Lipstatin, isolated from Streptomyces toxytricini as a potent and selective inhibitor of human pancreatic lipase, is a precursor for tetrahydrolipstatin (also known as orlistat, Xenical, and Alli), the only FDA-approved antiobesity medication for long-term use. Lipstatin features a 2-hexyl-3,5-dihydroxy-7,10-hexadecadienoic-beta-lactone structure with an N-formyl-l-leucine group attached as an ester to the 5-hydroxy group. It has been suggested that the alpha-branched 3,5-dihydroxy fatty acid beta-lactone moiety of lipstatin in S. toxytricini is derived from Claisen condensation between two fatty acid substrates, which are derived from incomplete oxidative degradation of linoleic acid based on feeding experiments. In this study, we identified a six-gene operon (lst) that was essential for the biosynthesis of lipstatin by large-deletion, complementation, and single-gene knockout experiments. lstA, lstB, and lstC, which encode two beta-ketoacyl-acyl carrier protein synthase III homologues and an acyl coenzyme A (acyl-CoA) synthetase homologue, were indicated to be responsible for the generation of the alpha-branched 3,5-dihydroxy fatty acid backbone. Subsequently, the nonribosomal peptide synthetase (NRPS) gene lstE and the putative formyltransferase gene lstF were involved in decoration of the alpha-branched 3,5-dihydroxy fatty acid chain with an N-formylated leucine residue. Finally, the 3beta-hydroxysteroid dehydrogenase-homologous gene lstD might be responsible for the reduction of the beta-keto group of the biosynthetic intermediate, thereby facilitating the formation of the unique beta-lactone ring. Title: mGlu5 receptors and cellular prion protein mediate amyloid-beta-facilitated synaptic long-term depression in vivo Hu NW, Nicoll AJ, Zhang D, Mably AJ, O'Malley T, Purro SA, Terry C, Collinge J, Walsh DM, Rowan MJ Ref: Nat Commun, 5:3374, 2014 : PubMed ESTHER: Hu_2014_Nat.Commun_5_3374 PubMedSearch: Hu 2014 Nat.Commun 5 3374 PubMedID: 24594908 Abstract NMDA-type glutamate receptors (NMDARs) are currently regarded as paramount in the potent and selective disruption of synaptic plasticity by Alzheimer's disease amyloid beta-protein (Abeta). Non-NMDAR mechanisms remain relatively unexplored. Here we describe how Abeta facilitates NMDAR-independent long-term depression of synaptic transmission in the hippocampus in vivo. Synthetic Abeta and Abeta in soluble extracts of Alzheimer's disease brain usurp endogenous acetylcholine muscarinic receptor-dependent long-term depression, to enable long-term depression that required metabotropic glutamate-5 receptors (mGlu5Rs). We also find that mGlu5Rs are essential for Abeta-mediated inhibition of NMDAR-dependent long-term potentiation in vivo. Blocking Abeta binding to cellular prion protein with antibodies prevents the facilitation of long-term depression. Our findings uncover an overarching role for Abeta-PrP(C)-mGlu5R interplay in mediating both LTD facilitation and LTP inhibition, encompassing NMDAR-mediated processes that were previously considered primary. Title: Acetylcholine plays an antinociceptive role by modulating pain-induced discharges of pain-related neurons in the caudate putamen of rats Li CM, Zhang DM, Yang CX, Ma X, Gao HR, Zhang D, Xu MY Ref: Neuroreport, 25:164, 2014 : PubMed ESTHER: Li_2014_Neuroreport_25_164 PubMedSearch: Li 2014 Neuroreport 25 164 PubMedID: 24128868 Abstract The caudate putamen (CPu) has been suggested to be involved in nociceptive modulation. Some neurotransmitters, including acetylcholine (ACh), participate in pain modulation in the central nervous system. However, the active mechanism of ACh on the pain-related neurons in the CPu remains unclear. This study aimed to investigate the effects of the cholinergic agonists ACh and pilocarpine and the muscarinic ACh receptor antagonist atropine on the pain-induced response of pain-related neurons in the CPu of Wistar rats. Trains of electrical impulses applied to the sciatic nerve of rat were used as the noxious stimulus. The electrical activities of pain-excited neurons (PENs) or pain-inhibited neurons (PINs) in the CPu were recorded by a glass microelectrode. Our results showed that an intra-CPu injection of 4 mug/2 mul ACh or pilocarpine decreased and increased the pain-induced discharge frequency in the PENs and PINs, respectively. Intra-CPu administration of 1 mug/2 mul atropine produced the opposite effect on these neurons. These findings indicate that ACh may play an analgesic role by affecting the electric activities of PENs and PINs, and the muscarinic pathway may be involved in the modulation of pain perception in the CPu. Title: Complete Genome Sequence of a Moderately Virulent Aeromonas hydrophila Strain, pc104A, Isolated from Soil of a Catfish Pond in West Alabama Pridgeon JW, Zhang D, Zhang L Ref: Genome Announc, 2:e00554, 2014 : PubMed ESTHER: Pridgeon_2014_Genome.Announc_2_e00554 PubMedSearch: Pridgeon 2014 Genome.Announc 2 e00554 PubMedID: 24903879 Gene_locus related to this paper: aerhh-a0kle4, aerhy-a0a028v5g9 Abstract Aeromonas hydrophila pc104A is a moderately virulent strain isolated from the soil of a catfish pond in west Alabama in 2010. Its full genome is 5,023,829 bp. The availability of this genome will allow comparative genomics to identify the virulence genes that are important for pathogenesis or immunogens for the purpose of vaccine development. Title: Complete Genome Sequence of the Highly Virulent Aeromonas hydrophila AL09-71 Isolated from Diseased Channel Catfish in West Alabama Pridgeon JW, Zhang D, Zhang L Ref: Genome Announc, 2:e00450, 2014 : PubMed ESTHER: Pridgeon_2014_Genome.Announc_2_e00450 PubMedSearch: Pridgeon 2014 Genome.Announc 2 e00450 PubMedID: 24855300 Gene_locus related to this paper: aerhh-a0kle4 Abstract Aeromonas hydrophila AL09-71 was isolated from diseased channel catfish in west Alabama during a 2009 disease outbreak. The full genome of A. hydrophila AL09-71 is 5,023,861 bp. The availability of this genome will allow comparative genomics to identify genes involved in pathogenesis or immunogens for the purpose of vaccine development. Title: Role for the nicotinic cholinergic system in movement disorders; therapeutic implications Quik M, Zhang D, Perez XA, Bordia T Ref: Pharmacol Ther, 144:50, 2014 : PubMed ESTHER: Quik_2014_Pharmacol.Ther_144_50 PubMedSearch: Quik 2014 Pharmacol.Ther 144 50 PubMedID: 24836728 Abstract A large body of evidence using experimental animal models shows that the nicotinic cholinergic system is involved in the control of movement under physiological conditions. This work raised the question whether dysregulation of this system may contribute to motor dysfunction and whether drugs targeting nicotinic acetylcholine receptors (nAChRs) may be of therapeutic benefit in movement disorders. Accumulating preclinical studies now show that drugs acting at nAChRs improve drug-induced dyskinesias. The general nAChR agonist nicotine, as well as several nAChR agonists (varenicline, ABT-089 and ABT-894), reduces l-dopa-induced abnormal involuntary movements or dyskinesias up to 60% in parkinsonian nonhuman primates and rodents. These dyskinesias are potentially debilitating abnormal involuntary movements that arise as a complication of l-dopa therapy for Parkinson's disease. In addition, nicotine and varenicline decrease antipsychotic-induced abnormal involuntary movements in rodent models of tardive dyskinesia. Antipsychotic-induced dyskinesias frequently arise as a side effect of chronic drug treatment for schizophrenia, psychosis and other psychiatric disorders. Preclinical and clinical studies also show that the nAChR agonist varenicline improves balance and coordination in various ataxias. Lastly, nicotine has been reported to attenuate the dyskinetic symptoms of Tourette's disorder. Several nAChR subtypes appear to be involved in these beneficial effects of nicotine and nAChR drugs including alpha4beta2*, alpha6beta2* and alpha7 nAChRs (the asterisk indicates the possible presence of other subunits in the receptor). Overall, the above findings, coupled with nicotine's neuroprotective effects, suggest that nAChR drugs have potential for future drug development for movement disorders. Title: Elevated 14,15- epoxyeicosatrienoic acid by increasing of cytochrome P450 2C8, 2C9 and 2J2 and decreasing of soluble epoxide hydrolase associated with aggressiveness of human breast cancer Wei X, Zhang D, Dou X, Niu N, Huang W, Bai J, Zhang G Ref: BMC Cancer, 14:841, 2014 : PubMed ESTHER: Wei_2014_BMC.Cancer_14_841 PubMedSearch: Wei 2014 BMC.Cancer 14 841 PubMedID: 25406731 Abstract BACKGROUND: Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid by cytochrome P450 (CYP) and metabolized by soluble epoxide hydrolase (sEH). EETs have been associated with cardiovascular disease, diabetes and several cancer diseases. However, the distribution in tissue and role of CYP2C8, 2C9, 2J2 and sEH in human breast carcinogenesis remains uncertain. METHODS: Breast cancer (BC) and adjacent noncancerous tissue was obtained from 40 breast cancer patients in the Chaoshan region in China from 2010 to 2012. The level of 14,15-EET/14,15-DHET in BC patients was detected by ELISA; the expression and distribution of CYP2C8, 2C9, 2J2 and sEH was determined by quantitative RT-PCR and immunohistochemical staining; and cell proliferation and migration was analyzed by MTT and transwell assays, respectively. RESULTS: The median 14,15-EET and 14,15-EET/DHET level was 2.5-fold higher in BC than noncancerous tissue. The mRNA and protein levels of CYP2C8, 2C9 and 2J2 were higher, and sEH was lower in BC than noncancerous tissue. Furthermore, CYP2C8 and 2C9 protein levels positively correlated with Ki67 status, and CYP2J2 levels positively correlated with histological grade and tumor size. The sEH protein level negatively correlated with tumor size, estrogen receptors and Ki67. In MDA-MB-231 cells, siRNA knockdown of CYP2C8, 2C9 or 2J2 reduced cell proliferation, by 24.5%, 29.13%, or 22.7% and decreased cell migration by 49.1%, 44.9%, and 50.9%, respectively. Similarly, with adenovirus overexpression of sEH, both cell proliferation and migration rates were reduced by 31.4% and 45.8%, respectively. CONCLUSIONS: The present study shows that elevated EET levels in BC tissues are associated with upregulation of CYP2C8, 2C9, and 2J2, and downregulation of sEH, and are also associated with aggressive cell behavior in BC patients. Title: Use of a carboxylesterase inhibitor of phenylmethanesulfonyl fluoride to stabilize epothilone D in rat plasma for a validated UHPLC-MS/MS assay Yuan L, Fu Y, Zhang D, Xia YQ, Peng Q, Aubry AF, Arnold ME Ref: Journal of Chromatography B Analyt Technol Biomed Life Sciences, 969C:60, 2014 : PubMed ESTHER: Yuan_2014_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_969C_60 PubMedSearch: Yuan 2014 J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci 969C 60 PubMedID: 25151331 Abstract A sensitive, accurate and rugged UHPLC-MS/MS method was developed and validated for the quantitation of Epothilone D (EpoD), a microtubule stabilizer in development for treatment of Alzeimer's disease, in rat plasma. The ester group in EpoD can be hydrolyzed by esterases in blood or plasma, which creates a stability concern for the bioanalysis of EpoD. Species differences in the stability of EpoD in plasma were observed. Carboxylesterases were identified as the likely esterases responsible for the hydrolysis of EpoD in plasma ex vivo, and the cause of the species different stability. Phenylmethanesulfonyl fluoride, a carboxylesterase inhibitor, was used to stabilize EpoD in rat blood during sample collection, processing, and storage. A systematic method screening and optimization strategy was used to improve the assay sensitivity and minimize potential bioanalytical risks. The stabilized plasma samples were extracted by liquid-liquid extraction. Chromatographic separation was achieved on an Acquity UPLC BEH Phenyl column with a gradient elution. EpoD and its stable isotope labeled internal standards were detected by positive ion electrospray tandem mass spectrometry. The standard curve, which ranged from 0.100 to 100ng/mL was fitted to a 1/x2 weighted linear regression model. The intra-assay precision was within +/-3.6% CV and inter-assay precision was within +/-4.2% CV. The assay accuracy was within +/-8.3% of the nominal values. Assay recovery of EpoD was high ( approximately 90%) and matrix effect was minimal (1.02-1.05). EpoD was stable in stabilized rat plasma for at least 30h at room temperature, 180 days at -20 degrees C, and following three freeze-thaw cycles. The validated method was successfully applied to sample analysis in toxicology studies. Title: ABT-089 and ABT-894 reduce levodopa-induced dyskinesias in a monkey model of Parkinson's disease Zhang D, Bordia T, McGregor M, McIntosh JM, Decker MW, Quik M Ref: Movement Disorders, 29:508, 2014 : PubMed ESTHER: Zhang_2014_Mov.Disord_29_508 PubMedSearch: Zhang 2014 Mov.Disord 29 508 PubMedID: 24515328 Abstract Levodopa-induced dyskinesias (LIDs) are a serious complication of levodopa therapy for Parkinson's disease for which there is little treatment. Accumulating evidence shows that nicotinic acetylcholine receptor (nAChR) drugs decrease LIDs in parkinsonian animals. Here, we examined the effect of two beta2 nAChR agonists, ABT-089 and ABT-894, that previously were approved for phase 2 clinical trials for other indications. Two sets of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys were administered levodopa/carbidopa (10 mg/kg and 2.5 mg/kg, respectively) twice daily 5 days a week until they were stably dyskinetic. Each set had a vehicle-treated group, an nAChR agonist-treated group, and a nicotine-treated group as a positive control. Set A monkeys had previously received other nAChR drugs (nAChR drug-primed), whereas Set B monkeys were initially nAChR drug-naive. Both sets were administered the partial agonist ABT-089 (range, 0.01-1.0 mg/kg) orally 5 days a week twice daily 30 minutes before levodopa with each dose given for 1 to 5 weeks. ABT-089 decreased LIDs by 30% to 50% compared with vehicle-treated monkeys. Nicotine reduced LIDs by 70% in a parallel group. After 4 weeks of washout, the effect of the full agonist ABT-894 (range, 0.0001-0.10 mg/kg) was assessed on LIDs in Set A and Set B. ABT-894 reduced LIDs by 70%, similar to nicotine. Both drugs acted equally well at alpha4beta2* and alpha6beta2* nAChRs; however, ABT-089 was 30 to 60 times less potent than ABT-894. Tolerance did not develop for the time periods tested (range, 3-4 months). The nAChR drugs did not worsen parkinsonism or cognitive ability. Emesis, a common problem with nAChR drugs, was not observed. ABT-894 and ABT-089 appear to be good candidate nAChR drugs for the management of LIDs in Parkinson's disease. Title: The protective effects of Donepezil (DP) against cartilage matrix destruction induced by TNF-alpha Zhang D, Zhou Y Ref: Biochemical & Biophysical Research Communications, 454:115, 2014 : PubMed ESTHER: Zhang_2014_Biochem.Biophys.Res.Commun_454_115 PubMedSearch: Zhang 2014 Biochem.Biophys.Res.Commun 454 115 PubMedID: 25450366 Abstract The extracellular matrix apparatuses containing collagen and proteoglycan (aggrecan) are important factors for maintaining the integrity of cartilage. Collagen type II, the main component of total cartilage, is mainly degraded by matrix metalloproteinase13 (MMP-13), which is an important molecule responsible for joint damage in Osteoarthritis (OA). Donepezil (DP), a potent and selective acetylcholinesterase inhibitor, is a medication approved by the US Food and Drug Administration and used in the alleviation of dementia in Alzheimer's disease (AD). In this study, we found that DP treatment prevented the degradation of collagen type II induced by TNF-alpha. Mechanistically, DP treatment leads to the inhibition of the transcriptional activity of interferon response factor-1 (IRF-1), thereby prevents the induction of MMP-13. These findings suggest the potential therapeutic effects of DP in OA. Title: The alpha7 nicotinic receptor agonist ABT-107 decreases L-Dopa-induced dyskinesias in parkinsonian monkeys Zhang D, McGregor M, Decker MW, Quik M Ref: Journal of Pharmacology & Experimental Therapeutics, 351:25, 2014 : PubMed ESTHER: Zhang_2014_J.Pharmacol.Exp.Ther_351_25 PubMedSearch: Zhang 2014 J.Pharmacol.Exp.Ther 351 25 PubMedID: 25034405 Abstract Previous studies in Parkinsonian rats and monkeys have shown that beta2-selective nicotinic acetylcholine receptor (nAChR) agonists reduce l-Dopa-induced dyskinesias (LIDs), a serious complication of l-Dopa therapy for Parkinson's disease. Since rodent studies also suggested an involvement of alpha7 nAChRs in LIDs, we tested the effect of the potent, selective alpha7 agonist ABT-107 [5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole]. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned monkeys were gavaged with l-Dopa/carbidopa (10 and 2.5 mg/kg, respectively) twice daily, which resulted in stable LIDs. A dose-response study (0.03-1.0 mg/kg) showed that oral ABT-107 decreased LIDs by 40-60%. LIDs returned to control levels only after a 6-week ABT-107 washout, suggesting that long-term molecular changes were involved. Subsequent readministration of ABT-107 decreased LIDs by 50-60%, indicating that tolerance did not develop. ABT-107 had no effect on Parkinsonism or cognitive performance. We next tested ABT-107 together with the beta2 agonist ABT-894 [(3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane], previously shown to reduce LIDs in Parkinsonian monkeys. In one study, the monkeys were first given oral ABT-894 (0.01 mg/kg), which maximally decreased LIDs by 50-60%; they were then also treated with 0.1 mg/kg ABT-107, a dose that maximally reduced LIDs. The effect of combined treatment on LIDs was similar to that with either drug alone. Comparable results were observed in a group of monkeys first treated with ABT-107 and then also given ABT-894. Thus, alpha7 and beta2 nAChR-selective drugs may function via a final common mechanism to reduce LIDs. The present results suggest that drugs targeting either alpha7 or beta2 nAChRs may be useful as antidyskinetic agents in Parkinson's disease. Title: Genome sequence of Anopheles sinensis provides insight into genetics basis of mosquito competence for malaria parasites Zhou D, Zhang D, Ding G, Shi L, Hou Q, Ye Y, Xu Y, Zhou H, Xiong C and Zhu C <12 more author(s)> Zhou D, Zhang D, Ding G, Shi L, Hou Q, Ye Y, Xu Y, Zhou H, Xiong C, Li S, Yu J, Hong S, Yu X, Zou P, Chen C, Chang X, Wang W, Lv Y, Sun Y, Ma L, Shen B, Zhu C (- 12) Ref: BMC Genomics, 15:42, 2014 : PubMed ESTHER: Zhou_2014_BMC.Genomics_15_42 PubMedSearch: Zhou 2014 BMC.Genomics 15 42 PubMedID: 24438588 Gene_locus related to this paper: anoga-Q7PVF9, 9dipt-a0a084vlt1, 9dipt-a0a084vdq2, 9dipt-sime3xf.a, 9dipt-sime3xf.b, 9dipt-a0a084vbj8, 9dipt-a0a084wan7, 9dipt-a0a084wik4, 9dipt-a0a084wk64, 9dipt-a0a084wez8, 9dipt-a0a084vji7, 9dipt-a0a084vlc2, 9dipt-a0a084vsa5, 9dipt-a0a084wlk0, 9dipt-a0a084wah8, 9dipt-a0a084wln4, 9dipt-a0a084we78, 9dipt-a0a084wjm6, 9dipt-a0a084wjm7, 9dipt-a0a084we77, 9dipt-a0a084wlk1, 9dipt-a0a084we80, 9dipt-a0a084wjm4, 9dipt-a0a084w1n7, 9dipt-a0a084we79, 9dipt-a0a084wev9, 9dipt-a0a084vlc3, 9dipt-a0a084vdq4, 9dipt-a0a084vdq5, 9dipt-a0a084vdq1, 9dipt-a0a084wah9, 9dipt-a0a084wan6, 9dipt-a0a084wlj8, 9dipt-a0a084wk45, 9dipt-a0a084wk46, 9dipt-a0a084wlj9, 9dipt-a0a084vsa4, 9dipt-a0a084vs93, 9dipt-a0a084wl93, anosi-a0a0f7kyf5, anosi-a0a0f7l1f2, anosi-a0a084wum0, anost-a0a182xxz0, anosi-a0a084vn28, anosi-a0a084vpt0, anoga-q7q887 Abstract BACKGROUND: Anopheles sinensis is an important mosquito vector of Plasmodium vivax, which is the most frequent and widely distributed cause of recurring malaria throughout Asia, and particularly in China, Korea, and Japan. Title: Microfluidic one-step synthesis of alginate microspheres immobilized with antibodies Chen W, Kim JH, Zhang D, Lee KH, Cangelosi GA, Soelberg SD, Furlong CE, Chung JH, Shen AQ Ref: J R Soc Interface, 10:20130566, 2013 : PubMed ESTHER: Chen_2013_J.R.Soc.Interface_10_20130566 PubMedSearch: Chen 2013 J.R.Soc.Interface 10 20130566 PubMedID: 23966617 Abstract Micrometre- and submicrometre-size functionalized beads are frequently used to capture targets of interest from a biological sample for biological characterizations and disease diagnosis. The main challenge of the microbead-based assay is in the immobilization of probe molecules onto the microbead surfaces. In this paper, we report a versatile droplet microfluidics method to fabricate alginate microspheres while simultaneously immobilizing anti-Mycobacterium tuberculosis complex IgY and anti-Escherichia coli IgG antibodies primarily on the porous alginate carriers for specific binding and binding affinity tests. The binding affinity of antibodies is directly measured by fluorescence intensity of stained target bacteria on the microspheres. We demonstrate that the functionalized alginate microspheres yield specificity comparable with an enzyme-linked immunosorbent assay. The high surface area-to-volume ratio of the functionalized porous alginate microspheres improves the detection limit. By using the droplet microfluidics, we can easily modify the size and shape of alginate microspheres, and increase the concentration of functionalized alginate microspheres to further enhance binding kinetics and enable multiplexing. Title: Dp44mT targets the AKT, TGF-beta and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells Dixon KM, Lui GY, Kovacevic Z, Zhang D, Yao M, Chen Z, Dong Q, Assinder SJ, Richardson DR Ref: Br J Cancer, 108:409, 2013 : PubMed ESTHER: Dixon_2013_Br.J.Cancer_108_409 PubMedSearch: Dixon 2013 Br.J.Cancer 108 409 PubMedID: 23287991 Abstract BACKGROUND: Effective treatment of prostate cancer should be based on targeting interactions between tumour cell signalling pathways and key converging downstream effectors. Here, we determined how the tumourigenic phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), tumour-suppressive phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and transforming growth factor-beta (TGF-beta) pathways are integrated via the metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1). Moreover, we assessed how the novel anti-tumour agent, Dp44mT, may target these integrated pathways by increasing NDRG1 expression. Title: Nicotine reduces established levodopa-induced dyskinesias in a monkey model of Parkinson's disease Quik M, Mallela A, Ly J, Zhang D Ref: Movement Disorders, 28:1398, 2013 : PubMed ESTHER: Quik_2013_Mov.Disord_28_1398 PubMedSearch: Quik 2013 Mov.Disord 28 1398 PubMedID: 23836409 Abstract Although 3,4-dihydroxyphenylalanine (levodopa) is the gold-standard treatment for Parkinson's disease, it can lead to disabling dyskinesias. Previous work demonstrated that nicotine reduces levodopa-induced dyskinesias (LIDs) in several parkinsonian animal models. The goal of this study was to determine whether the duration of nicotine administration affects its ability to reduce LIDs in levodopa-primed and levadopa-naive monkeys and also to test whether tolerance develops to the beneficial effects of nicotine. Monkeys were injected with MPTP (1.9-2.0 mg/kg subcutaneously) over 3 to 5 months until parkinsonism developed. Nicotine (300 mug/mL) was administered in drinking water (over 4-6 months) to levodopa-primed or levodopa-naive monkeys, with levodopa/carbidopa (10/2.5 mg/kg) gavaged twice daily. One set of MPTP-lesioned monkeys (n = 23) was first gavaged with levodopa and subsequently received nicotine 4 weeks later, when dyskinesias plateaued, or 8 weeks later, when dyskinesias were established. A 60% to 70% decrease in LIDs was observed after several weeks of nicotine treatment in both groups. A second set of monkeys (n = 26) received nicotine 8 or 2 weeks before levodopa. In the 8-week nicotine pretreatment group, there was an immediate reduction in LIDs, which plateaued at 60% to 70%. In the 2-week nicotine pretreatment group, there were initial small decreases in LIDs, which plateaued at 60% to 70% several weeks later. Thus, nicotine pretreatment and nicotine post-treatment were similarly efficacious in reducing LIDs. The beneficial effect of nicotine persisted throughout the study (17-23 weeks). Nicotine did not worsen parkinsonism. These data suggest that nicotine treatment has potential as a successful antidyskinetic therapy for patients with Parkinson's disease. (c) 2013 International Parkinson and Movement Disorder Society. Title: Targeting the Metastasis Suppressor, NDRG1, Using Novel Iron Chelators: Regulation of Stress Fiber-Mediated Tumor Cell Migration via Modulation of the ROCK1/pMLC2 Signaling Pathway Sun J, Zhang D, Zheng Y, Zhao Q, Zheng M, Kovacevic Z, Richardson DR Ref: Molecular Pharmacology, 83:454, 2013 : PubMed ESTHER: Sun_2013_Mol.Pharmacol_83_454 PubMedSearch: Sun 2013 Mol.Pharmacol 83 454 PubMedID: 23188716 Abstract The iron-regulated metastasis suppressor, N-myc downstream-regulated gene 1 (NDRG1), is up-regulated by cellular iron depletion mediated by iron chelators and can inhibit cancer cell migration. However, the mechanism of how NDRG1 achieves this effect remains unclear. In this study, we implemented established and newly constructed NDRG1 overexpression and knockdown models using the DU145, HT29, and HCT116 cancer cell lines to investigate the molecular basis by which NDRG1 exerts its inhibitory effect on cell migration. Using these models, we demonstrated that NDRG1 overexpression inhibits cell migration by preventing actin-filament polymerization, stress fiber assembly and formation. In contrast, NDRG1 knockdown had the opposite effect. Moreover, we identified that NDRG1 inhibited an important regulatory pathway mediated by the Rho-associated, coiled-coil containing protein kinase 1 (ROCK1)/phosphorylated myosin light chain 2 (pMLC2) pathway that modulates stress fiber assembly. The phosphorylation of MLC2 is a key process in inducing stress fiber contraction, and this was shown to be markedly decreased or increased by NDRG1 overexpression or knockdown, respectively. The mechanism involved in the inhibition of MLC2 phosphorylation by NDRG1 was mediated by a significant (P < 0.001) decrease in ROCK1 expression that is a key kinase involved in MLC2 phosphorylation. Considering that NDRG1 is up-regulated after cellular iron depletion, novel thiosemicarbazone iron chelators (e.g., di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone) were demonstrated to inhibit ROCK1/pMLC2-modulated actin-filament polymerization, stress fiber assembly, and formation via a mechanism involving NDRG1. These results highlight the role of the ROCK1/pMLC2 pathway in the NDRG1-mediated antimetastatic signaling network and the therapeutic potential of iron chelators at inhibiting metastasis. Title: Nicotinic Receptor Agonists Reduce L-DOPA-Induced Dyskinesias in a Monkey Model of Parkinson's Disease Zhang D, Mallela A, Sohn D, Carroll FI, Bencherif M, Letchworth SR, Quik M Ref: Journal of Pharmacology & Experimental Therapeutics, 347:225, 2013 : PubMed ESTHER: Zhang_2013_J.Pharmacol.Exp.Ther_347_225 PubMedSearch: Zhang 2013 J.Pharmacol.Exp.Ther 347 225 PubMedID: 23902940 Abstract Abnormal involuntary movements or dyskinesias are a serious complication of long-term l-DOPA treatment of Parkinson's disease, for which there are few treatment options. Accumulating preclinical data show that nicotine decreases l-DOPA-induced dyskinesias (LIDs), suggesting that it may be a useful antidyskinetic therapy for Parkinson's disease. Here, we investigated whether nicotinic acetylcholine receptor (nAChR) agonists reduced LIDs in nonhuman primates. We first tested the nonselective nAChR agonist 1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (varenicline), which offers the advantage that it is approved by the U.S. Food and Drug Administration for use in humans. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys (n = 23) were first administered l-DOPA/carbidopa (10/2.5 mg/kg) twice daily 5 days/week until stably dyskinetic. Oral varenicline (0.03-0.10 mg/kg) decreased LIDs approximately 50% compared with vehicle-treated monkeys, whereas nicotine treatment (300 microg/ml in drinking water) reduced LIDs by 70% in a parallel group of animals. We next tested the selective alpha4beta2*/alpha6beta2* nAChR agonist TC-8831 [3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane] on LIDs in the same set of monkeys after a 10-week washout. We also tested TC-8831 in another set of MPTP-lesioned monkeys (n = 16) that were nAChR drug-naive. Oral TC-8831 (0.03-0.3 mg/kg) reduced LIDs in both sets by 30-50%. After a washout period, repeat TC-8831 dosing led to a greater decline in LIDs (60%) in both sets of monkeys that was similar to the effect of nicotine. Tolerance to any nAChR drug did not develop over the course of the study (3-4 months). NAChR drug treatment did not worsen parkinsonism or cognitive ability. These data suggest that nAChR agonists may be useful for the management of dyskinesias in l-DOPA-treated Parkinson's disease patients. Title: The evolution and pathogenic mechanisms of the rice sheath blight pathogen Zheng A, Lin R, Zhang D, Qin P, Xu L, Ai P, Ding L, Wang Y, Chen Y and Li P <15 more author(s)> Zheng A, Lin R, Zhang D, Qin P, Xu L, Ai P, Ding L, Wang Y, Chen Y, Liu Y, Sun Z, Feng H, Liang X, Fu R, Tang C, Li Q, Zhang J, Xie Z, Deng Q, Li S, Wang S, Zhu J, Wang L, Liu H, Li P (- 15) Ref: Nat Commun, 4:1424, 2013 : PubMed ESTHER: Zheng_2013_Nat.Commun_4_1424 PubMedSearch: Zheng 2013 Nat.Commun 4 1424 PubMedID: 23361014 Gene_locus related to this paper: thaca-l8wv47, thaca-l8wp17, thaca-l8x532 Abstract Rhizoctonia solani is a major fungal pathogen of rice (Oryza sativa L.) that causes great yield losses in all rice-growing regions of the world. Here we report the draft genome sequence of the rice sheath blight disease pathogen, R. solani AG1 IA, assembled using next-generation Illumina Genome Analyser sequencing technologies. The genome encodes a large and diverse set of secreted proteins, enzymes of primary and secondary metabolism, carbohydrate-active enzymes, and transporters, which probably reflect an exclusive necrotrophic lifestyle. We find few repetitive elements, a closer relationship to Agaricomycotina among Basidiomycetes, and expand protein domains and families. Among the 25 candidate pathogen effectors identified according to their functionality and evolution, we validate 3 that trigger crop defence responses; hence we reveal the exclusive expression patterns of the pathogenic determinants during host infection. Title: Chromogenic platform based on recombinant Drosophila melanogaster acetylcholinesterase for visible unidirectional assay of organophosphate and carbamate insecticide residues Han Z, Chi C, Bai B, Liu G, Rao Q, Peng S, Liu H, Zhao Z, Zhang D, Wu A Ref: Anal Chim Acta, 720:126, 2012 : PubMed ESTHER: Han_2012_Anal.Chim.Acta_720_126 PubMedSearch: Han 2012 Anal.Chim.Acta 720 126 PubMedID: 22365130 Abstract In this study we propose a chromogenic platform for rapid analysis of organophosphate (OP) and carbamate (CM) insecticide residues, based on recombinant Drosophila melanogaster acetylcholinesterase (R-DmAChE) as enzyme and indoxyl acetate as substrate. The visible chromogenic strip had the advantages identical to those of commonly used lateral flow assays (LFAs) with utmost simplicity in sample loading and result observation. After optimization, depending on the color intensity (CI) values, the well-established assay has the capabilities of both qualitative measurement via naked eyes and quantitative analysis by colorimetric reader with the desirable IC(50) values against the tested six insecticides (0.06 mug mL(-1) of carbofuran, 0.28 mug mL(-1) of methomyl, 0.03 mug mL(-1) of dichlorvos, 31.6 mug mL(-1) of methamidophos, 2.0 mug mL(-1) of monocrotophos, 6.3 mug mL(-1) of omethoate). Acceptable matrix effects and satisfactory detection performance were confirmed by in-parallel LC-MS/MS analysis in different vegetable varieties at various spiked levels of 10(-3) to 10(1) mug g(-1). Overall, the testified suitability and applicability of this novel platform meet the requirements for practical use in food safety management and environmental monitoring, especially in the developing world. 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: Repeated polyploidization of Gossypium genomes and the evolution of spinnable cotton fibres Paterson AH, Wendel JF, Gundlach H, Guo H, Jenkins J, Jin D, Llewellyn D, Showmaker KC, Shu S and Schmutz J <64 more author(s)> Paterson AH, Wendel JF, Gundlach H, Guo H, Jenkins J, Jin D, Llewellyn D, Showmaker KC, Shu S, Udall J, Yoo MJ, Byers R, Chen W, Doron-Faigenboim A, Duke MV, Gong L, Grimwood J, Grover C, Grupp K, Hu G, Lee TH, Li J, Lin L, Liu T, Marler BS, Page JT, Roberts AW, Romanel E, Sanders WS, Szadkowski E, Tan X, Tang H, Xu C, Wang J, Wang Z, Zhang D, Zhang L, Ashrafi H, Bedon F, Bowers JE, Brubaker CL, Chee PW, Das S, Gingle AR, Haigler CH, Harker D, Hoffmann LV, Hovav R, Jones DC, Lemke C, Mansoor S, ur Rahman M, Rainville LN, Rambani A, Reddy UK, Rong JK, Saranga Y, Scheffler BE, Scheffler JA, Stelly DM, Triplett BA, Van Deynze A, Vaslin MF, Waghmare VN, Walford SA, Wright RJ, Zaki EA, Zhang T, Dennis ES, Mayer KF, Peterson DG, Rokhsar DS, Wang X, Schmutz J (- 64) Ref: Nature, 492:423, 2012 : PubMed ESTHER: Paterson_2012_Nature_492_423 PubMedSearch: Paterson 2012 Nature 492 423 PubMedID: 23257886 Gene_locus related to this paper: gosra-a0a0d2qg22, gosra-a0a0d2w3z1, gosra-a0a0d2uuz7, gosra-a0a0d2rxs2, gosra-a0a0d2sdk0, gosra-a0a0d2tng2, gosra-a0a0d2twz7, gosra-a0a0d2vdc5, gosra-a0a0d2vj24, gosra-a0a0d2sr31, goshi-a0a1u8knd1, goshi-a0a1u8nhw9, goshi-a0a1u8kis4, gosra-a0a0d2pul0, gosra-a0a0d2p3f2, gosra-a0a0d2ril5, gosra-a0a0d2s7d5, gosra-a0a0d2t9b3, gosra-a0a0d2tw88, gosra-a0a0d2umz5, gosra-a0a0d2pzd7 Abstract Polyploidy often confers emergent properties, such as the higher fibre productivity and quality of tetraploid cottons than diploid cottons bred for the same environments. Here we show that an abrupt five- to sixfold ploidy increase approximately 60 million years (Myr) ago, and allopolyploidy reuniting divergent Gossypium genomes approximately 1-2 Myr ago, conferred about 30-36-fold duplication of ancestral angiosperm (flowering plant) genes in elite cottons (Gossypium hirsutum and Gossypium barbadense), genetic complexity equalled only by Brassica among sequenced angiosperms. Nascent fibre evolution, before allopolyploidy, is elucidated by comparison of spinnable-fibred Gossypium herbaceum A and non-spinnable Gossypium longicalyx F genomes to one another and the outgroup D genome of non-spinnable Gossypium raimondii. The sequence of a G. hirsutum A(t)D(t) (in which 't' indicates tetraploid) cultivar reveals many non-reciprocal DNA exchanges between subgenomes that may have contributed to phenotypic innovation and/or other emergent properties such as ecological adaptation by polyploids. Most DNA-level novelty in G. hirsutum recombines alleles from the D-genome progenitor native to its New World habitat and the Old World A-genome progenitor in which spinnable fibre evolved. Coordinated expression changes in proximal groups of functionally distinct genes, including a nuclear mitochondrial DNA block, may account for clusters of cotton-fibre quantitative trait loci affecting diverse traits. Opportunities abound for dissecting emergent properties of other polyploids, particularly angiosperms, by comparison to diploid progenitors and outgroups. Title: [Elementary research of constructive feature and three-dimensional reconstruction of nerve bundles of C7 anterior and posterior division end] Qin B, Gu L, Xiang J, Fu G, Qi J, Wang H, Zhang D, Zheng J, Liu X, Zhu J Ref: Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi, 26:97, 2012 : PubMed ESTHER: Qin_2012_Zhongguo.Xiu.Fu.Chong.Jian.Wai.Ke.Za.Zhi_26_97 PubMedSearch: Qin 2012 Zhongguo.Xiu.Fu.Chong.Jian.Wai.Ke.Za.Zhi 26 97 PubMedID: 22332529 Abstract OBJECTIVE: To observe the distribution feature of nerve bundles in C7 nerve anterior and posterior division end. METHODS: The brachial plexus specimen was harvested from 1 fresh adult cadaver. After C7 nerve was confirmed, the distal end of anterior and posterior division was dissected and embedded by OCT. Then the samples were serially horizontally sliced with each 10 microm deep. After acetylcholinesterase (AChE) histochemical staining, the stain characteristics of different nerve fiber bundles were observed and amount of the nerve fiber bundles were counted under optic-microscope. At last, the imaging which were collected were three-dimensional (3-D) reconstructed by using Amira 4.1 software. RESULTS: There was no obvious difference in the stain between the anterior and posterior divisions. The running of the nerve fiber bundles were dispersive from proximal end of nerve to distal end of nerve. Nerve fiber bundles of anterior division were mainly sensor nerve fiber bundles, which located in medial side. Nerve fiber bundles of posterior division were mainly moter nerve fiber bundles, having no regularity in the distribution of nerve fiber bundles. The total number of nerve fiber bundles in distal end of anterior division was 7.85 +/- 1.04, the number of motor nerve fiber bundles was 2.85 +/- 0.36, and the number of sensor nerve fiber bundles was 5.13 +/- 1.01. The total number of nerve fiber bundles in distal end of posterior division was 9.79 +/- 1.53, the number of motor nerve fiber bundles was 6.00 +/- 0.69, and the number of sensor nerve fiber bundles was 3.78 +/- 0.94. There were significant differences in the numbers of motor and sensor nerve fiber bundles between anterior and posterior divisions (P < 0.05). The microstructure 3-D model was reconstructed based on serial slice through Amira 4.1. The intercross and recombination process of nerves bundles could be observed obviously. The nerve bundle distribution showed cross and combination. CONCLUSION: Nerve fiber bundles of anterior division are mainly sensor nerve fiber bundles and locate in medial side. Nerve fiber bundles of posterior division are mainly motor nerve fiber bundles, which has no regularity in the distribution of nerve fiber bundles. The 3-D reconstruction can display the internal structure feature of the C7 division end. 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: A new continuous fluorometric assay for acetylcholinesterase activity and inhibitor screening with emissive core-shell silica particles containing tetraphenylethylene fluorophore Shen X, Liang F, Zhang G, Zhang D Ref: Analyst, 137:2119, 2012 : PubMed ESTHER: Shen_2012_Analyst_137_2119 PubMedSearch: Shen 2012 Analyst 137 2119 PubMedID: 22430667 Abstract Emissive core-shell silica particles with tetraphenylethylene moieties were prepared and characterized. Fluorescence quenching was observed for the silica particles upon addition of compound 2 (Dabcyl-ACh). This was attributed to the electrostatic interaction between the silica particles and 2 and the resulting photoinduced energy transfer between them. After incubation with AChE, the fluorescence intensity started to increase. The fluorescence enhancement became more significant when the concentration of AChE was higher. The reaction kinetic parameters for AChE were successfully estimated with the silica particles and 2. These results reveal that the ensemble of the silica particles and 2 can be utilized for AChE assay. Moreover, the fluorescence spectra of the ensemble of the silica particles and 2 containing AChE were also measured after further addition of either neostigmine or tacrine which are typical inhibitors of AChE. The results manifest that the ensemble of the emissive silica particles and 2 is also useful for screening the inhibitors of AChE. Title: Impact of prefrontal cortex in nicotine-induced excitation of ventral tegmental area dopamine neurons in anesthetized rats Zhang D, Gao M, Xu D, Shi WX, Gutkin BS, Steffensen SC, Lukas RJ, Wu J Ref: Journal of Neuroscience, 32:12366, 2012 : PubMed ESTHER: Zhang_2012_J.Neurosci_32_12366 PubMedSearch: Zhang 2012 J.Neurosci 32 12366 PubMedID: 22956827 Abstract Systemic administration of nicotine increases dopaminergic (DA) neuron firing in the ventral tegmental area (VTA), which is thought to underlie nicotine reward. Here, we report that the medial prefrontal cortex (mPFC) plays a critical role in nicotine-induced excitation of VTA DA neurons. In chloral hydrate-anesthetized rats, extracellular single-unit recordings showed that VTA DA neurons exhibited two types of firing responses to systemic nicotine. After nicotine injection, the neurons with type-I response showed a biphasic early inhibition and later excitation, whereas the neurons with type-II response showed a monophasic excitation. The neurons with type-I, but not type-II, response exhibited pronounced slow oscillations (SOs) in firing. Pharmacological or structural mPFC inactivation abolished SOs and prevented systemic nicotine-induced excitation in the neurons with type-I, but not type-II, response, suggesting that these VTA DA neurons are functionally coupled to the mPFC and nicotine increases firing rate in these neurons in part through the mPFC. Systemic nicotine also increased the firing rate and SOs in mPFC pyramidal neurons. mPFC infusion of a non-alpha7 nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine blocked the excitatory effect of systemic nicotine on the VTA DA neurons with type-I response, but mPFC infusion of nicotine failed to excite these neurons. These results suggest that nAChR activation in the mPFC is necessary, but not sufficient, for systemic nicotine-induced excitation of VTA neurons. Finally, systemic injection of bicuculline prevented nicotine-induced firing alterations in the neurons with type-I response. We propose that the mPFC plays a critical role in systemic nicotine-induced excitation of VTA DA neurons. Title: A naked-eye visible and fluorescence turn-on probe for acetyl-cholinesterase assay and thiols as well as imaging of living cells Cui K, Chen Z, Wang Z, Zhang G, Zhang D Ref: Analyst, 136:191, 2011 : PubMed ESTHER: Cui_2011_Analyst_136_191 PubMedSearch: Cui 2011 Analyst 136 191 PubMedID: 20927440 Abstract A resorufin derivative with a DBS group (probe 1) was designed and investigated for the detection of acetylcholinesterase (AChE) and inhibitor screening. The new assay is based on cascade enzymatic and chemical reactions of ATC, AChE and probe 1, and it can be carried out in a dual-signal detection mode. Moreover, the results show that probe 1 can be used for cell fluorescence staining. Title: A novel NADH-dependent and FAD-containing hydroxylase is crucial for nicotine degradation by Pseudomonas putida Tang H, Yao Y, Zhang D, Meng X, Wang L, Yu H, Ma L, Xu P Ref: Journal of Biological Chemistry, 286:39179, 2011 : PubMed ESTHER: Tang_2011_J.Biol.Chem_286_39179 PubMedSearch: Tang 2011 J.Biol.Chem 286 39179 PubMedID: 21949128 Gene_locus related to this paper: psep6-f8g0m2 Abstract Nicotine, the main alkaloid produced by Nicotiana tabacum and other Solanaceae, is very toxic and may be a leading toxicant causing preventable disease and death, with the rise in global tobacco consumption. Several different microbial pathways of nicotine metabolism have been reported: Arthrobacter uses the pyridine pathway, and Pseudomonas, like mammals, uses the pyrrolidine pathway. We identified and characterized a novel 6-hydroxy-3-succinoyl-pyridine (HSP) hydroxylase (HspB) using enzyme purification, peptide sequencing, and sequencing of the Pseudomonas putida S16 genome. The HSP hydroxylase has no known orthologs and converts HSP to 2,5-dihydroxy-pyridine and succinic semialdehyde, using NADH. (18)O(2) labeling experiments provided direct evidence for the incorporation of oxygen from O(2) into 2,5-dihydroxy-pyridine. The hspB gene deletion showed that this enzyme is essential for nicotine degradation, and site-directed mutagenesis identified an FAD-binding domain. This study demonstrates the importance of the newly discovered enzyme HspB, which is crucial for nicotine degradation by the Pseudomonas strain. Title: Disposable screen-printed electrode coupled with recombinant Drosophila melanogaster acetylcholinesterase and multiwalled carbon nanotubes for rapid detection of pesticides Tang Z, Chen H, Song S, Fan C, Zhang D, Wu A Ref: Journal of AOAC International, 94:307, 2011 : PubMed ESTHER: Tang_2011_J.AOAC.Int_94_307 PubMedSearch: Tang 2011 J.AOAC.Int 94 307 PubMedID: 21391508 Abstract Recombinant Drosophila melanogaster acetylcholinesterase (R-DmAChE), multiwalled carbon nanotubes (MWCNTs), and Prussian blue have been combined for development of a three-electrode biosensor with more rapid responses and higher stability than in our previous study. A new disposable screen-printed electrode (SPE) was developed for rapid detection of organophosphate and carbamate pesticides. After optimization, 10 microg MWCNT and 5 microL enzyme immobilization solution consisting of 0.2% glutaraldehyde, 0.1% Nafion, 0.2% bovine serum albumin, 0.1 g/L MWCNT, and 1.5 mU R-DmAChE were fixed on each of the R-DmAChE/MWCNT SPEs. The LOD of this biosensor was 0.5 microg/L for pesticide standards of dichlorvos (DDV) and carbofuran. The performance of this biosensor was tested for vegetable and water samples at various spiked levels, and good stability and sensitivity were found. The obtained recoveries were from 82.6 to 110.5% for DDV at levels of 0.5-5 microg/L and 73.4 to 118.4% for carbofuran at 1-10 microg/L in lake and sea water samples, demonstrating that the proposed approach is an alternative means for rapid detection of pesticide residues and contaminants in food safety and environmental monitoring. Title: Comparative analysis of inactivated-state block of N-type (Ca(v)2.2) calcium channels Vortherms TA, Swensen AM, Niforatos W, Limberis JT, Neelands TR, Janis RS, Thimmapaya R, Donnelly-Roberts D, Namovic MT and Scott VE <5 more author(s)> Vortherms TA, Swensen AM, Niforatos W, Limberis JT, Neelands TR, Janis RS, Thimmapaya R, Donnelly-Roberts D, Namovic MT, Zhang D, Brent Putman C, Martin RL, Surowy CS, Jarvis MF, Scott VE (- 5) Ref: Inflamm Res, 60:683, 2011 : PubMed ESTHER: Vortherms_2011_Inflamm.Res_60_683 PubMedSearch: Vortherms 2011 Inflamm.Res 60 683 PubMedID: 21394563 Abstract OBJECTIVE: The aim of this study was to compare a diverse set of peptide and small-molecule calcium channel blockers for inactivated-state block of native and recombinant N-type calcium channels using fluorescence-based and automated patch-clamp electrophysiology assays. Title: Crystal structure of a novel esterase Rv0045c from Mycobacterium tuberculosis Zheng X, Guo J, Xu L, Li H, Zhang D, Zhang K, Sun F, Wen T, Liu S, Pang H Ref: PLoS ONE, 6:e20506, 2011 : PubMed ESTHER: Zheng_2011_PLoS.ONE_6_e20506 PubMedSearch: Zheng 2011 PLoS.ONE 6 e20506 PubMedID: 21637775 Gene_locus related to this paper: myctu-RV0045C Abstract There are at least 250 enzymes in Mycobacterium tuberculosis (M. tuberculosis) involved in lipid metabolism. Some of the enzymes are required for bacterial survival and full virulence. The esterase Rv0045c shares little amino acid sequence similarity with other members of the esterase/lipase family. Here, we report the 3D structure of Rv0045c. Our studies demonstrated that Rv0045c is a novel member of alpha/beta hydrolase fold family. The structure of esterase Rv0045c contains two distinct domains: the alpha/beta fold domain and the cap domain. The active site of esterase Rv0045c is highly conserved and comprised of two residues: Ser154 and His309. We proposed that Rv0045c probably employs two kinds of enzymatic mechanisms when hydrolyzing C-O ester bonds within substrates. The structure provides insight into the hydrolysis mechanism of the C-O ester bond, and will be helpful in understanding the ester/lipid metabolism in M. tuberculosis. Title: Mechanisms involved in systemic nicotine-induced glutamatergic synaptic plasticity on dopamine neurons in the ventral tegmental area Gao M, Jin Y, Yang K, Zhang D, Lukas RJ, Wu J Ref: Journal of Neuroscience, 30:13814, 2010 : PubMed ESTHER: Gao_2010_J.Neurosci_30_13814 PubMedSearch: Gao 2010 J.Neurosci 30 13814 PubMedID: 20943922 Abstract Systemic exposure to nicotine induces glutamatergic synaptic plasticity on dopamine (DA) neurons in the ventral tegmental area (VTA), but mechanisms are largely unknown. Here, we report that single, systemic exposure in rats to nicotine (0.17 mg/kg free base) increases the ratio of DA neuronal currents mediated by AMPA relative to NMDA receptors (AMPA/NMDA ratio) assessed 24 h later, based on slice-patch recording. The AMPA/NMDA ratio increase is evident within 1 h and lasts for at least 72 h after nicotine exposure (and up to 8 d after repeated nicotine administration). This effect cannot be prevented by systemic injection of either alpha7-nAChR (nicotinic ACh receptor)-selective [methyllycaconitine (MLA)] or beta2*-nAChR-selective [mecamylamine (MEC)] antagonists but is prevented by coinjection of MLA and MEC. In either nAChR alpha7 or beta2 subunit knock-out mice, systemic exposure to nicotine still increases the AMPA/NMDA ratio. Preinjection in rats of a NMDA receptor antagonist MK-801((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate), but neither DA receptor antagonists [SCH-23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) plus haloperidol] nor a calcineurin inhibitor (cyclosporine), prevents the nicotine-induced increase in AMPA/NMDA ratio. After systemic exposure to nicotine, glutamatergic (but not GABAergic) transmission onto rat VTA DA neuronal inputs is enhanced. Correspondingly, DA neuronal firing measured 24 h after nicotine exposure using extracellular single-unit recording in vivo is significantly faster, and there is conversion of silent to active DA neurons. Collectively, these findings demonstrate that systemic nicotine acting via either alpha7- or beta2*-nAChRs increases presynaptic and postsynaptic glutamatergic function, and consequently initiates glutamatergic synaptic plasticity, which may be an important, early neuronal adaptation in nicotine reward and reinforcement. Title: Disruption of the Arabidopsis CGI-58 homologue produces Chanarin-Dorfman-like lipid droplet accumulation in plants James CN, Horn PJ, Case CR, Gidda SK, Zhang D, Mullen RT, Dyer JM, Anderson RG, Chapman KD Ref: Proc Natl Acad Sci U S A, 107:17833, 2010 : PubMed ESTHER: James_2010_Proc.Natl.Acad.Sci.U.S.A_107_17833 PubMedSearch: James 2010 Proc.Natl.Acad.Sci.U.S.A 107 17833 PubMedID: 20876112 Gene_locus related to this paper: arath-LPAAT Abstract CGI-58 is the defective gene in the human neutral lipid storage disease called Chanarin-Dorfman syndrome. This disorder causes intracellular lipid droplets to accumulate in nonadipose tissues, such as skin and blood cells. Here, disruption of the homologous CGI-58 gene in Arabidopsis thaliana resulted in the accumulation of neutral lipid droplets in mature leaves. Mass spectroscopy of isolated lipid droplets from cgi-58 loss-of-function mutants showed they contain triacylglycerols with common leaf-specific fatty acids. Leaves of mature cgi-58 plants exhibited a marked increase in absolute triacylglycerol levels, more than 10-fold higher than in wild-type plants. Lipid levels in the oil-storing seeds of cgi-58 loss-of-function plants were unchanged, and unlike mutations in beta-oxidation, the cgi-58 seeds germinated and grew normally, requiring no rescue with sucrose. We conclude that the participation of CGI-58 in neutral lipid homeostasis of nonfat-storing tissues is similar, although not identical, between plant and animal species. This unique insight may have implications for designing a new generation of technologies that enhance the neutral lipid content and composition of crop plants. Title: The sequence and de novo assembly of the giant panda genome Li R, Fan W, Tian G, Zhu H, He L, Cai J, Huang Q, Cai Q, Li B and Yang H <103 more author(s)> Li R, Fan W, Tian G, Zhu H, He L, Cai J, Huang Q, Cai Q, Li B, Bai Y, Zhang Z, Zhang Y, Wang W, Li J, Wei F, Li H, Jian M, Nielsen R, Li D, Gu W, Yang Z, Xuan Z, Ryder OA, Leung FC, Zhou Y, Cao J, Sun X, Fu Y, Fang X, Guo X, Wang B, Hou R, Shen F, Mu B, Ni P, Lin R, Qian W, Wang G, Yu C, Nie W, Wang J, Wu Z, Liang H, Min J, Wu Q, Cheng S, Ruan J, Wang M, Shi Z, Wen M, Liu B, Ren X, Zheng H, Dong D, Cook K, Shan G, Zhang H, Kosiol C, Xie X, Lu Z, Li Y, Steiner CC, Lam TT, Lin S, Zhang Q, Li G, Tian J, Gong T, Liu H, Zhang D, Fang L, Ye C, Zhang J, Hu W, Xu A, Ren Y, Zhang G, Bruford MW, Li Q, Ma L, Guo Y, An N, Hu Y, Zheng Y, Shi Y, Li Z, Liu Q, Chen Y, Zhao J, Qu N, Zhao S, Tian F, Wang X, Wang H, Xu L, Liu X, Vinar T, Wang Y, Lam TW, Yiu SM, Liu S, Huang Y, Yang G, Jiang Z, Qin N, Li L, Bolund L, Kristiansen K, Wong GK, Olson M, Zhang X, Li S, Yang H (- 103) Ref: Nature, 463:311, 2010 : PubMed ESTHER: Li_2010_Nature_463_311 PubMedSearch: Li 2010 Nature 463 311 PubMedID: 20010809 Gene_locus related to this paper: ailme-ABH15, ailme-ACHE, ailme-BCHE, ailme-d2gtv3, ailme-d2gty9, ailme-d2gu87, ailme-d2gu97, ailme-d2gve7, ailme-d2gwu1, ailme-d2gx08, ailme-d2gyt0, ailme-d2gz36, ailme-d2gz37, ailme-d2gz38, ailme-d2gz39, ailme-d2gz40, ailme-d2h5r9, ailme-d2h7b7, ailme-d2h9c9, ailme-d2h794, ailme-d2hau7, ailme-d2hau8, ailme-d2hcd9, ailme-d2hdi6, ailme-d2heu6, ailme-d2hga4, ailme-d2hqw5, ailme-d2hs98, ailme-d2hsx4, ailme-d2hti6, ailme-d2htv3, ailme-d2htz6, ailme-d2huc7, ailme-d2hwj8, ailme-d2hwy7, ailme-d2hxm1, ailme-d2hyc8, ailme-d2hyv2, ailme-d2hz11, ailme-d2hza3, ailme-d2hzr4, ailme-d2i1l4, ailme-d2i2g8, ailme-g1l7m3, ailme-g1lu36, ailme-g1m769, ailme-g1mc29, ailme-g1mdj8, ailme-g1mdr5, ailme-g1mfp4, ailme-g1mfx5, ailme-g1lj41, ailme-g1lm28, ailme-g1l3u1, ailme-g1l7l1, ailme-g1m5i3, ailme-g1l2f6, ailme-g1lji5, ailme-g1lqk3, ailme-g1l8s9, ailme-d2h717, ailme-d2h718, ailme-d2h719, ailme-d2h720, ailme-g1m5v0, ailme-g1m5y7, ailme-g1lkt7, ailme-g1l2a1, ailme-g1lsc8, ailme-g1lrp4, ailme-d2gv02, ailme-g1mik5, ailme-g1ljr1, ailme-g1lxw7, ailme-d2h8b5, ailme-d2h2r2, ailme-d2h9w7, ailme-g1meh3, ailme-g1m719 Abstract Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes. Title: Pharmacokinetics of lipoyl vildagliptin, a novel dipeptidyl peptidase IV inhibitor after oral administration in rats Wang X, Zhang D, Xu W, Liu H, Wang W Ref: Xenobiotica, 40:707, 2010 : PubMed ESTHER: Wang_2010_Xenobiotica_40_707 PubMedSearch: Wang 2010 Xenobiotica 40 707 PubMedID: 20735236 Abstract The pharmacokinetics of lipoyl vildagliptin, a novel dipeptidyl peptidase IV (DPP IV) inhibitor, was studied in rats after oral administration for developing it as an antidiabetic agent. A liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method was developed to determine lipoyl vildagliptin in rat plasma. After an overnight fasting, rats were orally given lipoyl vildagliptin. Following a single oral dose of 25, 50, and 100 mg x kg(-1), T(max) values were from 1.25 to 1.84 h, CL/F values were around 100 l h(-1) kg(-1). In the dose range, C(max) values (63.9-296 mug x l(-1)) and AUC(0-infinity)values (260-1214 mug x h x l(-1)) were proportional to the doses. In conclusion, this LC-MS/MS method for the determination of lipoyl vildagliptin in rat plasma was selective and sensitive. In rats, lipoyl vildagliptin displayed linear pharmacokinetics after a single oral dose in the range of 25-100 mg x kg(-1). Lipoyl vildagliptin might have very high CL/F values and V(d)/F values, which indicated that the bioavailability of this drug might be low or lipoyl vildagliptin might distribute extensively or accumulate in tissues in view of its high liposolubility. Title: DNA methylation of the promoter of soluble epoxide hydrolase silences its expression by an SP-1-dependent mechanism Zhang D, Ai D, Tanaka H, Hammock BD, Zhu Y Ref: Biochimica & Biophysica Acta, 1799:659, 2010 : PubMed ESTHER: Zhang_2010_Biochim.Biophys.Acta_1799_659 PubMedSearch: Zhang 2010 Biochim.Biophys.Acta 1799 659 PubMedID: 20888937 Abstract Epoxyeicosatrienoic acids, derived from arachidonic acid, function as antihypertensive and antihypertrophic mediators in the cardiovascular system. They are hydrolyzed by soluble epoxide hydrolase (sEH). Pharmacological inhibition of sEH increases the level of epoxyeicosatrienoic acids, which may have a cardiovascular protective effect. However, the regulation and function of sEH in cancer are largely unknown. The present study investigated whether DNA methylation regulates the expression of sEH in carcinoma HepG2 cells. The mRNA and protein expressions of sEH in HepG2 cells were lower than those in transformed human embryonic kidney cells and in primary cultured human endothelial cells. Bioinformatic analysis revealed a putative CpG island and 5 SP-1 binding sites located in the promoter region of the sEH gene. Furthermore, the sEH expression was significantly enhanced by demethylation treatment with 5-Aza-CdR, a DNA methyltransferase inhibitor, and the sEH promoter was transformed from hypermethylation to hypomethylation as detected by methylation-specific PCR and bisulfite sequencing. Transient transfection assays showed that the activity of the human sEH promoter was increased in HepG2 cells in response to 5-Aza-CdR. Five SP-1 binding sites in the promoter region responding to treatment with 5-Aza-CdR were identified by construct deletion and mutation analysis and chromatin immunoprecipitation assay. Interestingly, adenoviral overexpression of sEH in HepG2 cells decreased cell proliferation. Thus, SP-1 is involved in the decrease in the transcription of sEH as a result of DNA methylation in HepG2 cells, which might contribute to epigenetic mechanism-induced carcinogenesis in hepatocytes. Title: New cholesterol-based gelators with maleimide unit and the relevant Michael adducts: chemoresponsive organogels Chen Q, Zhang D, Zhang G, Zhu D Ref: Langmuir, 25:11436, 2009 : PubMed ESTHER: Chen_2009_Langmuir_25_11436 PubMedSearch: Chen 2009 Langmuir 25 11436 PubMedID: 19507817 Abstract Compound 1 containing cholesteryl and maleimide units can gel a few organic solvents such as cyclohexane. It is interesting to note that the gel-sol transition can be triggered by addition of trace amounts of thiol and triethylamine. In this regard, we successfully demonstrate the proof of principle for designing chemoresponsive gels by incorporating the reactive groups into the gelators. Additionally, the Michael adducts 2 and 3 were prepared. Compounds 2 and 3 can also gel several organic solvents. The results also show that slight molecular structural variation has a large effect on the gelation ability of the compound. These organogels were characterized with SEM, AFM, CD, and XRD. Interestingly, gelation-induced CD spectra were observed for gels of 1, 2, and 3. Title: A fluorescence turn-on ensemble for acetylcholinesterase activity assay and inhibitor screening Peng L, Zhang G, Zhang D, Xiang J, Zhao R, Wang Y, Zhu D Ref: Org Lett, 11:4014, 2009 : PubMed ESTHER: Peng_2009_Org.Lett_11_4014 PubMedSearch: Peng 2009 Org.Lett 11 4014 PubMedID: 19708709 Abstract By making use of the aggregation-induced emission feature of compound 1 and the cascade reactions among acetylthiocholine iodide (ATC), AChE, and compound 2, a new fluorescence "turn-on" method is developed for AChE assay and inhibitor-screening. Title: Continuous colorimetric assay for acetylcholinesterase and inhibitor screening with gold nanoparticles Wang M, Gu X, Zhang G, Zhang D, Zhu D Ref: Langmuir, 25:2504, 2009 : PubMed ESTHER: Wang_2009_Langmuir_25_2504 PubMedSearch: Wang 2009 Langmuir 25 2504 PubMedID: 19154124 Abstract We report herein a new colorimetric assay method for acetylcholinesterase (AChE) activity and its inhibitor screening by making use of the following facts: (1) the aggregation of gold nanoparticles (Au-NPs) results in the red-shift of the plasmon absorption due to interparticle plasmon interactions and (2) AChE can catalyze the hydrolysis of acetylthiocholine into thiocholine which can induce the aggregation of Au-NPs. With this convenient method, the activity of AChE with a concentration as low as 0.6 mU/mL can be assayed. Moreover, this assay method is also useful for screening inhibitors of AChE. Given its simplicity and easy-operation, this method may extend to high-throughput screening of AChE inhibitors and relevant drug discovery. Title: Convenient and continuous fluorometric assay method for acetylcholinesterase and inhibitor screening based on the aggregation-induced emission Wang M, Gu X, Zhang G, Zhang D, Zhu D Ref: Analytical Chemistry, 81:4444, 2009 : PubMed ESTHER: Wang_2009_Anal.Chem_81_4444 PubMedSearch: Wang 2009 Anal.Chem 81 4444 PubMedID: 19374428 Abstract A new convenient and continuous fluorometric assay method for acetylcholinesterase (AChE) and its inhibitor screening is successfully established with the ensemble of 1 [a TPE (tetraphenylethylene) compound with two sulfonate (-SO(3)(-)) units] and myristoylcholine (an amphiphilic compound as a good substrate of AChE). This new assay method is designed by making use of the aggregation-induced emission (AIE) feature of TPE compounds. Both dynamic light scattering (DLS) and fluorescence confocal microscopic measurements indicated the formation of aggregation complex for the ensemble of 1 and myristoylcholine and further disassembly of the aggregation complex after introducing AChE. The analysis for AChE can be carried out continuously, and AChE with concentration as low as 0.5 U/mL can be assayed. The results also clearly demonstrate the usefulness of this convenient assay method for kinetic study of AChE-catalyzed myristoylcholine hydrolysis and screening inhibitors of AChE. Given its simplicity and easy operation, this method may extend to high-throughput screening of AChE inhibitors and relevant Alzheimer's disease (AD) drug discovery. Title: Crystal structure of human esterase D: a potential genetic marker of retinoblastoma Wu D, Li Y, Song G, Zhang D, Shaw N, Liu ZJ Ref: FASEB Journal, 23:1441, 2009 : PubMed ESTHER: Wu_2009_Faseb.J_23_1441 PubMedSearch: Wu 2009 Faseb.J 23 1441 PubMedID: 19126594 Gene_locus related to this paper: human-ESD Abstract Retinoblastoma (RB), a carcinoma of the retina, is caused by mutations in the long arm of chromosome 13, band 13q14. The esterase D (ESD) gene maps at a similar location as the RB gene locus and therefore serves as a potential marker for the prognosis of retinoblastoma. Because very little is known about the structure and function of ESD, we determined the 3-dimensional structure of the enzyme at 1.5 A resolution using X-ray crystallography. ESD shows a single domain with an alpha/beta-hydrolase fold. A number of insertions are observed in the canonical alpha/beta-hydrolase fold. The active site is located in a positively charged, shallow cleft on the surface lined by a number of aromatic residues. Superimposition studies helped identify the typical catalytic triad residues--Ser-153, His264, and Asp230--involved in catalysis. Mutagenesis of any of the catalytic triad residues to alanine abolished the enzyme activity. Backbone amides of Leu54 and Met150 are involved in the formation of the oxyanion hole. Interestingly, a M150A mutation increased the enzyme activity by 62%. The structure of human ESD determined in this study will aid the elucidation of the physiological role of the enzyme in the human body and will assist in the early diagnosis of retinoblastoma. Title: Mechanisms of composition change and toxic potentiation of chloramidophos emulsifiable concentrate during storage Zhou S, Zhang D, Yang H, Zhang Y, Liu W Ref: Journal of Agricultural and Food Chemistry, 57:930, 2009 : PubMed ESTHER: Zhou_2009_J.Agric.Food.Chem_57_930 PubMedSearch: Zhou 2009 J.Agric.Food.Chem 57 930 PubMedID: 19132886 Abstract Storage instability is one of the serious problems that greatly restrict pesticide use. Routine checks on the composition and toxicity of 30% emulsifiable concentrates (EC) of chloramidophos (CP) during storage indicated that 78.6% of the active ingredient had decreased, whereas the anti-acetylcholinesterase (AChE) activity of the formulation was potentiated by 3.5 times. To understand the mechanism for these changes, detailed knowledge of the products present and their effects on anti-AChE potential deserves attention. It was likely that the basis for these changes was methanol, the cosolvent of CP EC, because when the purified CP was stored in methanol at 50 degrees C for 2 weeks, CP drop and toxic potentiation similar to those observed in CP EC also appeared. The major products of the CP-methanol reaction mixture were isolated and identified by HPLC and GC-MS, respectively, and their inhibitory potentials against AChE and effectiveness as potentiators were assessed. Following redetermination of the main product (O,S-dimethyl-[(2,2,2)-trichloro-1-methoxyethyl]phosphoramidothioate (MCP)) and high anti-AChE material (methamidophos), which were preconfirmed in the reaction mixture in CP EC, it was successfully demonstrated that the majority of CP in the formulation had been transformed to a new stable compound, MCP. Meanwhile, formation of another product, methamidophos, resulted in toxic potentiation. Title: Sazetidine-A is a potent and selective agonist at native and recombinant alpha 4 beta 2 nicotinic acetylcholine receptors Zwart R, Carbone AL, Moroni M, Bermudez I, Mogg AJ, Folly EA, Broad LM, Williams AC, Zhang D and Sher E <2 more author(s)> Zwart R, Carbone AL, Moroni M, Bermudez I, Mogg AJ, Folly EA, Broad LM, Williams AC, Zhang D, Ding C, Heinz BA, Sher E (- 2) Ref: Molecular Pharmacology, 73:1838, 2008 : PubMed ESTHER: Zwart_2008_Mol.Pharmacol_73_1838 PubMedSearch: Zwart 2008 Mol.Pharmacol 73 1838 PubMedID: 18367540 Abstract Sazetidine-A has been recently proposed to be a "silent desensitizer" of alpha4beta2 nicotinic acetylcholine receptors (nAChRs), implying that it desensitizes alpha4beta2 nAChRs without first activating them. This unusual pharmacological property of sazetidine-A makes it, potentially, an excellent research tool to distinguish between the role of activation and desensitization of alpha4beta2 nAChRs in mediating the central nervous system effects of nicotine itself, as well as those of new nicotinic drugs. We were surprised to find that sazetidine-A potently and efficaciously stimulated nAChR-mediated dopamine release from rat striatal slices, which is mediated by alpha4beta2(*) and alpha6beta2(*) subtypes of nAChR. The agonist effects on native striatal nAChRs prompted us to re-examine the effects of sazetidine-A on recombinant alpha4beta2 nAChRs in more detail. We expressed the two alternative stoichiometries of alpha4beta2 nAChR in Xenopus laevis oocytes and investigated the agonist properties of sazetidine-A on both alpha4(2)beta2(3) and alpha4(3)beta2(2) nAChRs. We found that sazetidine-A potently activated both stoichiometries of alpha4beta2 nAChR: it was a full agonist on alpha4(2)beta2(3) nAChRs, whereas it had an efficacy of only 6% on alpha4(3)beta2(2) nAChRs. In contrast to what has been published before, we therefore conclude that sazetidine-A is an agonist of native and recombinant alpha4beta2 nAChRs but shows differential efficacy on alpha4beta2 nAChRs subtypes. Title: Finite element analysis of the time-dependent Smoluchowski equation for acetylcholinesterase reaction rate calculations Cheng Y, Suen JK, Zhang D, Bond SD, Zhang Y, Song Y, Baker NA, Bajaj CL, Holst MJ, McCammon JA Ref: Biophysical Journal, 92:3397, 2007 : PubMed ESTHER: Cheng_2007_Biophys.J_92_3397 PubMedSearch: Cheng 2007 Biophys.J 92 3397 PubMedID: 17307827 Abstract This article describes the numerical solution of the time-dependent Smoluchowski equation to study diffusion in biomolecular systems. Specifically, finite element methods have been developed to calculate ligand binding rate constants for large biomolecules. The resulting software has been validated and applied to the mouse acetylcholinesterase (mAChE) monomer and several tetramers. Rates for inhibitor binding to mAChE were calculated at various ionic strengths with several different time steps. Calculated rates show very good agreement with experimental and theoretical steady-state studies. Furthermore, these finite element methods require significantly fewer computational resources than existing particle-based Brownian dynamics methods and are robust for complicated geometries. The key finding of biological importance is that the rate accelerations of the monomeric and tetrameric mAChE that result from electrostatic steering are preserved under the non-steady-state conditions that are expected to occur in physiological circumstances. Title: Production of a novel recombinant Drosophila melanogaster acetylcholinesterase for detection of organophosphate and carbamate insecticide residues Xu S, Wu A, Chen H, Xie Y, Xu Y, Zhang L, Li J, Zhang D Ref: Biomol Eng, 24:253, 2007 : PubMed ESTHER: Xu_2007_Biomol.Eng_24_253 PubMedSearch: Xu 2007 Biomol.Eng 24 253 PubMedID: 17222583 Abstract A novel recombinant Drosophila melanogaster acetylcholinesterase (R-DmAChE) produced in Pichia pastoris was first reported in this study. We cloned the DmAChE cDNA by reverse transcription PCR with removal of the signal for glycosylphosphatidylinositol (GPI) anchor attachment and the endogenous signal peptide coding sequence, and inserted it into P. pastoris vector pPIC9K under control of the alcohol oxidase gene AOX1 promoter (5'AOX1). The expression cassette of AChE cDNA was then introduced into methylotrophic yeast GS115 and several recombinant strains expressing R-DmAChE were obtained. The secreted R-DmAChE showed high stability in neutral phosphate buffer at 4 degrees C, and its kinetic parameters were identical to those of the native DmAChE. The bimolecular rate constants of R-DmAChE to dichlorvos, aldicarb and carbaryl were ranging from three to six times higher than of native DmAChE. Within six insecticides, the R-DmAChE was more sensitive than EeAChE, NbAChE and HuAChE. For 10 widely used insecticides, the IC50 values to the R-DmAChE were much lower than those to AChEs commonly used in China. With the R-DmAChE-based assay, samples spiked with three concentrations of pesticides caused enzymatic activity inhibition with R.S.D. of 0-13.7%. These results suggest that the R-DmAChE can be useful for detection of organophosphate and carbamate insecticide residues. Title: Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets Zhang D, Saraf A, Kolasa T, Bhatia P, Zheng GZ, Patel M, Lannoye GS, Richardson P, Stewart A and Surowy CS <2 more author(s)> Zhang D, Saraf A, Kolasa T, Bhatia P, Zheng GZ, Patel M, Lannoye GS, Richardson P, Stewart A, Rogers JC, Brioni JD, Surowy CS (- 2) Ref: Neuropharmacology, 52:1095, 2007 : PubMed ESTHER: Zhang_2007_Neuropharmacol_52_1095 PubMedSearch: Zhang 2007 Neuropharmacol 52 1095 PubMedID: 17217969 Abstract Fatty acid amide hydrolase (FAAH) is the primary regulator of several bioactive lipid amides including anandamide. Inhibitors of FAAH are potentially useful for the treatment of pain, anxiety, depression, and other nervous system disorders. However, FAAH inhibitors must display selectivity for this enzyme relative to the numerous other serine hydrolases present in the human proteome in order to be therapeutically acceptable. Here we employed activity-based protein profiling (ABPP) to assess the selectivity of FAAH inhibitors in multiple rat and human tissues. We discovered that some inhibitors, including carbamate compounds SA-47 and SA-72, and AM404 are exceptionally selective while others, like URB597, BMS-1, OL-135, and LY2077855 are less selective, displaying multiple off-targets. Since proteins around 60kDa constitute the major off-targets for URB597 and several other FAAH inhibitors with different chemical structures, we employed the multi-dimensional protein identification technology (MudPIT) approach to analyze their identities. We identified multiple carboxylesterase isozymes as bona fide off-targets of FAAH inhibitors. Consistently, enzymatic assay confirmed inhibition of carboxylesterase activities in rat liver by FAAH inhibitors. Since carboxylesterases hydrolyze a variety of ester-containing drugs and prodrugs, we speculate that certain FAAH inhibitors, by inhibiting carboxylesterases, might have drug-drug interactions with other medicines if developed as therapeutic agents. Title: Tetrameric mouse acetylcholinesterase: continuum diffusion rate calculations by solving the steady-state Smoluchowski equation using finite element methods Zhang D, Suen J, Zhang Y, Song Y, Radic Z, Taylor P, Holst MJ, Bajaj C, Baker NA, McCammon JA Ref: Biophysical Journal, 88:1659, 2005 : PubMed ESTHER: Zhang_2005_Biophys.J_88_1659 PubMedSearch: Zhang 2005 Biophys.J 88 1659 PubMedID: 15626705 Abstract The tetramer is the most important form for acetylcholinesterase in physiological conditions, i.e., in the neuromuscular junction and the nervous system. It is important to study the diffusion of acetylcholine to the active sites of the tetrameric enzyme to understand the overall signal transduction process in these cellular components. Crystallographic studies revealed two different forms of tetramers, suggesting a flexible tetramer model for acetylcholinesterase. Using a recently developed finite element solver for the steady-state Smoluchowski equation, we have calculated the reaction rate for three mouse acetylcholinesterase tetramers using these two crystal structures and an intermediate structure as templates. Our results show that the reaction rates differ for different individual active sites in the compact tetramer crystal structure, and the rates are similar for different individual active sites in the other crystal structure and the intermediate structure. In the limit of zero salt, the reaction rates per active site for the tetramers are the same as that for the monomer, whereas at higher ionic strength, the rates per active site for the tetramers are approximately 67%-75% of the rate for the monomer. By analyzing the effect of electrostatic forces on ACh diffusion, we find that electrostatic forces play an even more important role for the tetramers than for the monomer. This study also shows that the finite element solver is well suited for solving the diffusion problem within complicated geometries. Title: The association of tetrameric acetylcholinesterase with ColQ tail: a block normal mode analysis Zhang D, McCammon JA Ref: PLoS Comput Biol, 1:e62, 2005 : PubMed ESTHER: Zhang_2005_PLoS.Comput.Biol_1_e62 PubMedSearch: Zhang 2005 PLoS.Comput.Biol 1 e62 PubMedID: 16299589 Abstract Acetylcholinesterase (AChE) rapidly hydrolyzes acetylcholine in the neuromuscular junctions and other cholinergic synapses to terminate the neuronal signal. In physiological conditions, AChE exists as tetramers associated with the proline-rich attachment domain (PRAD) of either collagen-like Q subunit (ColQ) or proline-rich membrane-anchoring protein. Crystallographic studies have revealed that different tetramer forms may be present, and it is not clear whether one or both are relevant under physiological conditions. Recently, the crystal structure of the tryptophan amphiphilic tetramerization (WAT) domain of AChE associated with PRAD ([WAT]4PRAD), which mimics the interface between ColQ and AChE tetramer, became available. In this study we built a complete tetrameric mouse [AChE(T)]4-ColQ atomic structure model, based on the crystal structure of the [WAT]4PRAD complex. The structure was optimized using energy minimization. Block normal mode analysis was done to investigate the low-frequency motions of the complex and to correlate the structure model with the two known crystal structures of AChE tetramer. Significant low-frequency motions among the catalytic domains of the four AChE subunits were observed, while the [WAT]4PRAD part held the complex together. Normal mode involvement analysis revealed that the two lowest frequency modes were primarily involved in the conformational changes leading to the two crystal structures. The first 30 normal modes can account for more than 75% of the conformational changes in both cases. The evidence further supports the idea of a flexible tetramer model for AChE. This model can be used to study the implications of the association of AChE with ColQ. Title: Metabolism and molecular toxicology of isoprene Watson WP, Cottrell L, Zhang D, Golding BT Ref: Chemico-Biological Interactions, 135-136:223, 2001 : PubMed ESTHER: Watson_2001_Chem.Biol.Interact_135-136_223 PubMedSearch: Watson 2001 Chem.Biol.Interact 135-136 223 PubMedID: 11397393 Abstract Isoprene (2-methylbuta-1,3-diene) is a large-scale petrochemical used principally in the manufacture of synthetic rubbers. It is also produced by plants and trees and is the major endogenous hydrocarbon formed by mammals, probably from mevalonic acid. Isoprene is metabolised by mammals in processes that involve epoxidation by cytochrome P450-dependent monooxygenases to the isomeric mono-epoxides, (1-methylethenyl)-oxirane and 2-ethenyl-2-methyloxirane. Further metabolism of the mono-epoxides to mutagenic isoprene di-epoxides, (2, 2')-2-methylbioxiranes, can also occur. The oxidations to the mono- and di-epoxides occur enantioselectively and diastereoselectively. The mono-epoxides are hydrolysed enantioselectively to vicinal diols under catalysis by epoxide hydrolase. 2-Ethenyl-2-methyloxirane is also readily hydrolysed non-enzymatically. Because of the stereochemical possibilities for metabolites, the metabolism of isoprene is complex. The metabolism of isoprene by liver microsomes in vitro from a range of species including rat, mouse and human shows significant differences between species, strains and gender in respect of the diastereoselectivity and enantioselectivity of the metabolic oxidation and hydrolysis reactions. The impact of the extra methyl in isoprene on di-epoxide reactivity also appears to be critically important for the resulting biological effects. Isoprene di-epoxides may exhibit a lower cross-linking potential in vivo compared to butadiene di-epoxides. Differences in metabolism and reactivity of metabolites may be factors contributing to the significant differences in toxicological response to isoprene observed between species. | |||||||
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