Author Report for: Zhang BNo contact information in database for Zhang B
Li Z, Zhang B, Liu Q, Tao Z, Ding L, Guo B, Zhang E, Zhang H, Meng Z and Wu Y <7 more author(s)> Li Z, Zhang B, Liu Q, Tao Z, Ding L, Guo B, Zhang E, Zhang H, Meng Z, Guo S, Chen Y, Peng J, Li J, Wang C, Huang Y, Xu H, Wu Y (- 7) Ref: EBioMedicine, 90:104543, 2023 : PubMed ESTHER: Li_2023_EBioMedicine_90_104543 PubMedSearch: Li 2023 EBioMedicine 90 104543 PubMedID: 37002989 Abstract BACKGROUND: Some observational studies found that dyslipidaemia is a risk factor for non-alcoholic fatty liver disease (NAFLD), and lipid-lowering drugs may lower NAFLD risk. However, it remains unclear whether dyslipidaemia is causative for NAFLD. This Mendelian randomisation (MR) study aimed to explore the causal role of lipid traits in NAFLD and evaluate the potential effect of lipid-lowering drug targets on NAFLD. METHODS: Genetic variants associated with lipid traits and variants of genes encoding lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). Summary statistics for NAFLD were obtained from two independent GWAS datasets. Lipid-lowering drug targets that reached significance were further tested using expression quantitative trait loci data in relevant tissues. Colocalisation and mediation analyses were performed to validate the robustness of the results and explore potential mediators. FINDINGS: No significant effect of lipid traits and eight lipid-lowering drug targets on NAFLD risk was found. Genetic mimicry of lipoprotein lipase (LPL) enhancement was associated with lower NAFLD risks in two independent datasets (OR(1) = 0.60 [95% CI 0.50-0.72], p(1) = 2.07 x 10(-8); OR(2) = 0.57 [95% CI 0.39-0.82], p(2) = 3.00 x 10(-3)). A significant MR association (OR = 0.71 [95% CI, 0.58-0.87], p = 1.20 x 10(-3)) and strong colocalisation association (PP.H(4) = 0.85) with NAFLD were observed for LPL expression in subcutaneous adipose tissue. Fasting insulin and type 2 diabetes mediated 7.40% and 9.15%, respectively, of the total effect of LPL on NAFLD risk. INTERPRETATION: Our findings do not support dyslipidaemia as a causal factor for NAFLD. Among nine lipid-lowering drug targets, LPL is a promising candidate drug target in NAFLD. The mechanism of action of LPL in NAFLD may be independent of its lipid-lowering effects. FUNDING: Capital's Funds for Health Improvement and Research (2022-4-4037). CAMS Innovation Fund for Medical Sciences (CIFMS, grant number: 2021-I2M-C&T-A-010). Title: Developmental Neurotoxicity of Trichlorfon in Zebrafish Larvae Shi Q, Yang H, Chen Y, Zheng N, Li X, Wang X, Ding W, Zhang B Ref: Int J Mol Sci, 24:, 2023 : PubMed ESTHER: Shi_2023_Int.J.Mol.Sci_24_ PubMedSearch: Shi 2023 Int.J.Mol.Sci 24 PubMedID: 37446277 Abstract Trichlorfon is an organophosphorus pesticide widely used in aquaculture and has potential neurotoxicity, but the underlying mechanism remains unclear. In the present study, zebrafish embryos were exposed to trichlorfon at concentrations (0, 0.1, 2 and 5 mg/L) used in aquaculture from 2 to 144 h post fertilization. Trichlorfon exposure reduced the survival rate, hatching rate, heartbeat and body length and increased the malformation rate of zebrafish larvae. The locomotor activity of larvae was significantly reduced. The results of molecular docking revealed that trichlorfon could bind to acetylcholinesterase (AChE). Furthermore, trichlorfon significantly inhibited AChE activity, accompanied by decreased acetylcholine, dopamine and serotonin content in larvae. The transcription patterns of genes related to acetylcholine (e.g., ache, chrna7, chata, hact and vacht), dopamine (e.g., drd4a and drd4b) and serotonin systems (e.g., tph1, tph2, tphr, serta, sertb, htrlaa and htrlab) were consistent with the changes in acetylcholine, dopamine, serotonin content and AChE activity. The genes related to the central nervous system (CNS) (e.g., a1-tubulin, mbp, syn2a, shha and gap-43) were downregulated. Our results indicate that the developmental neurotoxicity of trichlorfon might be attributed to disorders of cholinergic, dopaminergic and serotonergic signaling and the development of the CNS. Title: Alcoholic Setdb1 suppression promotes hepatosteatosis in mice by strengthening Plin2 Zhang Y, Li Y, Liu Y, Wang H, Chen Y, Zhang B, Song M, Song L, Ding Q and Wang Z <3 more author(s)> Zhang Y, Li Y, Liu Y, Wang H, Chen Y, Zhang B, Song M, Song L, Ding Q, Qiu J, Fan M, Qu L, Wang Z (- 3) Ref: Metabolism, :155656, 2023 : PubMed ESTHER: Zhang_2023_Metabolism__155656 PubMedSearch: Zhang 2023 Metabolism 155656 PubMedID: 37419179 Abstract BACKGROUND AND AIMS: Hepatosteatosis is one of the early features of alcoholic liver disease (ALD) and pharmaceutical or genetic interfering of the development of hepatosteatosis will efficiently alleviate the progression of ALD. Currently, the role of histone methyltransferase Setdb1 in ALD is not yet well understood. METHOD: Lieber-De Carli diet mice model and NIAAA mice model were constructed to confirm the expression of Setdb1. The hepatocyte-specific Setdb1-knockout (Setdb1-HKO) mice was established to determine the effects of Setdb1 in vivo. Adenovirus-Setdb1 were produced to rescue the hepatic steatosis in both Setdb1-HKO and Lieber-De Carli mice. The enrichment of H3k9me3 in the upstream sequence of Plin2 and the chaperone-mediated autophagy (CMA) of Plin2 were identified by ChIP and co-IP. Dual-luciferase reporter assay was used to detect the interaction of Setdb1 3'UTR and miR216b-5p in AML12 or HEK 293 T cells. RESULTS: We found that Setdb1 was downregulated in the liver of alcohol-fed mice. Setdb1 knockdown promoted lipid accumulation in AML12 hepatocytes. Meanwhile, hepatocyte-specific Setdb1-knockout (Setdb1-HKO) mice exhibited significant lipid accumulation in the liver. Overexpression of Setdb1 was performed with an adenoviral vector through tail vein injection, which ameliorated hepatosteatosis in both Setdb1-HKO and alcoholic diet-fed mice. Mechanistically, downregulated Setdb1 promoted the mRNA expression of Plin2 by desuppressing H3K9me3-mediated chromatin silencing in its upstream sequence. Pin2 acts as a critical membrane surface-associated protein to maintain lipid droplet stability and inhibit lipase degradation. The downregulation of Setdb1 also maintained the stability of Plin2 protein through inhibiting Plin2-recruited chaperone-mediated autophagy (CMA). To explore the reasons for Setdb1 suppression in ALD, we found that upregulated miR-216b-5p bound to the 3'UTR of Setdb1 mRNA, disturbed its mRNA stability, and eventually aggravated hepatic steatosis. CONCLUSIONS: Setdb1 suppression plays an important role in the progression of alcoholic hepatosteatosis via elevating the expression of Plin2 mRNA and maintaining the stability of Plin2 protein. Targeting hepatic Setdb1 might be a promising diagnostic or therapeutic strategy for ALD. Title: Diketopyrrolopyrrole-based fluorescent probe for visualizing over-expressed carboxylesterase in fever via ratiometric imaging Zhang B, Qin S, Wang N, Lu X, Jiao J, Zhang J, Zhao W Ref: Talanta, 266:124971, 2023 : PubMed ESTHER: Zhang_2023_Talanta_266_124971 PubMedSearch: Zhang 2023 Talanta 266 124971 PubMedID: 37480822 Abstract Fever is the result of inflammation and the innate self-defense response of organisms, can cause abnormal changes in the activity of many enzymes in organisms, including the important carboxylesterase (CE). Monitoring the activity changes of CE in vivo during a fever will help to understand heat-related pathological mechanisms. In this paper, we designed diketopyrrolopyrrole-based ratiometric fluorescent probes DPP-FBC-P and DPP-FBO-P containing alkyl chain and diethylene glycol monomethyl ether chain respective for detection of CE. Both probes could realized fast response to CE and displayed good selectivity and high sensitivity. Compared with DPP-FBO-P, DPP-FBC-P had better biocompatibility, larger signal to noise ratio (225-fold vs 125-fold) and lower detection limit (1.6 x 10(-5) U/mL vs 4.2 x 10(-5) U/mL). Moreover, the probe DPP-FBC-P had been successfully applied to image the endogenous CE in HepG2 cells and solid tumors, and also visualized the over expressed CE in fever cells. Most importantly, the changes of CE level in the liver of fever mice model induced by LPS were monitored with the assistance of DPP-FBC-Pvia dual channel ratio imaging for the first time. In addition, fluorescence color signal in solution was captured by smart phone, and the linear relationship between RGB ratio (G/R) and CE concentration was established. This work will provide a potential approach for investigating the physiological and pathological processes of heat related diseases. Title: The Therapeutic Effects of Seven Lycophyte Compounds on Cell Models of Alzheimer's Disease Guo Q, Cai Q, Huang F, Wei Z, Wang JZ, Zhang B, Liu R, Yang Y, Wang X, Li HL Ref: J Alzheimers Dis, :, 2022 : PubMed ESTHER: Guo_2022_J.Alzheimers.Dis__ PubMedSearch: Guo 2022 J.Alzheimers.Dis PubMedID: 36189599 Abstract BACKGROUND: As an acetylcholinesterase inhibitor (AChEI), Huperzine-A (Hup-A) is marketed for treatment of mild to moderate Alzheimer's disease (AD) for decades in China. However, Hup-A causes some side effects. To search for new analogs or derivatives of Hup-A, we produced five Lycophyte alkaloids and two analogues by chemical synthesis: Lyconadins A-E, H-R-NOB, and 2JY-OBZ4. OBJECTIVE: To systematically evaluated the therapeutic effects of the seven compounds on AD cell models. METHODS: We assessed the effects of the seven compounds on cell viability via CCK-8 kit and used HEK293-hTau cells and N2a-hAPP cells as AD cell models to evaluate their potential therapeutic effects. We examined their effects on cholinesterase activity by employing the mice primary neuron. RESULTS: All compounds did not affect cell viability; in addition, Lyconadin A and 2JY-OBZ4 particularly increased cell viability. Lyconadin D and Lyconadin E restored tau phosphorylation at Thr231, and H-R-NOB and 2JY-OBZ4 restored tau phosphorylation at Thr231 and Ser396 in GSK-3beta-transfected HEK293-hTau cells. 2JY-OBZ4 decreased the level of PP2Ac-pY307 and increased the level of PP2Ac-mL309, supporting that 2JY-OBZ4 may activate PP2A. Lyconadin B, Lyconadin D, Lyconadin E, H-R-NOB, and 2JY-OBZ4 increased sAbetaPPalpha level in N2a-hAPP cells. 2JY-OBZ4 decreased the levels of BACE1 and sAbetaPPbeta, thereby reduced Abeta production. Seven compounds exhibited weaker AChE activity inhibition efficiency than Hup-A. Among them, 2JY-OBZ4 showed the strongest AChE inhibition activity with an inhibition rate of 17% at 10microM. CONCLUSION: Among the seven lycophyte compounds, 2JY-OBZ4 showed the most expected effects on promoting cell viability, downregulating tau hyperphosphorylation, and Abeta production and inhibiting AChE in AD. Title: Novel small molecular compound 2JY-OBZ4 alleviates AD pathology in cell models via regulating multiple targets Guo Q, Wu G, Huang F, Wei Z, Wang JZ, Zhang B, Liu R, Yang Y, Wang X, Li HL Ref: Aging (Albany NY), 14:, 2022 : PubMed ESTHER: Guo_2022_Aging.(Albany.NY)_14_ PubMedSearch: Guo 2022 Aging.(Albany.NY) 14 PubMedID: 36227154 Abstract Alzheimer's disease (AD) is the most common form of neurodegenerative dementia, characterized by cognitive deficits and memory dysfunction, which is clinically incurable so far. Novel small molecular compound 2JY-OBZ4 is one of structural analogue of Huperzine A (Hup-A), an anti-AD drug in China. In our previous work, 2JY-OBZ4 exhibited potent effects on tau hyperphosphorylation, Abeta production and acetylcholinesterase (AChE) activity. However, 2JY-OBZ4's anti-AD effects and the underlying molecular mechanisms remain unclear. We here reported that 2JY-OBZ4 resisted tau hyperphosphorylation at Thr181 and Ser396 sites in HEK293-hTau cells transfected with GSK-3beta, decreased tau phosphorylation via upregulating the activity of PP2A in HEK293-hTau cells and reduced Abeta production through regulating protein levels of APP cleavage enzymes in N2a-hAPP cells. Meanwhile, we found that 2JY-OBZ4 had no adverse effects on cell viability of mice primary neuron even at high concentration, and ameliorated synaptic loss induced by human oligomeric Abeta42. 2JY-OBZ4 had moderate AChE inhibitory activity with the half maximal inhibitory concentration (IC50) to be 39.48 microg/ml in vitro, which is more than two times higher than Hup-A. Together, 2JY-OBZ4 showed promising therapeutic effects in AD cell models through regulating multiple targets. The research provides a new candidate for the therapeutic development of AD. Title: Neuroligin-3 confines AMPA receptors into nanoclusters, thereby controlling synaptic strength at the calyx of Held synapses Han Y, Cao R, Qin L, Chen LY, Tang AH, Sudhof TC, Zhang B Ref: Sci Adv, 8:eabo4173, 2022 : PubMed ESTHER: Han_2022_Sci.Adv_8_eabo4173 PubMedSearch: Han 2022 Sci.Adv 8 eabo4173 PubMedID: 35704570 Abstract The subsynaptic organization of postsynaptic neurotransmitter receptors into nanoclusters that are aligned with presynaptic release sites is essential for the high fidelity of synaptic transmission. However, the mechanisms controlling the nanoscale organization of neurotransmitter receptors in vivo remain incompletely understood. Here, we deconstructed the role of neuroligin-3 (Nlgn3), a postsynaptic adhesion molecule linked to autism, in organizing AMPA-type glutamate receptors in the calyx of Held synapse. Deletion of Nlgn3 lowered the amplitude and slowed the kinetics of AMPA receptor-mediated synaptic responses. Super-resolution microscopy revealed that, unexpectedly, these impairments in synaptic transmission were associated with an increase in the size of postsynaptic PSD-95 and AMPA receptor nanoclusters but a decrease of the densities in these clusters. Modeling showed that a dilution of AMPA receptors into larger nanocluster volumes decreases synaptic strength. Nlgn3, likely by binding to presynaptic neurexins, thus is a key organizer of AMPA receptor nanoclusters that likely acts via PSD-95 adaptors to optimize the fidelity of synaptic transmission. Title: Probiotic effect of ferulic acid esterase-producing Lactobacillus plantarum inoculated alfalfa silage on digestion, antioxidant, and immunity status of lactating dairy goats Li F, Zhang B, Zhang Y, Zhang X, Usman S, Ding Z, Hao L, Guo X Ref: Anim Nutr, 11:38, 2022 : PubMed ESTHER: Li_2022_Anim.Nutr_11_38 PubMedSearch: Li 2022 Anim.Nutr 11 38 PubMedID: 36091259 Abstract A feeding experiment was conducted to determine the effects of inoculating alfalfa silage with a ferulic acid esterase-producing inoculum on feed digestibility, rumen fermentation, antioxidant, and immunity status of lactating dairy goats. Twenty dairy goats were distributed into 2 experimental groups consisting of control diet (Lp MTD/1, including Lactobacillus plantarum MTD/1 inoculated silage) against diet containing silage treated with ferulic acid esterase-producing L. plantarum A1 (Lp A1). Alfalfa silage inoculated with a ferulic acid esterase-producing Lp A1 had better fermentation quality than the Lp MTD/1 inoculation. The application of Lp A1 improved silage antioxidant capacity as indicated by greater total antioxidant capacity (T-AOC), superoxide dismutase (SOD) and glutathion peroxidase (GSH-Px) activities in Lp A1 treated silage versus Lp MTD/1 treatment. Compared with Lp MTD/1 treated group, inoculation of silage with Lp A1 increased apparent total tract digestibility of dietary dry matter, organic matter and crude protein, and ruminal concentrations of total volatile fatty acids, acetate, propionate and isobutyrate as well. The results of current study also demonstrated improved antioxidant capacity and immune performance of dairy goats with Lp A1 inoculation. Feeding Lp A1-treated silage increased dairy goats' serum antioxidase activity, such as T-AOC, SOD, GSH-Px and catalase, and the serum concentration of immunoglobulin A, while decreased tumor necrosis factor alpha, interleukin (IL)-2 and IL-6. In addition, compared with Lp MTD/1, diet containing alfalfa silage inoculated with Lp A1 endowed dairy goats' milk with greater fat and protein contents, improved dairy goat milk quality without affecting feed efficiency. Title: Discovery of novel hybrids containing clioquinol-1-benzyl-1,2,3,6-tetrahydropyridine as multi-target-directed ligands (MTDLs) against Alzheimer's disease Li X, Li T, Zhang P, Lu L, Sun Y, Zhang B, Allen S, White L, Phillips J and Xu J <2 more author(s)> Li X, Li T, Zhang P, Lu L, Sun Y, Zhang B, Allen S, White L, Phillips J, Zhu Z, Yao H, Xu J (- 2) Ref: Eur Journal of Medicinal Chemistry, 244:114841, 2022 : PubMed ESTHER: Li_2022_Eur.J.Med.Chem_244_114841 PubMedSearch: Li 2022 Eur.J.Med.Chem 244 114841 PubMedID: 36257284 Inhibitor(s) related to this paper: Compound19n-quinolinol Abstract Based on the multitarget strategy, a series of novel clioquinol-1-benzyl-1,2,3,6-tetrahydropyridine hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation in vitro revealed that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE). The optimal compound, 19n, exhibited excellent AChE inhibitory potency (IC(50) = 0.11 microM), appropriate metal chelating functions, modulation of AChE- and metal-induced Abeta aggregation, neuroprotection against okadaic acid-induced mitochondrial dysfunction and ROS damage, and interesting properties that reduced p-Tau levels in addition to no toxicity on SH-SY5Y cells observed at a concentration up to 50 microM. Most importantly, compound 19n was more well tolerated (>1200 mg/kg) than donepezil (LD(50) = 28.124 mg/kg) in vivo. Moreover, compound 19n demonstrated marked improvements in cognitive and spatial memory in two AD mice models (scopolamine-induced and Abeta(1-42)-induced) and suppressed inflammation induced by Abeta(1-42) in the cortex. The multifunctional profiles of compound 19n demonstrate that it deserves further investigation as a promising lead in the development of innovatively multifunctional drugs for Alzheimer's disease. Title: Design, Synthesis, and Biological Evaluation of Novel Chromanone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease Li X, Li T, Zhan F, Cheng F, Lu L, Zhang B, Li J, Hu Z, Zhou S and Yao H <6 more author(s)> Li X, Li T, Zhan F, Cheng F, Lu L, Zhang B, Li J, Hu Z, Zhou S, Jia Y, Allen S, White L, Phillips J, Zhu Z, Xu J, Yao H (- 6) Ref: ACS Chem Neurosci, :, 2022 : PubMed ESTHER: Li_2022_ACS.Chem.Neurosci__ PubMedSearch: Li 2022 ACS.Chem.Neurosci PubMedID: 36383455 Abstract Based on a multitarget strategy, a series of novel chromanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). The optimal compound C10 possessed excellent dual AChE/MAO-B inhibition both in terms of potency and equilibrium (AChE: IC(50) = 0.58 0.05 M; MAO-B: IC(50) = 0.41 0.04 M). Further molecular modeling and kinetic investigations revealed that compound C10 was a dual-binding inhibitor bound to both the catalytic anionic site and peripheral anionic site of AChE. In addition, compound C10 exhibited low neurotoxicity and potently inhibited AChE enzymatic activity. Furthermore, compound C10 more effectively protected against mitochondrial dysfunction and oxidation than donepezil, strongly inhibited AChE-induced amyloid aggregation, and moderately reduced glutaraldehyde-induced phosphorylation of tau protein in SH-SY5Y cells. Moreover, compound C10 displayed largely enhanced improvements in cognitive behaviors and spatial memory in a scopolamine-induced AD mice model with better efficacy than donepezil. Overall, the multifunctional profiles of compound C10 suggest that it deserves further investigation as a promising lead for the prospective treatment of AD. Title: Moringa Oleifera Alleviates Abeta Burden and Improves Synaptic Plasticity and Cognitive Impairments in APP/PS1 Mice Mahaman YAR, Feng J, Huang F, Salissou MTM, Wang J, Liu R, Zhang B, Li H, Zhu F, Wang X Ref: Nutrients, 14:, 2022 : PubMed ESTHER: Mahaman_2022_Nutrients_14_ PubMedSearch: Mahaman 2022 Nutrients 14 PubMedID: 36296969 Abstract Alzheimer's disease is a global public health problem and the most common form of dementia. Due to the failure of many single therapies targeting the two hallmarks, Abeta and Tau, and the multifactorial etiology of AD, there is now more and more interest in nutraceutical agents with multiple effects such as Moringa oleifera (MO) that have strong anti-oxidative, anti-inflammatory, anticholinesterase, and neuroprotective virtues. In this study, we treated APP/PS1 mice with a methanolic extract of MO for four months and evaluated its effect on AD-related pathology in these mice using a multitude of behavioral, biochemical, and histochemical tests. Our data revealed that MO improved behavioral deficits such as anxiety-like behavior and hyperactivity and cognitive, learning, and memory impairments. MO treatment abrogated the Abeta burden to wild-type control mice levels via decreasing BACE1 and AEP and upregulating IDE, NEP, and LRP1 protein levels. Moreover, MO improved synaptic plasticity by improving the decreased GluN2B phosphorylation, the synapse-related proteins PSD95 and synapsin1 levels, the quantity and quality of dendritic spines, and neurodegeneration in the treated mice. MO is a nutraceutical agent with promising therapeutic potential that can be used in the management of AD and other neurodegenerative diseases. Title: Parallel pathways for serotonin biosynthesis and metabolism in C. elegans Yu J, Vogt MC, Fox BW, Wrobel CJJ, Fajardo Palomino D, Curtis BJ, Zhang B, Le HH, Tauffenberger A and Schroeder FC <1 more author(s)> Yu J, Vogt MC, Fox BW, Wrobel CJJ, Fajardo Palomino D, Curtis BJ, Zhang B, Le HH, Tauffenberger A, Hobert O, Schroeder FC (- 1) Ref: Nat Chemical Biology, :, 2022 : PubMed ESTHER: Yu_2022_Nat.Chem.Biol__ PubMedSearch: Yu 2022 Nat.Chem.Biol PubMedID: 36216995 Abstract The neurotransmitter serotonin plays a central role in animal behavior and physiology, and many of its functions are regulated via evolutionarily conserved biosynthesis and degradation pathways. Here we show that in Caenorhabditis elegans, serotonin is abundantly produced in nonneuronal tissues via phenylalanine hydroxylase, in addition to canonical biosynthesis via tryptophan hydroxylase in neurons. Combining CRISPR-Cas9 genome editing, comparative metabolomics and synthesis, we demonstrate that most serotonin in C. elegans is incorporated into N-acetylserotonin-derived glucosides, which are retained in the worm body and further modified via the carboxylesterase CEST-4. Expression patterns of CEST-4 suggest that serotonin or serotonin derivatives are transported between different tissues. Last, we show that bacterial indole production interacts with serotonin metabolism via CEST-4. Our results reveal a parallel pathway for serotonin biosynthesis in nonneuronal cell types and further indicate that serotonin-derived metabolites may serve distinct signaling functions and contribute to previously described serotonin-dependent phenotypes. Title: Chemical profile, anti-hepatoma activity, anti-acetylcholinesterase and antioxidant activity of aerial part of Aconitum carmichaeli Debx Yu J, Xia J, Xu J, Chen S, Zhang Y, Yin F, Fang J, Cai L, Zhang B and Liang Z <3 more author(s)> Yu J, Xia J, Xu J, Chen S, Zhang Y, Yin F, Fang J, Cai L, Zhang B, Zhan Y, Zhang X, Zeng Z, Liang Z (- 3) Ref: Nat Prod Res, :1, 2022 : PubMed ESTHER: Yu_2022_Nat.Prod.Res__1 PubMedSearch: Yu 2022 Nat.Prod.Res 1 PubMedID: 36503283 Abstract Five extracts of the aerial parts of Aconitum carmichaeli were obtained by different solvent extraction or macroporous adsorption resin purification: ethyl acetate layer extract (EAE), n-butanol layer extract (BuE), water layer extract (WE), extract eluted by 10% ethanol from macroporous resin (10%EE), extract eluted by 80% ethanol from macroporous resin (80%EE). Antioxidant activities of the five extracts were determined by ABTS, DPPH, FRAP assays, anti-AChE activities by modified Ellman's method, insvitro anti-hepatoma activities by CCK-8 assay, and chemical constituents of 80%EE were identified by UPLC-QE-Orbitrap-MS. The results demonstrated that the 80%EE showed the best insvitro anti-hepatoma activity on Huh-7 cell line with an IC(50) of 103.91 +/- 11.02 microg/mL. 10%EE and 80%EE gave the highest antioxidant activity. Furthermore, current findings demonstrated that the aerial part of Aconitum carmichaeli Debx. has high medicinal value and may be a good natural medicine. Title: Hepatitis B virus genotype is an independent prognostic factor of telbivudine and tenofovir treatment in hepatitis B surface antigen-positive pregnant women Zhang B, Yu L, Cheng M, Zhang Q, Wu J, Yang J, Liu Q, Lu S, Zhao X and Zhao P <3 more author(s)> Zhang B, Yu L, Cheng M, Zhang Q, Wu J, Yang J, Liu Q, Lu S, Zhao X, Deng K, Liu Y, Wang J, Zhao P (- 3) Ref: Food Sci Nutr, 10:3, 2022 : PubMed ESTHER: Zhang_2022_Food.Sci.Nutr_10_3 PubMedSearch: Zhang 2022 Food.Sci.Nutr 10 3 PubMedID: 35035905 Abstract To investigate whether HBV genotype influences the effect of tenofovir and telbivudine on HBV DNA and RNA levels in HBsAg-positive pregnant women. This was a retrospective study of 74 HBsAg-positive pregnant women in Guizhou of China. All patients were treated with telbivudine or tenofovir from 12 weeks of pregnancy and HBV infection to the date of delivery. Blood samples were collected at 12-24, 28-32, and 36-40 weeks of pregnancy for the measurement of genotype, HBsAg, hepatitis B e antigen (HBeAg), HBV DNA, HBV RNA, and liver function, including alanine transaminase, aspartate transaminase, total bilirubin, total bile acids, cholinesterase, alkaline phosphatase (ALP), and gamma-glutamyl transferase. All women with HBsAg were followed up. The HBV genotype was B in 64.9% and C in 35.1%. There were 37 patients of telbivudine and tenofovir group respectively. The telbivudine and tenofovir groups showed no differences in demographic and clinical characteristics, including liver function tests, HBsAg, HBeAg, log(10)(HBV DNA), and log(10)(HBV RNA). Compared with baseline (12-24 weeks), telbivudine group showed a significant increase in ALP and significant reductions in HBsAg, HBeAg, log(10)(HBV DNA), and log(10)(HBV RNA) at 36-40 weeks (p < .05). Tenofovir group exhibited a significant increase in ALP and significant reductions in HBeAg, log(10)(HBV DNA), and log(10)(HBV RNA) at 36-40 weeks, compared with baseline (p < .05). HBV genotype (B vs. C) was independently associated with HBV DNA change after therapy (p = .005). In telbivudine group, log(10) (HBV DNA) increased from 3.38 (2.00-7.30) to 7.43 (4.68-8.70). In tenofovir group, log(10) (HBV DNA) decreased from 7.52 (3.32-8.70) to 2.98 (2.00-5.01). HBV genotype was independently associated with HBV DNA change response to telbivudine or tenofovir in pregnant women with hepatitis B. These findings might be helpful for risk assessment regarding vertical transmission of HBV in HBeAg-positive mothers treated with nucleos(t)ide analogues. Title: Strategy to small intestine obstruction caused by Crohn's disease on the basis of transnasal ileus tube insertion Zuo L, Cao L, Ding C, Tu H, Wei C, Yuan L, Wang H, Zhang B Ref: BMC Surg, 22:183, 2022 : PubMed ESTHER: Zuo_2022_BMC.Surg_22_183 PubMedSearch: Zuo 2022 BMC.Surg 22 183 PubMedID: 35568851 Abstract BACKGROUND: Previous studies reported that transnasal ileus tube was a new and useful method for rapid relief of small intestinal obstruction. However, no study reported the impacts of the transnasal ileus tube for Crohn's disease combined with intestinal obstruction. We aimed to describe the strategy to the small intestine obstruction caused by Crohn's disease on the basis of transnasal ileus tube insertion. METHODS: From November 2019 to November 2021, the data of 6 hospitalized patients with CD, diagnosed and conservatively treated in The Second Hospital of Nanjing, were not relived and retrospectively collected. After the insertion of transnasal ileus tube, demographic information, clinical features and treatment data were extracted from medical records. RESULTS: Six Crohn's disease patients with intestinal obstruction were included. Half of them were male. The patients aged from 29 to 70 years. Five patients had chronic intestinal obstruction more than one year. Three patients had intestinal surgery history. One patient had colonic abdominal fistula and anastomotic fistula, when she took intermittent usage of sulfsalazine and steroid. On admission, all the patients had abdominal pain, distention and mass. Five patients had anemia, low albumin and cholinesterase. All CDAI scores were more than 400. Compared to 19 patients with incomplete intestinal obstruction improved by nasogastric decompression tube, 6 patients with intestinal obstruction catheter had significant difference in time for relieving abdominal pain and distension (p = 0.003), time for alleviating abnormal mass (p >= 0.01), drainage volume (p = 0.004), and preoperative CDAI score (p = 0.001). Compared with X-ray image before insertion, complete remission of obstruction of 5 patients were observed in intestinal cavity after insertion. After 1-2 months nutrition, all the patients had small intestine resection and ileostomy, half of them underwent colectomy and fistula repair, and 4 patients were performed enterolysis at the same time, the residual small intestine length ranging from 250 to 400 cm. 1 patient had permanent ileostomy;1 patient had abdominal infection after operation. The typical manifestations of acute and chronic inflammation, transmural inflammation, pseudopolyps and serous fiber hyperplasia could be seen in pathological findings of patients 1 to 5. All the patients continued enteral nutrition after surgery. Four patients were treated with infliximab or vedolizumab. CONCLUSION: The current intestinal obstruction catheter which is used to treat patients with Crohn's combined obstruction can afford quick clinical remission, longer nutrition time, and suitable preoperative CDAI score for operation, which is worthy of wildly being used. Title: Synthesis, Enzymatic Degradation, and Polymer-Miscibility Evaluation of Nonionic Antimicrobial Hyperbranched Polyesters with Indole or Isatin Functionalities Li X, Ilk S, Linares-Pasten JA, Liu Y, Raina DB, Demircan D, Zhang B Ref: Biomacromolecules, 22:2256, 2021 : PubMed ESTHER: Li_2021_Biomacromolecules_22_2256 PubMedSearch: Li 2021 Biomacromolecules 22 2256 PubMedID: 33900740 Abstract Most macromolecular antimicrobials are ionic and thus lack miscibility/compatibility with nonionic substrate materials. In this context, nonionic hyperbranched polyesters (HBPs) with indole or isatin functionality were rationally designed, synthesized, and characterized. Antimicrobial disk diffusion assay indicated that these HBPs showed significant antibacterial activity against 8 human pathogenic bacteria compared to small molecules with indole or isatin groups. According to DSC measurements, up to 20% indole-based HBP is miscible with biodegradable polyesters (polyhydroxybutyrate or polycaprolactone), which can be attributed to the favorable hydrogen bonding between the N-H moiety of indole and the CO of polyesters. HBPs with isatin or methylindole were completely immiscible with the same matrices. None of the HBPs leaked out from plastic matrix after being immersed in water for 5 days. The incorporation of indole into HBPs as well as small molecules facilitated their enzymatic degradation with PETase from Ideonella sakaiensis, while isatin had a complex impact. Molecular docking simulations of monomeric molecules with PETase revealed different orientations of the molecules at the active site due to the presence of indole or isatin groups, which could be related to the observed different enzymatic degradation behavior. Finally, biocompatibility analysis with a mammalian cell line showed the negligible cytotoxic effect of the fabricated HBPs. Title: Blood-Brain Barrier Permeable and NO-Releasing Multifunctional Nanoparticles for Alzheimer's Disease Treatment: Targeting NO/cGMP/CREB Signaling Pathways Liu Z, Liu Q, Zhang B, Fang L, Gou S Ref: Journal of Medicinal Chemistry, 64:13853, 2021 : PubMed ESTHER: Liu_2021_J.Med.Chem_64_13853 PubMedSearch: Liu 2021 J.Med.Chem 64 13853 PubMedID: 34517696 Abstract The development of novel therapeutic strategies for combating Alzheimer's disease (AD) is challenging but imperative. Multifunctional nanoparticles are promising tools for regulating complex pathological dysfunctions for AD treatment. Herein, we constructed multifunctional nanoparticles consisting of regadenoson (Reg), nitric oxide (NO) donor, and YC-1 in a single molecular entity that can spontaneously self-assemble into nanoparticles and load donepezil to yield Reg-nanoparticles (Reg-NPs). The Reg moiety enabled the Reg-NPs to effectively regulate tight junction-associated proteins in the blood-brain barrier, thus facilitating the permeation of donepezil through the barrier and its accumulation in the brain. Moreover, the released NO and YC-1 activated the NO/cGMP/CREB signaling pathway by stimulating soluble guanylyl cyclase and inhibiting phosphodiesterase activity, which finally reduced cytotoxicity induced by aggregated Abeta in the neurons and was beneficial for synaptic plasticity and memory formation. Title: The protective effects of Omarigliptin against Lipopolysaccharide (LPS)- induced inflammatory response and expression of mucin 5AC (MUC5AC) in human bronchial epithelial cells Ma L, Chang E, Ruan X, Zhang B, Tang F, Zhang J Ref: Mol Immunol, 141:108, 2021 : PubMed ESTHER: Ma_2021_Mol.Immunol_141_108 PubMedSearch: Ma 2021 Mol.Immunol 141 108 PubMedID: 34871838 Abstract The epidemic of chronic inflammatory lung diseases such as asthma, bronchitis, and chronic obstructive pulmonary disease (COPD) has become a global public health problem. Oxidative stress, inflammation, and overproduction of airway mucus play critical roles in the progression of these diseases. Omarigliptin, an oral dipeptidyl peptidase 4 (DPP-4) inhibitor, has been demonstrated to have anti-inflammatory effects in patients with type II diabetes. However, its role in chronic inflammatory lung diseases remains enigmatic. This study is to investigate whether Omarigliptin possesses a beneficial effect against Lipopolysaccharide (LPS)-induced injuries in human BEAS-2B bronchial epithelial cells. Our results show that Omarigliptin suppressed LPS-induced oxidative stress by attenuating the generation of mitochondrial reactive oxygen species (ROS) and decrease in reduced glutathione (GSH) in BEAS-2B cells. Additionally, Omarigliptin mitigated inflammatory response by inhibiting the expression of pro-inflammatory mediators, including interleukin-1beta (IL-1beta), interleukin-12 (IL-12), and macrophage chemoattractant protein-1 (MCP-1) in LPS-challenged BEAS-2B cells. Moreover, Omarigliptin mitigated the LPS-induced overproduction of MUC5AC by rescuing the expression of the suppressor of cytokine signaling 1(SOCS1). Importantly, we found that this process is mediated by the Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway. Based on these findings, we conclude that Omarigliptin might be a promising agent for the treatment of chronic inflammatory lung diseases. Title: Vitamins A and D fail to protect against tuberculosis-drug-induced liver injury: A post hoc analysis of a previous randomized controlled trial Xiong K, Wang J, Zhang B, Xu L, Hu Y, Ma A Ref: Nutrition, 86:111155, 2021 : PubMed ESTHER: Xiong_2021_Nutrition_86_111155 PubMedSearch: Xiong 2021 Nutrition 86 111155 PubMedID: 33601121 Abstract OBJECTIVES: Vitamins A and D provided protection from xenobiotic-induced liver injury in previous animal studies. We conducted a post hoc analysis of our previous randomized controlled trial to investigate the effects of vitamin A and D supplementation on tuberculosis-drug-induced liver injury. METHODS: The trial was conducted in a hospital in Qingdao, China, from October 2012 to March, 2015. The control group received only tuberculosis treatment. The vitamin A, vitamin D, and vitamins A & D groups received, respectively, additional supplementation of 2000 IU/d vitamin A, 400 IU/d vitamin D, and a combination of 2000 IU/d vitamin A and 400 IU/d vitamin D. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, gamma-glutamyltransferase, and cholinesterase were monitored throughout the treatment. Liver injury was defined as ALT or AST three times higher than the upper limit of normal, which was defined for AST, ALT, alkaline phosphatase, gamma-glutamyltransferase, and cholinesterase, respectively, as 40 U/L, 40 U/L, 150 U/L, 40 U/L, and 10 500 U/L. RESULTS: Among the 753 participants, 11% exhibited liver injury. No significant effect of vitamin A or D supplementation was observed on the incidence of liver injury or on elevated liver indices including ALT, AST, alkaline phosphatase, gamma-glutamyltransferase, and cholinesterase. The interaction between vitamin A and D supplementation was not significant. CONCLUSIONS: Vitamin A and D supplementation did not protect against tuberculosis-drug-induced liver injury. Future work should evaluate the effects of higher dosages of vitamins A and D and the effects of different genotypes for vitamin A and D metabolic enzymes or receptors. Title: Design and synthesis of novel tacrine-dipicolylamine dimers that are multiple-target-directed ligands with potential to treat Alzheimer's disease Zhang P, Wang Z, Mou C, Zou J, Xie Y, Liu Z, Benjamin Naman C, Mao Y, Wei J and Cui W <11 more author(s)> Zhang P, Wang Z, Mou C, Zou J, Xie Y, Liu Z, Benjamin Naman C, Mao Y, Wei J, Huang X, Dong J, Yang M, Wang N, Jin H, Liu F, Lin D, Liu H, Zhou F, He S, Zhang B, Cui W (- 11) Ref: Bioorg Chem, 116:105387, 2021 : PubMed ESTHER: Zhang_2021_Bioorg.Chem_116_105387 PubMedSearch: Zhang 2021 Bioorg.Chem 116 105387 PubMedID: 34628225 Inhibitor(s) related to this paper: Tacrine-dipicolylamine-13a Abstract Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that has multiple causes. Therefore, multiple-target-directed ligands (MTDLs), which act on multiple targets, have been developed as a novel strategy for AD therapy. In this study, novel drug candidates were designed and synthesized by the covalent linkings of tacrine, a previously used anti-AD acetylcholinesterase (AChE) inhibitor, and dipicolylamine, an beta-amyloid (Abeta) aggregation inhibitor. Most tacrine-dipicolylamine dimers potently inhibited AChE and Abeta(1-42) aggregation in vitro, and 13a exhibited nanomolar level inhibition. Molecular docking analysis suggested that 13a could interact with the catalytic active sites and the peripheral anion site of AChE, and bind to Abeta(1-42) pentamers. Moreover, 13a effectively attenuated Abeta(1-42) oligomers-induced cognitive dysfunction in mice by activating the cAMP-response element binding protein/brain-derived neurotrophic factor signaling pathway, decreasing tau phosphorylation, preventing synaptic toxicity, and inhibiting neuroinflammation. The safety profile of 13a in mice was demonstrated by acute toxicity experiments. All these results suggested that novel tacrine-dipicolylamine dimers, especially 13a, have multi-target neuroprotective and cognitive-enhancing potentials, and therefore might be developed as MTDLs to combat AD. Title: Donepezil prevents morphine tolerance by regulating N-methyl-d-aspartate receptor, protein kinase C and CaM-dependent kinase II expression in rats Zhu QM, Wu LX, Zhang B, Dong YP, Sun L Ref: Pharmacol Biochem Behav, :173209, 2021 : PubMed ESTHER: Zhu_2021_Pharmacol.Biochem.Behav__173209 PubMedSearch: Zhu 2021 Pharmacol.Biochem.Behav 173209 PubMedID: 34058253 Abstract Current studies have indicated that donepezil as a cholinesterase inhibitor can attenuate morphine-induced tolerance. The present study aimed to evaluate the possible role of N-methyl-d-aspartate receptors (NMDARs), protein kinase C (PKC) and CaM-dependent kinase II (CaMKII) pathways in this effect. Female Wistar rats received daily morphine (10 mg/kg, i.p.) alone or in combination with donepezil (1.5 or 2 mg/kg, gavaged) for 14 days. The analgesic effect was assessed by Von-frey, hotplate and tail flick test. On the 15th day, the periaqueductal gray (PAG) and lumbar spinal cord of rats were dissected. Then, protein levels of NMDAR-NR1, NR2B, PKCgamma and CaMKIIalpha were tested using Western blot method. The results showed that morphine tolerance was seen after 8-10 days of injection compared with control group, while daily co-administration of donepezil with morphine prolonged the occurrence of analgesic tolerance. Western blot showed that morphine significantly increased NR1, PKCgamma and CaMKIIalpha expressions in PAG, and significantly increased PKCgamma and CaMKIIalpha in spinal cord. In contrast, donepezil downregulated NR1 and PKCgamma in PAG, and downregulated PKCgamma and CaMKIIalpha in spinal cord. Moreover, donepezil alone activates NR1 and NR2B in spinal cord, which needs to be further studied. Thus, the present results suggest that the attenuation effects of donepezil on morphine tolerance are possibly mediated by preventing morphine-induced upregulations in NR1, PKCgamma and CaMKIIalpha expressions. Title: Enzymatic Synthesis of beta-Sitosterol Laurate by Candida rugosa Lipase AY30 in the Water/AOT/Isooctane Reverse Micelle Chen S, Li J, Fu Z, Wei G, Li H, Zhang B, Zheng L, Deng Z Ref: Appl Biochem Biotechnol, :, 2020 : PubMed ESTHER: Chen_2020_Appl.Biochem.Biotechnol__ PubMedSearch: Chen 2020 Appl.Biochem.Biotechnol PubMedID: 32388606 Abstract Phytosterols are regarded as compounds able to reduce total and low-density lipoprotein cholesterol in the blood, and their esterified derivatives could help to improve the effectiveness of this function. In the present study, the water/sodium 1,4-bis-2-ethylhexylsulfosuccinate (AOT)/isooctane reverse micelle (RM) system was set up as a reaction medium for Candida rugosa lipase AY30 (CRL AY30) to synthesize beta-sitosterol laurate (beta-SLE). The product was identified by TLC, FT-IR, and HPLC-APCI-QqQ-MS/MS and quantified by HPLC. Through stepwise optimization, it was found that CRL AY30 had the highest activity in the water/AOT/isooctane RM system where 50 mM PBS with a pH of 7.5 was adopted as water core to carry CRL AY30, and the proportion of [CRL AY30] (mg/mL), [water] (mM), and [AOT] (mM) was set in 3:375:25, respectively, in isooctane. After screened with single-factor experiments, the esterification reaction conditions in the CRL AY30-water/AOT/isooctane RM system were further optimized by the response surface method as follows: the mole ratio of beta-sitosterol to lauric acid of 1:3.5 (25 mM beta-sitosterol), the enzyme load of 18% (w/w total reactants), the reaction temperature of 47 degrees C, and the reaction time of 48 h. As a result, the maximum esterification rate was up to 88.12 +/- 0.79%. Title: Sensitive and reversible perylene derivative-based fluorescent probe for acetylcholinesterase activity monitoring and its inhibitor Chen Y, Liu W, Zhang B, Suo Z, Xing F, Feng L Ref: Analytical Biochemistry, :113835, 2020 : PubMed ESTHER: Chen_2020_Anal.Biochem__113835 PubMedSearch: Chen 2020 Anal.Biochem 113835 PubMedID: 32739347 Abstract A reversible fluorescence probe for acetylcholinesterase activity detection was developed based on water soluble perylene derivative, N,N'-di(2-aspartic acid)-perylene-3,4,9,10-tetracarboxylic diimide (PASP). Based on the photo-induced electron transfer (PET), PASP fluorescence in aqueous is quenched after combining with copper ions (Cu(2+)). Acetylcholinesterase (AChE) is well known to catalyze the hydrolysis of acetylcholine (ATCh) to produce thiocholine, whose affinity is strong enough to capture Cu(2+) by thiol (-SH) group from the complex PASP-Cu, resulting in the fluorescence signal of PASP recovers up to 90%. This optical switch is highly sensitive depended on the coordination and dissociation between PASP and Cu(2+). We proposed its application for AChE activity detection, as well as its inhibitor screening. According to the change of fluorescence intensity, quantifying the detection limit of AChE was 1.78 mU.mL(-1). Classical inhibitors, tacrine and organophosphate pesticide diazinon, were further evaluated for drug screening. The IC(50) value of tacrine was calculated to be 0.43 muM, and the detection limit of diazinon was 0.22 muM. Both of these performances were much better than previous results, revealing our probe is sensitive and reversible for screening applications. Title: Old Mice Have Less Transcriptional Activation but Similar Periosteal Cell Proliferation Compared to Young-Adult Mice in Response to In Vivo Mechanical Loading Chermside-Scabbo CJ, Harris TL, Brodt MD, Braenne I, Zhang B, Farber CR, Silva MJ Ref: J Bone Miner Res, :, 2020 : PubMed ESTHER: Chermside-Scabbo_2020_J.Bone.Miner.Res__ PubMedSearch: Chermside-Scabbo 2020 J.Bone.Miner.Res PubMedID: 32311160 Abstract Mechanical loading is a potent strategy to induce bone formation, but with aging, the bone formation response to the same mechanical stimulus diminishes. Our main objectives were to 1) discover the potential transcriptional differences and 2) compare the periosteal cell proliferation between tibias of young-adult and old mice in response to strain-matched mechanical loading. First, to discover potential age-related transcriptional differences, we performed RNA sequencing (RNA-seq) to compare the loading responses between tibias of young-adult (5-month) and old (22-month) C57BL/6N female mice following 1, 3, or 5 days of axial loading (loaded vs non-loaded). Compared to young-adult mice, old mice had less transcriptional activation following loading at each time point, as measured by the number of differentially expressed genes (DEGs) and the fold-changes of the DEGs. Old mice engaged fewer pathways and gene ontology (GO) processes, showing less activation of processes related to proliferation and differentiation. In tibias of young-adult mice, we observed prominent Wnt signaling, extracellular matrix (ECM), and neuronal responses, which were diminished with aging. Additionally, we identified several targets that may be effective in restoring the mechanoresponsiveness of aged bone, including nerve growth factor (NGF), Notum, prostaglandin signaling, Nell-1, and the AP-1 family. Second, to directly test the extent to which periosteal cell proliferation was diminished in old mice, we used bromodeoxyuridine (BrdU) in a separate cohort of mice to label cells that divided during the 5-day loading interval. Young-adult and old mice had an average of 15.5 and 16.7 BrdU+ surface cells/mm, respectively, suggesting that impaired proliferation in the first 5 days of loading does not explain the diminished bone formation response with aging. We conclude that old mice have diminished transcriptional activation following mechanical loading, but periosteal proliferation in the first 5 days of loading does not differ between tibias of young-adult and old mice. This article is protected by copyright. All rights reserved. Title: Positive correlation between human exposure to organophosphate esters and gastrointestinal cancer in patients from Wuhan, China Li Y, Fu Y, Hu K, Zhang Y, Chen J, Zhang S, Zhang B, Liu Y Ref: Ecotoxicology & Environmental Safety, 196:110548, 2020 : PubMed ESTHER: Li_2020_Ecotoxicol.Environ.Saf_196_110548 PubMedSearch: Li 2020 Ecotoxicol.Environ.Saf 196 110548 PubMedID: 32278140 Abstract As kinds of endocrine disruptors, organophosphate esters (OPEs) pollution in the environment had received increasing attention recently. Food and water intake were two important exposure pathways for OPEs. However, the studies about the potential association between OPEs and gastrointestinal cancer were limited. This study investigated the possible association between OPEs and gastrointestinal cancer. All cancer patients were diagnosed with gastrointestinal cancer from a Grade 3 A hospital in Wuhan, China, while the control group was non-cancer healthy persons. The results showed that 6 OPEs were found in the control samples, while 8 in the samples from patients with gastrointestinal cancer. The detection frequencies of OPEs in gastrointestinal cancer patients were significantly higher than those in the control group (p < 0.05 or p < 0.01), except for triethyl phosphate (TEP) and tris (methylphenyl) phosphate (TMPP) in the gastric cancer group. The concentrations of OPEs in the control group were significantly lower than those in the gastric cancer group and colorectal cancer group (p < 0.01). In the control group and gastrointestinal cancer group, TEP was the dominant pollutant. Correlation analysis found that concentrations of TEP, tris(2-chloroisopropyl) phosphate (TCIPP), triphenyl phosphate (TPHP), TMPP, tris(2-ethylhexyl) phosphate (TEHP), and 2-ethylhexyl diphenyl phosphate (EHDPP) were associated with gastric cancer (p < 0.01), and concentrations of TEP, TCIPP, TPHP, TMPP and TEHP were associated with colorectal cancer (p < 0.01). A cluster analysis divided the 34 patients with gastric cancer and 40 patients with colorectal cancer in four groups. The results showed that the elderly male patients with gastric cancer were more sensitive to the exposure of EHDPP, while the TEP exposure was more sensitive to the relatively young gastrointestinal cancer patients. These findings indicated that OPEs might play a role in developing gastrointestinal cancer. Title: ROS-responsive and multifunctional anti-Alzheimer prodrugs: Tacrine-ibuprofen hybrids via a phenyl boronate linker Liu Z, Zhang B, Xia S, Fang L, Gou S Ref: Eur Journal of Medicinal Chemistry, :112997, 2020 : PubMed ESTHER: Liu_2020_Eur.J.Med.Chem__112997 PubMedSearch: Liu 2020 Eur.J.Med.Chem 112997 PubMedID: 33189440 Abstract Current drugs available in clinic for Alzheimer's disease (AD) treatment can only alleviate disease symptoms without clearly curing or delaying the process of AD. And some AD drugs failed in Phase III clinical trials are only focused on targeting amyloid-beta (Abeta). Therefore, an alternative strategy in AD drug design is meaningful to be involved in the multiple pathogenic factors which can affect each other at multiple levels. Herein, we report a series of ROS-responsive prodrugs based on multi-target-directed ligands (MTDLs) approach, which can specifically release tacrine derivatives and ibuprofen under oxidation of ROS and show acetylcholinesterase (AChE)-inhibiting, neuron-protective and anti-inflammatory effects in extracellular or intracellular assays. Related biological study illustrated that compound 22 was able to permeate blood-brain-barrier (BBB) showing little hepatotoxicity in comparison to tacrine. Besides, 22 hinted a therapeutic clue in AD-treatment by regulating proinflammatory factors (IL-1beta and TNF-alpha) and apoptosis related proteins (Bax, Bcl-2 and cleaved caspase-3). Further spatial memory assays in Abeta-induced AD model showed that 22 enhanced the ability of learning and memory. Our study proves that the strategy of ROS-responsive prodrugs has promise for AD treatments in future and offers a way for AD drug development. Title: Increased cross-linking micelle retention in the brain of Alzheimer's disease mice by elevated asparagine endopeptidase protease responsive aggregation Ren J, Jiang F, Wang M, Hu H, Zhang B, Chen L, Dai F Ref: Biomater Sci, 8:6533, 2020 : PubMed ESTHER: Ren_2020_Biomater.Sci_8_6533 PubMedSearch: Ren 2020 Biomater.Sci 8 6533 PubMedID: 33111725 Abstract Current forms of medication for Alzheimer's disease (AD) provide a symptomatic benefit limited to those with early onset, but there is no single drug available for later stage patients. Given the recent failures of AD drugs in clinical trials, an intensive treatment strategy based on drug combination that is approved is attractive. At present, the greatest difficulty lies in the low accumulation of drugs in the brain. All hydrophilic drugs are limited by the physical and biochemical barriers within the blood-brain barrier and lipophilic drugs are often transported back into the blood by efflux pumps located in the blood-brain barrier. Here, we select elevated asparagine endopeptidase (AEP) as a target to trigger in situ cross-linking of small sized particles to form large sized drug clusters to block the efflux of the brain. Subsequently, responsive cross-linking micelles (RCMs) loaded with the acetylcholinesterase inhibitor, donepezil (DON), the microtubule therapeutic agent, Paclitaxel (PTX), and the glucose metabolism disorder regulator, insulin (INS) are investigated, with a focus on high levels of drug accumulation in the brain in AD. These smart multi-drug delivery RCMs provide a powerful system for AD treatment and can be adapted for other central nervous system (CNS) disorders. Title: Network Pharmacology-Based Analysis of Xiao-Xu-Ming Decoction on the Treatment of Alzheimer's Disease Shen Y, Zhang B, Pang X, Yang R, Chen M, Zhao J, Wang J, Wang Z, Yu Z and Du G <3 more author(s)> Shen Y, Zhang B, Pang X, Yang R, Chen M, Zhao J, Wang J, Wang Z, Yu Z, Wang Y, Li L, Liu A, Du G (- 3) Ref: Front Pharmacol, 11:595254, 2020 : PubMed ESTHER: Shen_2020_Front.Pharmacol_11_595254 PubMedSearch: Shen 2020 Front.Pharmacol 11 595254 PubMedID: 33390981 Abstract Alzheimer's disease (AD) has become a worldwide disease that is harmful to human health and brings a heavy economic burden to healthcare system. Xiao-Xu-Ming Decoction (XXMD) has been widely used to treat stroke and other neurological diseases for more than 1000 years in China. However, the synergistic mechanism of the constituents in XXMD for the potential treatment of AD is still unclear. Therefore, the present study aimed to predict the potential targets and uncover the material basis of XXMD for the potential treatment of AD. A network pharmacology-based method, which combined data collection, drug-likeness filtering and absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties filtering, target prediction and network analysis, was used to decipher the effect and potential targets of XXMD for the treatment of AD. Then, the acetylcholinesterase (AChE) inhibitory assay was used to screen the potential active constituents in XXMD for the treatment of AD, and the molecular docking was furtherly used to identify the binding ability of active constituents with AD-related target of AChE. Finally, three in vitro cell models were applied to evaluate the neuroprotective effects of potential lead compounds in XXMD. Through the China Natural Products Database, Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database, Traditional Chinese Medicine (TCM)-Database @Taiwan and literature, a total of 1481 compounds in XXMD were finally collected. After ADME/T properties filtering, 908 compounds were used for the further study. Based on the prediction data, the constituents in XXMD formula could interact with 41 AD-related targets. Among them, cyclooxygenase-2 (COX-2), estrogen receptor alpha (ERalpha) and AChE were the major targets. The constituents in XXMD were found to have the potential to treat AD through multiple AD-related targets. 62 constituents in it were found to interact with more than or equal to 10 AD-related targets. The prediction results were further validated by in vitro biology experiment, resulting in several potential anti-AD multitarget-directed ligands (MTDLs), including two AChE inhibitors with the IC(50) values ranging from 4.83 to 10.22 microM. Moreover, fanchinoline was furtherly found to prevent SH-SY5Y cells from the cytotoxicities induced by sodium nitroprusside, sodium dithionate and potassium chloride. In conclusion, XXMD was found to have the potential to treat AD by targeting multiple AD-related targets and canonical pathways. Fangchinoline and dauricine might be the potential lead compounds in XXMD for the treatment of AD. Title: Synthesis, Molecular Docking Simulation, and Enzymatic Degradation of AB-Type Indole-Based Polyesters with Improved Thermal Properties Wang P, Linares-Pasten JA, Zhang B Ref: Biomacromolecules, 21:1078, 2020 : PubMed ESTHER: Wang_2020_Biomacromolecules_21_1078 PubMedSearch: Wang 2020 Biomacromolecules 21 1078 PubMedID: 31951388 Abstract We report the facile synthesis of a series of indole-based hydroxyl-carboxylate (AB-type) monomers by a one-step procedure. These monomers were successfully polymerized by melt polycondensation to yield AB-type polyesters with a varied number of flexible methylene units in the backbones. These indole-based AB-polyesters showed decent thermal stability according to the TGA results (onset thermal degradation temperature of >330 degC), and their glass transition temperatures are dependent on the length of the methylene bridge (T(g) = 62-102 degC) according to the DSC results. Furthermore, DSC and WAXD measurements revealed that these polymers did not crystallize from melt, but the ones with flexible structures could crystallize from solution. Molecular docking simulations showed favorable interactions between indole-based polyesters and polyethylene terephthalate hydrolase (PETase) from Ideonella sakaiensis. This was corroborated by the experimental results, which indicated that the PETase enzyme has degrading activity on the indole-based AB polyesters except for the one with the highest degree of crystallinity. Title: Endothelial Lipase Exerts its Anti-Atherogenic Effect through Increased Catabolism of beta-VLDLs Yan H, Niimi M, Wang C, Chen Y, Zhou H, Matsuhisa F, Nishijima K, Kitajima S, Zhang B and Fan J <5 more author(s)> Yan H, Niimi M, Wang C, Chen Y, Zhou H, Matsuhisa F, Nishijima K, Kitajima S, Zhang B, Yokomichi H, Nakajima K, Murakami M, Zhang J, Chen YE, Fan J (- 5) Ref: J Atheroscler Thromb, :, 2020 : PubMed ESTHER: Yan_2020_J.Atheroscler.Thromb__ PubMedSearch: Yan 2020 J.Atheroscler.Thromb PubMedID: 32448826 Abstract AIM: Endothelial lipase (EL) plays an important role in lipoprotein metabolism. Our recent study showed that increased hepatic expression of EL attenuates diet-induced hypercholesterolemia, thus subsequently reducing atherosclerosis in transgenic (Tg) rabbits. However, it is yet to be determined whether increased EL activity itself per se is anti-atherogenic or whether the anti-atherogenic effect of EL is exclusively dependent on its lipid-lowering effect. METHODS: To determine the mechanisms underlying EL-mediated anti-atherogenic effect, we fed Tg and non-Tg rabbits diets containing different amounts of cholesterol to make their plasma cholesterol levels similarly high. Sixteen weeks later, we examined their lipoprotein profiles and compared their susceptibility to atherosclerosis. RESULTS: With Tg and non-Tg rabbits having hypercholesterolemia, the plasma lipids and lipoprotein profiles were observed to be similar, while pathological examinations revealed that lesion areas of both aortic and coronary atherosclerosis of Tg rabbits were not significantly different from non-Tg rabbits. Moreover, Tg rabbits exhibited faster clearance of DiI-labeled beta-VLDLs than non-Tg rabbits. CONCLUSION: The results of our study suggest that the enhancement of beta-VLDL catabolism is the major mechanism for atheroprotective effects of EL in Tg rabbits. Title: DL0410 attenuates oxidative stress and neuroinflammation via BDNF/TrkB/ERK/CREB and Nrf2/HO-1 activation Zhang B, Zhao J, Wang Z, Xu L, Liu A, Du G Ref: Int Immunopharmacol, 86:106729, 2020 : PubMed ESTHER: Zhang_2020_Int.Immunopharmacol_86_106729 PubMedSearch: Zhang 2020 Int.Immunopharmacol 86 106729 PubMedID: 32645628 Abstract Oxidative stress and neuroinflammation have been deeply associated with Alzheimer's disease. DL0410 is a novel acetylcholinesterase inhibitor with potential anti-oxidative effects in AD-related animal models, while the specific mechanism has not been fully clarified. In this study, DL0410 was predicted to be related to the modification of cell apoptosis, oxidation-reduction process, inflammatory response and ERK1/ERK2 cascade by in silico target fishing and GO enrichment analysis. Then the possible protective effects of DL0410 were evaluated by hydrogen peroxide (H2O2)-induced oxidative stress model and lipopolysaccharides (LPS)-induced neuroinflammation model H2O2 decreased the viability of SH-SY5Y cells, induced malondialdehyde (MDA) accumulation, mitochondrial membrane potential (Deltapsim) loss and cell apoptosis, which could be reversed by DL0410 dose-dependently, indicating that DL0410 protected SH-SY5Y cells against H2O2-mediated oxidative stress. Western blot analysis showed that DL0410 increased the H2O2-triggered down-regulated TrkB, ERK and CREB phosphorylation and the expression of BDNF. In addition, TrkB inhibitor ANA-12, ERK inhibitor SCH772984 and CREB inhibitor 666-15 eliminated the inhibition of DL0410 on MDA accumulation and Deltapsim loss. Furthermore, DL0410 attenuates inflammatory responses and ROS production in LPS-treated BV2 cells, which is responsible for Nrf2 and HO-1 up-regulation. The present study demonstrates that DL0410 is a potential activator of the BDNF/TrkB/ERK/CREB and Nrf2/HO-1 pathway and may be a potential candidate for regulating oxidative stress and neuroinflammatory response in the brain. Together, the results showed that DL0410 is a promising drug candidate for treating AD and possibly other nervous system diseases associated with oxidative stress and neuroinflammation. Title: [Determination of gastrodin activity inhibition on acetylcholinesterase by capillary electrophoresis] Zhang J, Zhang B, He M, Han L, Gao D, Liu C Ref: Se Pu, 38:1102, 2020 : PubMed ESTHER: Zhang_2020_Se.Pu_38_1102 PubMedSearch: Zhang 2020 Se.Pu 38 1102 PubMedID: 34213277 Abstract Alzheimer's disease (AD) is the most common cause of dementia in elderly individuals. Currently, acetylcholinesterase inhibitors (AChEI) are the most effective clinical treatment for AD. AChEIs in natural products may have therapeutic potential and should be screened for use in AD treatment. The authors describe a simple and reliable method for AChEI screening by capillary electrophoresis (CE). A hexadimethrine bromide (HDB) solution was pushed into a capillary (0.015 MPax10 s) and incubated for 5 min. The capillary was flushed with deionized water for 5 min to remove free HDB, followed by plugging with an acetylcholinesterase (AChE) solution. After a 5 min incubation, the AChE was immobilized on the positively charged coating by ion binding, and the micro-reactor was created. The substrate solution, acetylthiocholine iodide (AThC), was injected into the capillary and incubated in the micro-reactor for 1 min. The unreacted substrate and the enzymolysis product were separated by CE. Gastrodin, an important component of Gastrodia elata, can inhibit AChE activity. After a certain amount of gastrodin was spiked into the substance solution, the peak area of the product decreased. Greater peak area reduction indicated stronger inhibition of AChEI. We observed good reproducibility of the product peak, with relative standard deviation (RSD) values less than 5.3%. The micro-reactor can be reused up to 300 times, which greatly improves efficiency. When the concentration of gastrodin was 5.24 micromol/L, the inhibition rate of AChE reached 64.8%. The IC(50) of gastrodin was (2.26+/-0.14) micromol/L (R(2)=0.9983), which was consistent with the result of traditional UV method (2.09+/-0.18 micromol/L). If the function of the micro-reactor deteriorates, it can be conveniently renewed by flushing the column to remove the enzyme and repeating the AChE immobilization protocol. The proposed method is simple, efficient, and low cost, and can be used to screen AChEI from natural products, thus contributing to the improvement of AD treatment. Title: Peach Carboxylesterase PpCXE1 Is Associated with Catabolism of Volatile Esters Cao X, Xie K, Duan W, Zhu Y, Liu M, Chen K, Klee H, Zhang B Ref: Journal of Agricultural and Food Chemistry, 67:5189, 2019 : PubMed ESTHER: Cao_2019_J.Agric.Food.Chem_67_5189 PubMedSearch: Cao 2019 J.Agric.Food.Chem 67 5189 PubMedID: 30997798 Gene_locus related to this paper: prupe-m5w2v0, prupe-m5vkk2, prupe-m5vq13 Abstract Peach fruit volatile acetate esters impact consumer sensory preference and contribute to defense against biotic stresses. Previous studies showed that alcohol acyltransferase (AAT) family PpAAT1 is correlated with volatile ester formation in peach fruits. However, fruits also contain carboxylesterase (CXE) enzymes that hydrolyze esters. The functions of this family with regard to volatile ester content has not been explored. Here, we observed that content of acetate ester was negatively correlated with expression of PpCXE1. Recombinant PpCXE1 protein exhibited hydrolytic activity toward acetate esters present in peach fruit. Kinetic analysis showed that PpCXE1 showed the highest catalytic activity toward E-2-hexenyl acetate. Subcellular localization demonstrated that PpCXE1 is present in the cytoplasm. Transient expression in peach fruit and stable overexpression in tomato fruit resulted in significant reduction of volatile esters in vivo. Taken together, the results indicate that PpCXE1 expression is associated with catabolism of volatile acetate esters in peach fruit. Title: Genome-Wide Identification and Functional Analysis of Carboxylesterase and Methylesterase Gene Families in Peach (Prunus persica L. Batsch) Cao X, Duan W, Wei C, Chen K, Grierson D, Zhang B Ref: Front Plant Sci, 10:1511, 2019 : PubMed ESTHER: Cao_2019_Front.Plant.Sci_10_1511 PubMedSearch: Cao 2019 Front.Plant.Sci 10 1511 PubMedID: 31824538 Gene_locus related to this paper: prupe-m5w2v0, prupe-m5vkk2, prupe-m5vq13, prupe-m5x0p5, prupe-m5xkg4, prupe-m5x0q4, prupe-m5wiw5, prupe-a0a0u2wu32, prupe-a0a251mtk1, prupe-m5vl29, prupe-m5vn82, prupe-m5vz47, prupe-m5vq88, prupe-m5y2s7, prupe-m5wye7, prupe-m5y9v4, prupe-m5wxm4, prupe-m5xqp6, prupe-m5x4q4, prupe-m5x4m1, prupe-m5x6b3, prupe-m5vlb6, prupe-m5w4h3, prupe-m5vlu4, prupe-m5vln3, prupe-a0a251myy7, prupe-a0a251mws4, prupe-m5vi18, prupe-m5vh66, prupe-m5xd54, prupe-m5xqn2, prupe-m5xr64, prupe-m5vrm7, prupe-m5vrk6, prupe-m5vqp6, prupe-a0a251nbb1, prupe-a0a251nbd3, prupe-a0a251nbb3, prupe-a0a251nba0, prupe-a0a251ndd4, prupe-a0a251nbb6, prupe-m5w315, prupe-a0a251mwh1, prupe-a0a251qn57, prupe-m5vzh8, prupe-m5xpz7, prupe-m5xrp5, prupe-m5wsr5 Abstract Carboxylesterases (CXE) and methylesterases (MES) are hydrolytic enzymes that act on carboxylic esters and are involved in plant metabolic processes and defense responses. A few functions of plant CXE and MES genes have been identified but very little information is available about the role of most members. We made a comprehensive study of this gene family in a commercially important species, peach (Prunus persica L. Batsch). A total of 33 peach CXE genes and 18 MES genes were identified and shown to be distributed unevenly between the chromosomes. Based on phylogenetic analysis, CXEs and MESs clustered into two different branches. Comparison of the positions of intron and differences in motifs revealed the evolutionary relationships between CXE and MES genes. RNA-seq revealed differential expression patterns of CXE/MESs in peach flower, leaf, and ripening fruit and in response to methyl jasmonate (MeJA) and ultraviolet B treatment. Transcript levels of candidate genes were verified by real-time quantitative PCR. Heterologous expression in Escherichia coli identified three CXEs that were involved in the hydrolysis of volatile esters in vitro. Furthermore, two recombinant MES proteins were identified that could hydrolyze MeJA and methyl salicylate. Our results provide an important resource for the identification of functional CXE and MES genes involved in the catabolism of volatile esters, responses to biotic and abiotic stresses and activation of signaling molecules such as MeJA and methyl salicylate. Title: Bioactive phenazines from an earwig-associated Streptomyces sp Han H, Guo ZK, Zhang B, Zhang M, Shi J, Li W, Jiao RH, Tan RX, Ge HM Ref: Chin J Nat Med, 17:475, 2019 : PubMed ESTHER: Han_2019_Chin.J.Nat.Med_17_475 PubMedSearch: Han 2019 Chin.J.Nat.Med 17 475 PubMedID: 31262460 Abstract Three new phenazine-type compounds, named phenazines SA-SC (1-3), together with four new natural products (4-7), were isolated from the fermentation broth of an earwig-associated Streptomyces sp. NA04227. The structures of these compounds were determined by extensive analyses of NMR, high resolution mass spectroscopic data, as well as single-crystal X-ray diffraction measurement. Sequencing and analysis of the genome data allowed us to identify the gene cluster (spz) and propose a biosynthetic pathway for these phenazine-type compounds. Additionally, compounds 1-5 exhibited moderate inhibitory activity against acetylcholinesterase (AChE), and compound 3 showed antimicrobial activities against Micrococcus luteus. Title: 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) Urea, a Selective and Potent Dual Inhibitor of Soluble Epoxide Hydrolase and p38 Kinase Intervenes in Alzheimer's Signaling in Human Nerve Cells Liang Z, Zhang B, Xu M, Morisseau C, Hwang SH, Hammock BD, Li QX Ref: ACS Chem Neurosci, 10:4018, 2019 : PubMed ESTHER: Liang_2019_ACS.Chem.Neurosci_10_4018 PubMedSearch: Liang 2019 ACS.Chem.Neurosci 10 4018 PubMedID: 31378059 Inhibitor(s) related to this paper: TPPU Abstract Alzheimer's disease (AD) is the most common neurodegenerative disorder. Neuroinflammation is a prevalent pathogenic stress leading to neuronal death in AD. Targeting neuroinflammation to keep neurons alive is an attractive strategy for AD therapy. 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) is a potent inhibitor of soluble epoxide hydrolase (sEH) and can enter into the brain. It has good efficacy on a wide range of chronic inflammatory diseases in preclinical animal models. However, the anti-neuroinflammatory effects and molecular mechanisms of TPPU for potential AD interventions remain elusive. With an aim to develop multitarget therapeutics for neurodegenerative diseases, we screened TPPU against sEH from different mammalian species and a broad panel of human kinases in vitro for potential new targets relevant to neuroinflammation in AD. TPPU inhibits both human sEH and p38beta kinase, two key regulators of inflammation, with nanomolar potencies and distinct selectivity. To further elucidate the molecular mechanisms, differentiated SH-SY5Y human neuroblastoma cells were used as an AD cell model, and we investigated the neuroprotection of TPPU against amyloid oligomers. We found that TPPU effectively prevents neuronal death by mitigating amyloid neurotoxicity, tau hyperphosphorylation, and mitochondrial dysfunction, promoting neurite outgrowth and suppressing activation and nuclear translocation of NF-kappaB for inflammatory responses in human nerve cells. The results indicate that TPPU is a potent and selective dual inhibitor of sEH and p38beta kinase, showing a synergistic action in multiple AD signaling pathways. Our study sheds light upon TPPU and other sEH/p38beta dual inhibitors for potential pharmacological interventions in AD. Title: Overexpression of multiple cytochrome P450 genes associated with sulfoxaflor resistance in Aphis gossypii Glover Ma K, Tang Q, Zhang B, Liang P, Wang B, Gao X Ref: Pestic Biochem Physiol, 157:204, 2019 : PubMed ESTHER: Ma_2019_Pestic.Biochem.Physiol_157_204 PubMedSearch: Ma 2019 Pestic.Biochem.Physiol 157 204 PubMedID: 31153470 Inhibitor(s) related to this paper: Diethyl-maleate Abstract Sulfoxaflor is the first commercially available sulfoximine insecticide, which exhibits highly efficacy against many sap-feeding insect pests and has been applied as an alternative insecticide against cotton aphid in China. This study was conducted to investigate the risk of resistance development, the cross-resistance pattern and the potential resistance mechanisms of sulfoxaflor in Aphis gossypii. A colony (SulR strain) of A. gossypii with 245-fold resistance, originated from Xinjiang field population, was established by continuous selection using sulfoxaflor. The SulR strain has developed cross-resistance to imidacloprid (80.8-fold), acetamiprid (19.3-fold), thiamethoxam (10.0-fold), and flupyradifurone (107.5-fold), while no cross-resistance was detected to malathion, omethoate, bifenthrin, methomyl, and carbosulfan. Piperonyl butoxide and S, S, S-tributyl phosphorotrithioate could significantly increase the toxicity of sulfoxaflor to the SulR strain by 5.99- and 4.18-fold, respectively, whereas no synergistic effect with diethyl maleate was observed. The activities of P450s and carboxylesterase were significantly higher in the SulR strain than that in the SS strain. Further gene expression determination demonstrated that nine P450 genes were significantly increased in SulR strain and suppression the expression of CYP6CY13 and CYP6CY19 by RNAi significantly increased the susceptibility of SulR adult aphids to sulfoxaflor. These results demonstrated that the enhancing detoxification by cytochrome P450 monooxygenase may be involved in A.gossypii resistance to sulfoxaflor. Title: Recent Advances in Multi-target Anti-Alzheimer Disease Compounds (2013 Up to the Present) Wang N, Qiu P, Cui W, Yan X, Zhang B, He S Ref: Curr Med Chem, 26:5684, 2019 : PubMed ESTHER: Wang_2019_Curr.Med.Chem_26_5684 PubMedSearch: Wang 2019 Curr.Med.Chem 26 5684 PubMedID: 30501591 Abstract Since the last century, when scientists proposed the lock-and-key model, the discovery of drugs has focused on the development of drugs acting on single target. However, single-target drug therapies are not effective to complex diseases with multi-factorial pathogenesis. Moreover, the combination of single-target drugs readily causes drug resistance and side effects. In recent years, multi-target drugs have increasingly been represented among FDA-approved drugs. Alzheimer's Disease (AD) is a complex and multi-factorial disease for which the precise molecular mechanisms are still not fully understood. In recent years, rational multi-target drug design methods, which combine the pharmacophores of multiple drugs, have been increasingly applied in the development of anti-AD drugs. In this review, we give a brief description of the pathogenesis of AD and provide detailed discussions about the recent development of chemical structures of anti-AD agents (2013 up to present) that have multiple targets, such as amyloid-beta peptide, Tau protein, cholinesterases, monoamine oxidase, beta-site amyloid-precursor protein-cleaving enzyme 1, free radicals, metal ions (Fe2+, Cu2+, Zn2+) and so on. In this paper, we also added some novel targets or possible pathogenesis which have been reported in recent years for AD therapy. We hope that these findings may provide new perspectives for the pharmacological treatment of AD. Title: Potential Pharmacokinetic Herb-Drug Interactions: Have we Overlooked the Importance of Human Carboxylesterases 1 and 2? Xu J, Qiu JC, Ji X, Guo HL, Wang X, Zhang B, Wang T, Chen F Ref: Curr Drug Metab, 20:130, 2019 : PubMed ESTHER: Xu_2019_Curr.Drug.Metab_20_130 PubMedSearch: Xu 2019 Curr.Drug.Metab 20 130 PubMedID: 29600756 Abstract BACKGROUND: Herbal products have grown steadily across the globe and have increasingly been incorporated into western medicine for healthcare aims, thereby causing potential pharmacokinetic Herb-drug Interactions (HDIs) through the inhibition or induction of drug-metabolizing enzymes and transporters. Human Carboxylesterases 1 (CES1) and 2 (CES2) metabolize endogenous and exogenous chemicals including many important therapeutic medications. The growing number of CES substrate drugs also underscores the importance of the enzymes. Herein, we summarized those potential inhibitors and inducers coming from herbal constituents toward CES1 and CES2. We also reviewed the reported HDI studies focusing on herbal products and therapeutic agents metabolized by CES1 or CES2. METHODS: We searched in PubMed for manuscript published in English after Jan 1, 2000 combining terms "carboxylesterase 1", "carboxylesterase 2", "inhibitor", "inducer", "herb-drug interaction", "inhibitory", and "herbal supplement". We also searched specific websites including FDA and EMA. The data of screened papers were analyzed and summarized. RESULTS: The results showed that more than 50 natural inhibitors of CES1 or CES2, including phenolic chemicals, triterpenoids, and tanshinones were found from herbs, whereas only few inducers of CES1 and CES2 were reported. Systemic exposure to some commonly used drugs including oseltamivir, irinotecan, and clopidogrel were changed when they were co-administered with herb products such as goldenseal, black cohosh, ginger, St. John's Wort, curcumin, and some Chinese compound formula in animals. CONCLUSION: Nonclinical and clinical studies on HDIs are warranted in the future to provide safety information toward better clinical outcomes for the combination of herbal products and conventional drugs. Title: Clinical implications of genetic variation in carboxylesterase drug metabolism Chen F, Zhang B, Parker RB, Laizure SC Ref: Expert Opin Drug Metab Toxicol, 14:131, 2018 : PubMed ESTHER: Chen_2018_Expert.Opin.Drug.Metab.Toxicol_14_131 PubMedSearch: Chen 2018 Expert.Opin.Drug.Metab.Toxicol 14 131 PubMedID: 29264996 Gene_locus related to this paper: human-CES1, human-CES2 Abstract INTRODUCTION: Mammalian carboxylesterase enzymes are a highly conserved metabolic pathway involved in the metabolism of endogenous and exogenous compounds including many widely prescribed therapeutic agents. Recent advances in our understanding of genetic polymorphisms affecting enzyme activity have exposed potential therapeutic implications. Areas covered: The aims of this review are to provide an overview of carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) gene structure, to summarize the known polymorphism affecting substrate-drug metabolism, and to assess the potential therapeutic implications of genetic variations affecting enzyme function. Expert opinion: Genetic variability in carboxylesterase drug metabolism is a nascent area of research with only a handful of the thousands of SNPs investigated for their potential effects of enzyme activity or carboxylesterase-substrate disposition and therapeutics. It remains to be determined if the wide variability in enzyme activity can be explained by genetic variation, and used in personalized medicine to improve clinical outcomes. Title: Alterations of drug-metabolizing enzymes and transporters under diabetic conditions: what is the potential clinical significance? Chen F, Li DY, Zhang B, Sun JY, Sun F, Ji X, Qiu JC, Parker RB, Laizure SC, Xu J Ref: Drug Metabolism Reviews, :1, 2018 : PubMed ESTHER: Chen_2018_Drug.Metab.Rev__1 PubMedSearch: Chen 2018 Drug.Metab.Rev 1 PubMedID: 30221555 Abstract There will be 642 million people worldwide by 2040 suffering from diabetes mellitus. Long-term multidrug therapy aims to achieve normal glycemia and minimize complications, and avoid severe hypoglycemic events. The appreciation of the drug-metabolizing enzymes and drug transporters as critical players in the treatment of diabetes has attracted much attention regarding their potential alterations in the pathogenesis of the disease. This review discusses pharmacokinetics-based alterations of cytochrome P450 enzymes, phase-II metabolizing enzymes, and membrane transporter proteins, as well as the potential mechanisms underlying these alterations. We also discuss the potential influences of altered enzymes and transporters on the disposition of commonly prescribed glucose-lowering medicines. Future studies should delve into the impact of altered drug-metabolizing enzymes and transporters on the progression toward abnormal glucose homeostasis. Title: Bidirectional interactions between beet armyworm and its host in response to different fertilization conditions Wang S, Ding T, Xu M, Zhang B Ref: PLoS ONE, 13:e0190502, 2018 : PubMed ESTHER: Wang_2018_PLoS.One_13_e0190502 PubMedSearch: Wang 2018 PLoS.One 13 e0190502 PubMedID: 29293621 Abstract Fertilizer with different ratios of nitrogen (N) to phosphorus (P) can influence crop plant performance and defense against herbivores. Spodoptera exigua is an important agricultural pest that has caused serious economic loss, especially in recent decades. In the present study, we explored effects of different intensities and durations of S. exigua herbivory on host plant biomass and on S. exigua enzyme activities in response to five fertilizer treatments with different N: P ratios of 1: 5, 1: 3, 1: 1, 3: 1 and 5: 1. The results showed that fertilizer type can significantly influence interactions between caterpillars and its hosts. Compensatory growth of leaf biomass was detected under fertilizer with N: P = 3: 1. Fertilizer with a higher proportion of N appears to maintain stem biomass in defoliated seedlings similar to controls that are not exposed to herbivory. There was no significant difference in root biomass under most conditions. High proportion of N also enhanced the activity of two antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD) in low density of beet armyworm. However, with increased herbivorous intensity, a higher proportion of P played a more important role in increasing the activities of CAT and SOD. Higher P likely enhanced acetylcholine esterase (AChE) activity at lower degrees of defoliation, but a higher N proportion resulted in higher AChE activity at higher degrees of defoliation. Higher N proportion contributed to reduced carboxylesterase (CarE) activity at high intensity, short-term defoliation. However, when defoliation intensity increased, the difference in CarE activity between fertilizer categories was little. The study explored the interaction between the damage of S. exigua and the biomass accumulation of its host plant Brassica rapa, and the influence of the N/P ratio in plant fertilizer on this interaction. Systematic analysis was provided on the biomass of B. rapa and the activity of metabolic enzymes of S. exigua under different treatments. Title: Enhanced lincomycin production by co-overexpression of metK1 and metK2 in Streptomyces lincolnensis Xu Y, Tan G, Ke M, Li J, Tang Y, Meng S, Niu J, Wang Y, Liu R and Zhang B <3 more author(s)> Xu Y, Tan G, Ke M, Li J, Tang Y, Meng S, Niu J, Wang Y, Liu R, Wu H, Bai L, Zhang L, Zhang B (- 3) Ref: J Ind Microbiol Biotechnol, 45:345, 2018 : PubMed ESTHER: Xu_2018_J.Ind.Microbiol.Biotechnol_45_345 PubMedSearch: Xu 2018 J.Ind.Microbiol.Biotechnol 45 345 PubMedID: 29574602 Gene_locus related to this paper: strln-a0a1b1ma73, strln-a0a1b1m575 Abstract Streptomyces lincolnensis is generally utilized for the production of lincomycin A (Lin-A), a clinically useful antibiotic to treat Gram-positive bacterial infections. Three methylation steps, catalyzed by three different S-adenosylmethionine (SAM)-dependent methyltransferases, are required in the biosynthesis of Lin-A, and thus highlight the significance of methyl group supply in lincomycin production. In this study, we demonstrate that externally supplemented SAM cannot be taken in by cells and therefore does not enhance Lin-A production. Furthermore, bioinformatics and in vitro enzymatic assays revealed there exist two SAM synthetase homologs, MetK1 (SLCG_1651) and MetK2 (SLCG_3830) in S. lincolnensis that could convert L-methionine into SAM in the presence of ATP. Even though we attempted to inactivate metK1 and metK2, only metK2 was deleted in S. lincolnensis LCGL, named as DeltametK2. Following a reduction of the intracellular SAM concentration, DeltametK2 mutant exhibited a significant decrease of Lin-A in comparison to its parental strain. Individual overexpression of metK1 or metK2 in S. lincolnensis LCGL either elevated the amount of intracellular SAM, concomitant with 15% and 22% increase in Lin-A production, respectively. qRT-PCR assays showed that overexpression of either metK1 or metK2 increased the transcription of lincomycin biosynthetic genes lmbA and lmbR, and regulatory gene lmbU, indicating SAM may also function as a transcriptional activator. When metK1 and metK2 were co-expressed, Lin-A production was increased by 27% in LCGL, while by 17% in a high-yield strain LA219X. Title: Autism-associated neuroligin-4 mutation selectively impairs glycinergic synaptic transmission in mouse brainstem synapses Zhang B, Gokce O, Hale WD, Brose N, Sudhof TC Ref: J Exp Med, 215:1543, 2018 : PubMed ESTHER: Zhang_2018_J.Exp.Med_215_1543 PubMedSearch: Zhang 2018 J.Exp.Med 215 1543 PubMedID: 29724786 Gene_locus related to this paper: mouse-4neur Abstract In human patients, loss-of-function mutations of the postsynaptic cell-adhesion molecule neuroligin-4 were repeatedly identified as monogenetic causes of autism. In mice, neuroligin-4 deletions caused autism-related behavioral impairments and subtle changes in synaptic transmission, and neuroligin-4 was found, at least in part, at glycinergic synapses. However, low expression levels precluded a comprehensive analysis of neuroligin-4 localization, and overexpression of neuroligin-4 puzzlingly impaired excitatory but not inhibitory synaptic function. As a result, the function of neuroligin-4 remains unclear, as does its relation to other neuroligins. To clarify these issues, we systematically examined the function of neuroligin-4, focusing on excitatory and inhibitory inputs to defined projection neurons of the mouse brainstem as central model synapses. We show that loss of neuroligin-4 causes a profound impairment of glycinergic but not glutamatergic synaptic transmission and a decrease in glycinergic synapse numbers. Thus, neuroligin-4 is essential for the organization and/or maintenance of glycinergic synapses. Title: New 2-Aryl-9-methyl-beta-carbolinium salts as Potential Acetylcholinesterase Inhibitor agents: Synthesis, Bioactivity and Structure-Activity Relationship Zhou B, Zhang B, Li X, Liu X, Li H, Li D, Cui Z, Geng H, Zhou L Ref: Sci Rep, 8:1559, 2018 : PubMed ESTHER: Zhou_2018_Sci.Rep_8_1559 PubMedSearch: Zhou 2018 Sci.Rep 8 1559 PubMedID: 29367595 Abstract A series of 2-aryl-9-methyl-beta-carbolinium bromides (B) were synthesized and explored for anti-acetylcholinesterase (AChE) activities in vitro, action mechanism and structure-activity relationship. All the compounds B along with their respective 3,4-dihydro intermediates (A) presented anti-AChE activity at 10 muM. Thirteen compounds B showed the excellent activity with IC50 values of 0.11-0.76 muM and high selectivity toward AChE relative to butyrylcholinesterase (BChE), superior to galantamine (IC50 = 0.79 muM), a selective AChE inhibitor drug. Kinetic analysis showed that the action mechanisms of both compounds B and A are a competitive inhibition model. Structure-activity relationship analyses showed that the C = N(+) moiety is a determinant for the activity. Substituents at 6, 7 or 4' site, the indole-N-alkyl and the aromatization of the C-ring can significantly improve the activity. Molecular docking studies showed that the compounds could combine with the active site of AChE by the pi-pi or cation-pi action between the carboline ring and the phenyl rings of the residues, and the beta-carboline moiety is embedded in a cavity surrounded by four aromatic residues of Trp86, Tyr337, Trp439 and Tyr449. The present results strongly suggest that the para-position of the D-ring should be a preferred modification site for further structural optimization design. Thus, 2-aryl-9-methyl-beta-carboliniums emerged as novel and promising tool compounds for the development of new AChE inhibitor agents. Title: Unique versus Redundant Functions of Neuroligin Genes in Shaping Excitatory and Inhibitory Synapse Properties Chanda S, Hale WD, Zhang B, Wernig M, Sudhof TC Ref: Journal of Neuroscience, 37:6816, 2017 : PubMed ESTHER: Chanda_2017_J.Neurosci_37_6816 PubMedSearch: Chanda 2017 J.Neurosci 37 6816 PubMedID: 28607166 Abstract Neuroligins are evolutionarily conserved postsynaptic cell adhesion molecules that interact with presynaptic neurexins. Neurons express multiple neuroligin isoforms that are targeted to specific synapses, but their synaptic functions and mechanistic redundancy are not completely understood. Overexpression or RNAi-mediated knockdown of neuroligins, respectively, causes a dramatic increase or decrease in synapse density, whereas genetic deletions of neuroligins impair synapse function with only minor effects on synapse numbers, raising fundamental questions about the overall physiological role of neuroligins. Here, we have systematically analyzed the effects of conditional genetic deletions of all major neuroligin isoforms (i.e., NL1, NL2, and NL3), either individually or in combinations, in cultured mouse hippocampal and cortical neurons. We found that conditional genetic deletions of neuroligins caused no change or only a small change in synapses numbers, but strongly impaired synapse function. This impairment was isoform specific, suggesting that neuroligins are not functionally redundant. Sparse neuroligin deletions produced phenotypes comparable to those of global deletions, indicating that neuroligins function in a cell-autonomous manner. Mechanistically, neuroligin deletions decreased the synaptic levels of neurotransmitter receptors and had no effect on presynaptic release probabilities. Overexpression of neuroligin-1 in control or neuroligin-deficient neurons increased synaptic transmission and synapse density but not spine numbers, suggesting that these effects reflect a gain-of-function mechanism; whereas overexpression of neuroligin-3, which, like neuroligin-1 is also targeted to excitatory synapses, had no comparable effect. Our data demonstrate that neuroligins are required for the physiological organization of neurotransmitter receptors in postsynaptic specializations and suggest that they do not play a major role in synapse formation.SIGNIFICANCE STATEMENT Human neuroligin genes have been associated with autism, but the cellular functions of different neuroligins and their molecular mechanisms remain incompletely understood. Here, we performed comparative analyses in cultured mouse neurons of all major neuroligin isoforms, either individually or in combinations, using conditional knockouts. We found that neuroligin deletions did not affect synapse numbers but differentially impaired excitatory or inhibitory synaptic functions in an isoform-specific manner. These impairments were due, at least in part, to a decrease in synaptic distribution of neurotransmitter receptors upon deletion of neuroligins. Conversely, the overexpression of neuroligin-1 increased synapse numbers but not spine numbers. Our results suggest that various neuroligin isoforms perform unique postsynaptic functions in organizing synapses but are not essential for synapse formation or maintenance. Title: Conditional Deletion of All Neurexins Defines Diversity of Essential Synaptic Organizer Functions for Neurexins Chen LY, Jiang M, Zhang B, Gokce O, Sudhof TC Ref: Neuron, 94:611, 2017 : PubMed ESTHER: Chen_2017_Neuron_94_611 PubMedSearch: Chen 2017 Neuron 94 611 PubMedID: 28472659 Inhibitor(s) related to this paper: Tri-M-cresyl-phosphate Abstract Neurexins are recognized as key organizers of synapses that are essential for normal brain function. However, it is unclear whether neurexins are fundamental building blocks of all synapses with similar overall functions or context-dependent specifiers of synapse properties. To address this question, we produced triple cKO (conditional knockout) mice that allow ablating all neurexin expression in mice. Using neuron-specific manipulations combined with immunocytochemistry, paired recordings, and two-photon Ca2+ imaging, we analyzed excitatory synapses formed by climbing fibers on Purkinje cells in cerebellum and inhibitory synapses formed by parvalbumin- or somatostatin-positive interneurons on pyramidal layer 5 neurons in the medial prefrontal cortex. After pan-neurexin deletions, we observed in these synapses severe but dramatically different synaptic phenotypes that ranged from major impairments in their distribution and function (climbing-fiber synapses) to large decreases in synapse numbers (parvalbumin-positive synapses) and severe alterations in action potential-induced presynaptic Ca2+ transients (somatostatin-positive synapses). Thus, neurexins function primarily as context-dependent specifiers of synapses. Title: Conditional ablation of neuroligin-1 in CA1 pyramidal neurons blocks LTP by a cell-autonomous NMDA receptor-independent mechanism Jiang M, Polepalli J, Chen LY, Zhang B, Sudhof TC, Malenka RC Ref: Mol Psychiatry, 22:375, 2017 : PubMed ESTHER: Jiang_2017_Mol.Psychiatry_22_375 PubMedSearch: Jiang 2017 Mol.Psychiatry 22 375 PubMedID: 27217145 Abstract Neuroligins are postsynaptic cell-adhesion molecules implicated in autism and other neuropsychiatric disorders. Despite extensive work, the role of neuroligins in synapse function and plasticity, especially N-methyl-d-aspartate (NMDA) receptor (NMDAR)-dependent long-term potentiation (LTP), remains unclear. To establish which synaptic functions unequivocally require neuroligins, we analyzed single and triple conditional knockout (cKO) mice for all three major neuroligin isoforms (NL1-NL3). We inactivated neuroligins by stereotactic viral expression of Cre-recombinase in hippocampal CA1 region pyramidal neurons at postnatal day 0 (P0) or day 21 (P21) and measured synaptic function, synaptic plasticity and spine numbers in acute hippocampal slices 2-3 weeks later. Surprisingly, we find that ablation of neuroligins in newborn or juvenile mice only modestly impaired basal synaptic function in hippocampus and caused no alteration in postsynaptic spine numbers. However, triple cKO of NL1-NL3 or single cKO of NL1 impaired NMDAR-mediated excitatory postsynaptic currents and abolished NMDAR-dependent LTP. Strikingly, the NL1 cKO also abolished LTP elicited by activation of L-type Ca2+-channels during blockade of NMDARs. These findings demonstrate that neuroligins are generally not essential for synapse formation in CA1 pyramidal neurons but shape synaptic properties and that NL1 specifically is required for LTP induced by postsynaptic Ca2+-elevations, a function which may contribute to the pathophysiological role of neuroligins in brain disorders. Title: A new facet of NDRG1 in pancreatic ductal adenocarcinoma: Suppression of glycolytic metabolism Liu W, Zhang B, Hu Q, Qin Y, Xu W, Shi S, Liang C, Meng Q, Xiang J and Xu J <9 more author(s)> Liu W, Zhang B, Hu Q, Qin Y, Xu W, Shi S, Liang C, Meng Q, Xiang J, Liang D, Ji S, Liu J, Hu P, Liu L, Liu C, Long J, Ni Q, Yu X, Xu J (- 9) Ref: Int J Oncol, 50:1792, 2017 : PubMed ESTHER: Liu_2017_Int.J.Oncol_50_1792 PubMedSearch: Liu 2017 Int.J.Oncol 50 1792 PubMedID: 28350132 Abstract N-myc downstream-regulated gene 1 (NDRG1) is known as tumor/metastasis suppressor in a variety of cancers including pancreas, being involved in angiogenesis, cancer growth and metastasis. However, the precise molecular mechanism how NDRG1 exerts its inhibitory function in pancreatic cancer remains unclear. In this investigation, we demonstrated that K-Ras plays a vital role in modulating NDRG1 protein level in PDAC cancer cells in vitro, which is mediated through ERK signaling. Noteworthy, K-Ras downstream Akt/mTOR signaling is inhibited upon NDRG1 overexpression, resulting in decease of HIF1alpha level. Moreover, NDRG1 has a unique role in modulating cancer metabolism of pancreatic ductal adenocarcinoma (PDAC). The mechanism accounting for NDRG1 in modulating aerobic glycolysis, at least partly, relied on its regulation of glycolysis genes including GLUT1, HK2, LDHA and PDK1. Additionally, NDRG1 is shown to suppress the activity of HIF1alpha, which is responsible for regulation of glycolysis enzymes. The current study is the first to elucidate a unique facet of the potent tumor/metastasis suppressor NDRG1 in the regulation of PDAC glycolysis, leading to important insights into the mechanism by which NDRG1 exert inhibitory function in PDAC. Title: 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: A novel mechanism of ascorbate direct modulation of soluble epoxide hydrolase Zhang B, Kandhi S, Yang YM, Le Y, Deng W, Qin J, Jiang H, Froogh G, Sun D, Huang A Ref: Prostaglandins Other Lipid Mediat, 131:59, 2017 : PubMed ESTHER: Zhang_2017_Prostaglandins.Other.Lipid.Mediat_131_59 PubMedSearch: Zhang 2017 Prostaglandins.Other.Lipid.Mediat 131 59 PubMedID: 28827137 Abstract To test the hypothesis that VitC downregulates soluble epoxide hydrolase (sEH, responsible for converting EETs to DHETs) to stabilize tissue EETs, the heart, lung, liver, kidney, and mesenteric arteries isolated from normal rats were incubated with VitC (1000muM) for 72h, and tissue sEH expression, along with EET and DHET profiles were assessed. VitC caused significant reductions in sEH mRNA and protein content in the liver, heart and vessels, but had no effect on renal and pulmonary sEH expression, revealing a tissue-specific regulatory mechanism. The functional consequence of reduced sEH expression was validated by LC/MS/MS-based analysis, indicating that in VitC-treated tissues that displayed downregulation of sEH mRNA and protein expression, total DHETs were significantly lower, accompanied with a greater ratio of EETs/DHETs than those in VitC-untreated groups. Thus, VitC elicits a transcriptional downregulation of sEH in normal liver, heart, and vessels to reduce EET degradation and increase EET bioavailability. Title: Developmental plasticity shapes synaptic phenotypes of autism-associated neuroligin-3 mutations in the calyx of Held Zhang B, Seigneur E, Wei P, Gokce O, Morgan J, Sudhof TC Ref: Mol Psychiatry, 22:1483, 2017 : PubMed ESTHER: Zhang_2017_Mol.Psychiatry_22_1483 PubMedSearch: Zhang 2017 Mol.Psychiatry 22 1483 PubMedID: 27725662 Abstract Neuroligins are postsynaptic cell-adhesion molecules that bind to presynaptic neurexins. Mutations in neuroligin-3 predispose to autism, but how such mutations affect synaptic function remains incompletely understood. Here we systematically examined the effect of three autism-associated mutations, the neuroligin-3 knockout, the R451C knockin, and the R704C knockin, on synaptic transmission in the calyx of Held, a central synapse ideally suited for high-resolution analyses of synaptic transmission. Surprisingly, germline knockout of neuroligin-3 did not alter synaptic transmission, whereas the neuroligin-3 R451C and R704C knockins decreased and increased, respectively, synaptic transmission. These puzzling results prompted us to ask whether neuroligin-3 mutant phenotypes may be reshaped by developmental plasticity. Indeed, conditional knockout of neuroligin-3 during late development produced a marked synaptic phenotype, whereas conditional knockout of neuroligin-3 during early development caused no detectable effect, mimicking the germline knockout. In canvassing potentially redundant candidate genes, we identified developmentally early expression of another synaptic neurexin ligand, cerebellin-1. Strikingly, developmentally early conditional knockout of cerebellin-1 only modestly impaired synaptic transmission, whereas in contrast to the individual single knockouts, developmentally early conditional double knockout of both cerebellin-1 and neuroligin-3 severely decreased synaptic transmission. Our data suggest an unanticipated mechanism of developmental compensation whereby cerebellin-1 and neuroligin-3 functionally occlude each other during development of calyx synapses. Thus, although acute manipulations more likely reveal basic gene functions, developmental plasticity can be a major factor in shaping the overall phenotypes of genetic neuropsychiatric disorders. Title: Associations of Rs3744841 and Rs3744843 Polymorphisms in Endothelial Lipase Gene with Risk of Coronary Artery Disease and Lipid Levels in a Chinese Population Cai G, Zhang B, Ma C, Shi G, Weng W, Xue S Ref: PLoS ONE, 11:e0162727, 2016 : PubMed ESTHER: Cai_2016_PLoS.One_11_e0162727 PubMedSearch: Cai 2016 PLoS.One 11 e0162727 PubMedID: 27612170 Abstract OBJECTIVE: The aim of the present study was to assess the association between the 2037T/C and 2237G/A polymorphisms in the EL gene and the risk of CAD and lipid levels in a Chinese population. Title: Endothelial lipase genetic polymorphisms and the lipid-lowering response in patients with coronary artery disease on rosuvastatin Cai G, Zhang B, Shi G, Weng W, Yang L, Xue S Ref: Lipids Health Dis, 15:148, 2016 : PubMed ESTHER: Cai_2016_Lipids.Health.Dis_15_148 PubMedSearch: Cai 2016 Lipids.Health.Dis 15 148 PubMedID: 27600285 Abstract BACKGROUND: Endothelial lipase (EL) plays an important role in the regulation of lipid metabolism by reducing the high density lipoprotein cholesterol (HDL-C) levels and inducing the macrophages to take up native low density lipoprotein cholesterol (LDL-C). Our purpose was to investigate the impact of EL genetic polymorphisms on the lipid-lowering effects of rosuvastatin in Chinese coronary artery disease (CAD) patients. Title: Targeting Insulin Signaling for the Treatment of Alzheimer's Disease Chen Y, Zhang J, Zhang B, Gong CX Ref: Curr Top Med Chem, 16:485, 2016 : PubMed ESTHER: Chen_2016_Curr.Top.Med.Chem_16_485 PubMedSearch: Chen 2016 Curr.Top.Med.Chem 16 485 PubMedID: 26268336 Abstract Sporadic Alzheimer's disease (AD) is caused by multiple etiological factors, among which impaired brain insulin signaling and decreased brain glucose metabolism are important metabolic factors. Contrary to previous belief that insulin would not act in the brain, studies in the last three decades have proven important roles of insulin and insulin signaling in various biological functions in the brain. Impaired brain insulin signaling or brain insulin resistance and its role in the molecular pathogenesis of sporadic AD have been demonstrated. Thus, targeting brain insulin signaling for the treatment of cognitive impairment and AD has now attracted much attention in the field of AD drug discovery. This article reviews recent studies that target brain insulin signaling, especially those investigations on intranasal insulin administration and drugs that improve insulin sensitivity, including incretins, dipeptidyl peptidase IV inhibitors, thiazolidinediones, and metformin. These drugs have been previously approved for the treatment of diabetes mellitus, which could expedite their development for the treatment of AD. Although larger clinical trials are needed for validating their efficacy for the treatment of cognitive impairment and AD, results of animal studies and clinical trials available to date are encouraging. Title: Molecular evaluation of herbal compounds as potent inhibitors of acetylcholinesterase for the treatment of Alzheimer's disease Chen YX, Li GZ, Zhang B, Xia ZY, Zhang M Ref: Mol Med Rep, 14:446, 2016 : PubMed ESTHER: Chen_2016_Mol.Med.Rep_14_446 PubMedSearch: Chen 2016 Mol.Med.Rep 14 446 PubMedID: 27176468 Abstract Alzheimer's disease (AD) is a progressive disease and the predominant cause of dementia. Common symptoms include short-term memory loss, and confusion with time and place. Individuals with AD depend on their caregivers for assistance, and may pose a burden to them. The acetylcholinesterase (AChE) enzyme is a key target in AD and inhibition of this enzyme may be a promising strategy in the drug discovery process. In the present study, an inhibitory assay was carried out against AChE using total alkaloidal plants and herbal extracts commonly available in vegetable markets. Subsequently, molecular docking simulation analyses of the bioactive compounds present in the plants were conducted, as well as a proteinligand interaction analysis. The stability of the docked proteinligand complex was assessed by 20 ns molecular dynamics simulation. The inhibitory assay demonstrated that Uncaria rhynchophylla and Portulaca oleracea were able to inhibit AChE. In addition, molecular docking simulation analyses indicated that catechin present in Uncaria rhynchophylla, and dopamine and norepinephrine present in Portulaca oleracea, had the best docking scores and interaction energy. In conclusion, catechin in Uncaria rhynchophylla, and dopamine and norepinephrine in Portulaca oleracea may be used to treat AD. Title: Metabolic Profile of 3-Acetyl-11-Keto-beta-Boswellic Acid and 11-Keto-beta-Boswellic Acid in Human Preparations In Vitro, Species Differences, and Bioactivity Variation Cui Y, Tian X, Ning J, Wang C, Yu Z, Wang Y, Huo X, Jin L, Deng S and Ma X <1 more author(s)> Cui Y, Tian X, Ning J, Wang C, Yu Z, Wang Y, Huo X, Jin L, Deng S, Zhang B, Ma X (- 1) Ref: AAPS J, 18:1273, 2016 : PubMed ESTHER: Cui_2016_AAPS.J_18_1273 PubMedSearch: Cui 2016 AAPS.J 18 1273 PubMedID: 27329304 Abstract 3-Acetyl-11-keto-beta-boswellic acid (AKBA) and 11-keto-beta-boswellic acid (KBA) are widely used in the clinic as anti-inflammatory drugs. However, these drugs have the poor bioavailability, which may be caused by their extensive metabolism. In this study, we systemically characterized both phase I and II metabolism of AKBA and KBA in vitro. In total, four major metabolites were firstly biosynthesized and identified using 1D and 2D NMR spectroscopy. Among them, three metabolites were novel. The kinetic parameters (K m , V max , CL int, and K i ) were also analyzed systematically in various biological samples. Finally, the deacetylation of AKBA and hydroxylation of KBA were confirmed to be the major metabolic pathways based on their large CL int and the high amounts of KBA (46.7%) and hydroxylated KBA (50.8%) along with a low amount of AKBA (2.50%) in human primary hepatocytes. Carboxylesterase 2 (CE2) selectively catalyzed the deacetylation of AKBA to form KBA. Although CYP3A4, CYP3A5, and CYP3A7 catalyzed the metabolism of KBA, CYP3A4 played a predominant role in the hydroxylation reaction of KBA in human. Notably, deacetylation and regioselective hydroxylation exhibited considerable species differences. Deacetylation was only observed in human liver microsomes and primary human hepatocytes; 21- and 20-mono-hydroxylation of KBA were primarily observed in human, monkey, and dog; and 16- and 30-mono-hydroxylation were observed in other species. More importantly, all four mono-hydroxylation metabolites exhibited a moderate anti-inflammatory activity. The 21- and 20-hydroxylation metabolites inhibited the expression of iNOS, the LPS-induced activation of IkBalpha and p65 phosphorylation, and suppressed p65 nuclear translocation in RAW264.7 cells. Title: Targeting of cancerassociated fibroblasts enhances the efficacy of cancer chemotherapy by regulating the tumor microenvironment Li M, Yin T, Shi H, Wen Y, Zhang B, Chen M, Xu G, Ren K, Wei Y Ref: Mol Med Rep, 13:2476, 2016 : PubMed ESTHER: Li_2016_Mol.Med.Rep_13_2476 PubMedSearch: Li 2016 Mol.Med.Rep 13 2476 PubMedID: 26846566 Abstract Cancerassociated fibroblasts (CAFs), key components of the tumor stroma, can regulate tumorigenesis by altering the tumor microenvironment in variety of ways to promote angiogenesis, recruit inflammatory immune cells and remodel the extracellular matrix. Using a murine xenograft model of colon carcinoma, the present study observed that oxaliplatin increased the accumulation of CAFs and stimulated the production of cytokines associated with CAFs. When oxaliplatin was combined with the smallmolecule dipeptidyl peptidase inhibitor PT100, which inhibits CAFs by targeting fibroblast activation protein (FAP), the accumulation of CAFs was markedly reduced, xenograft tumor growth was significantly suppressed and the survival of the mice increased, compared to those of mice treated with oxaliplatin or PT100 alone. Furthermore, the xenograft tumor tissues of mice treated with oxaliplatin and PT100 contained lower numbers of tumorassociated macrophages and dendritic cells, expressed lower levels of cytokines associated with CAFs and had a lower density of CD31+ endothelial cells. The present study demonstrated that pharmacological inhibition of CAFs improved the response to chemotherapy, reduced the recruitment of immune tumorpromoting cells and inhibited angiogenesis. Combining chemotherapy with agents which target CAFs may represent a novel strategy for improving the efficacy of chemotherapy and reducing chemoresistance. Title: Synthesis and biological evaluation of triazole based uracil derivatives as novel DPP-4 inhibitors Li Q, Han L, Zhang B, Zhou J, Zhang H Ref: Org Biomol Chem, 14:9598, 2016 : PubMed ESTHER: Li_2016_Org.Biomol.Chem_14_9598 PubMedSearch: Li 2016 Org.Biomol.Chem 14 9598 PubMedID: 27714283 Abstract A series of triazole based uracil derivatives were designed and synthesized as novel DPP-4 inhibitors. Compound A01 was identified as a lead compound for SAR studies focused on the structural modification at the S(2') subsite of DPP-4. The novel analogues A02-A25 were obtained by modifying the substituents at the phenyl group, and B01-B09, by introducing the carbonyl group. On screening in DPP-4, compounds B03, B04 and B08 showed a significant improvement in DPP-4 inhibitory activities compared to compound A01 and showed comparable activities to the marketed DPP-4 inhibitor, alogliptin. Docking studies revealed new favorable binding modes of designed compounds in the S(2') subsite and proved that structural modifications in the S(2') subsite were an effective option to increase the inhibition of DPP-4. In vitro DPP-8 and DPP-9 tests indicated that all compounds showed excellent selectivity against DPP-8 and DPP-9. Further in vivo evaluation showed that compound B04 could significantly improve oral glucose tolerance in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice. These data suggest that compound B04 could be a promising DPP-4 inhibitor for future treatment of T2DM. Title: Comparative Genomics Analysis of Streptomyces Species Reveals Their Adaptation to the Marine Environment and Their Diversity at the Genomic Level Tian X, Zhang Z, Yang T, Chen M, Li J, Chen F, Yang J, Li W, Zhang B and Xiao J <3 more author(s)> Tian X, Zhang Z, Yang T, Chen M, Li J, Chen F, Yang J, Li W, Zhang B, Wu J, Zhang C, Long L, Xiao J (- 3) Ref: Front Microbiol, 7:998, 2016 : PubMed ESTHER: Tian_2016_Front.Microbiol_7_998 PubMedSearch: Tian 2016 Front.Microbiol 7 998 PubMedID: 27446038 Gene_locus related to this paper: 9actn-a0a1e7k9d4, 9actn-a0a1e7l883, 9actn-a0a1e7kw84, 9actn-a0a1e7kkk9, 9actn-a0a1e7jip1, 9actn-a0a1e7jjj1, 9actn-a0a1e7k159, 9actn-a0a1e7kfw2, 9actn-a0a1e7l1n0, 9actn-a0a1e7jf99 Abstract Over 200 genomes of streptomycete strains that were isolated from various environments are available from the NCBI. However, little is known about the characteristics that are linked to marine adaptation in marine-derived streptomycetes. The particularity and complexity of the marine environment suggest that marine streptomycetes are genetically diverse. Here, we sequenced nine strains from the Streptomyces genus that were isolated from different longitudes, latitudes, and depths of the South China Sea. Then we compared these strains to 22 NCBI downloaded streptomycete strains. Thirty-one streptomycete strains are clearly grouped into a marine-derived subgroup and multiple source subgroup-based phylogenetic tree. The phylogenetic analyses have revealed the dynamic process underlying streptomycete genome evolution, and lateral gene transfer is an important driving force during the process. Pan-genomics analyses have revealed that streptomycetes have an open pan-genome, which reflects the diversity of these streptomycetes and guarantees the species a quick and economical response to diverse environments. Functional and comparative genomics analyses indicate that the marine-derived streptomycetes subgroup possesses some common characteristics of marine adaptation. Our findings have expanded our knowledge of how ocean isolates of streptomycete strains adapt to marine environments. The availability of streptomycete genomes from the South China Sea will be beneficial for further analysis on marine streptomycetes and will enrich the South China Sea's genetic data sources. Title: Neuroligins Are Selectively Essential for NMDAR Signaling in Cerebellar Stellate Interneurons Zhang B, Sudhof TC Ref: Journal of Neuroscience, 36:9070, 2016 : PubMed ESTHER: Zhang_2016_J.Neurosci_36_9070 PubMedSearch: Zhang 2016 J.Neurosci 36 9070 PubMedID: 27581450 Abstract Neuroligins are postsynaptic cell-adhesion molecules that contribute to synapse specification. However, many other postsynaptic cell-adhesion molecules are known and the relative contributions of neuroligins versus other such molecules in different types of synapses and neurons remains largely unknown. Here, we have studied the role of neuroligins in cerebellar stellate interneurons that participate in a well defined circuit that converges on Purkinje cells as the major output neurons of cerebellar cortex. By crossing triple conditional knock-out (cKO) mice targeting all three major neuroligins [neuroligin-1 to neuroligin-3 (NL123)] with parvalbumin-Cre (PV-Cre) transgenic mice, we deleted neuroligins from inhibitory cerebellar interneurons and Purkinje cells, allowing us to study the effects of neuroligin deletions on cerebellar stellate cell synapses by electrophysiology in acute slices. PV-Cre/NL123 cKO mice did not exhibit gross alterations of cerebellar structure or cerebellar interneuron morphology. Strikingly, electrophysiological recordings in stellate cells from these PV-Cre/NL123 cKO mice revealed a large decrease in NMDAR-mediated excitatory synaptic responses, which, in stellate cells, are largely extrasynaptic, without a change in AMPA-receptor-mediated responses. Parallel analyses in PV-Cre/NL1 mice that are single NL1 cKO mice uncovered the same phenotype, demonstrating that NL1 is responsible for recruiting extrasynaptic NMDARs. Moreover, we observed only a modest impairment in inhibitory synaptic responses in stellate cells lacking NL123 despite a nearly complete suppression of inhibitory synaptic transmission in Purkinje cells by the same genetic manipulation. Our results suggest that, unlike other types of neurons investigated, neuroligins are selectively essential in cerebellar stellate interneurons for enabling the function of extrasynaptic NMDARs. SIGNIFICANCE STATEMENT: Neuroligins are postsynaptic cell-adhesion molecules genetically linked to autism. However, the contributions of neuroligins to interneuron functions remain largely unknown. Here, we analyzed the role of neuroligins in cerebellar stellate interneurons. We deleted neuroligin-1, neuroligin-2, and neuroligin-3, the major cerebellar neuroligin isoforms, from stellate cells in triple NL123 conditional knock-out mice and analyzed synaptic responses by acute slice electrophysiology. We find that neuroligins are selectively essential for extrasynaptic NMDAR-mediated signaling, but dispensable for both AMPAR-mediated and inhibitory synaptic transmission. Our results reveal a critical and selective role for neuroligins in the regulation of NMDAR responses in cerebellar stellate interneurons. Title: Pretreatment serum pseudocholinesterase level as a novel prognostic biomarker for upper tract urothelial carcinoma Zhang B, Shen C, Jin J, Song Y, Zhao Z, Zhang X, Wang G, Fan Y, Mi Y and Han W <5 more author(s)> Zhang B, Shen C, Jin J, Song Y, Zhao Z, Zhang X, Wang G, Fan Y, Mi Y, Hu S, Cui Y, Zhou L, He Z, Yu W, Han W (- 5) Ref: International Urology & Nephrology, 48:1993, 2016 : PubMed ESTHER: Zhang_2016_Int.Urol.Nephrol_48_1993 PubMedSearch: Zhang 2016 Int.Urol.Nephrol 48 1993 PubMedID: 27554671 Abstract PURPOSE: Pretreatment serum pseudocholinesterase (PChE) has been reported to be a prognostic predictor in several cancers. However, the prognostic significance of serum PChE level in patients with upper tract urothelial carcinoma (UTUC) remains unknown. Title: Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: Evidence from an endocannabinoid system-level analysis Carey CE, Agrawal A, Zhang B, Conley ED, Degenhardt L, Heath AC, Li D, Lynskey MT, Martin NG and Bogdan R <5 more author(s)> Carey CE, Agrawal A, Zhang B, Conley ED, Degenhardt L, Heath AC, Li D, Lynskey MT, Martin NG, Montgomery GW, Wang T, Bierut LJ, Hariri AR, Nelson EC, Bogdan R (- 5) Ref: J Abnorm Psychol, 124:860, 2015 : PubMed ESTHER: Carey_2015_J.Abnorm.Psychol_124_860 PubMedSearch: Carey 2015 J.Abnorm.Psychol 124 860 PubMedID: 26595473 Abstract Despite evidence for heritable variation in cannabis involvement and the discovery of cannabinoid receptors and their endogenous ligands, no consistent patterns have emerged from candidate endocannabinoid (eCB) genetic association studies of cannabis involvement. Given interactions between eCB and stress systems and associations between childhood stress and cannabis involvement, it may be important to consider childhood adversity in the context of eCB-related genetic variation. We employed a system-level gene-based analysis of data from the Comorbidity and Trauma Study (N = 1,558) to examine whether genetic variation in six eCB genes (anabolism: DAGLA, DAGLB, NAPEPLD; catabolism: MGLL, FAAH; binding: CNR1; SNPs N = 65) and childhood sexual abuse (CSA) predict cannabis dependence symptoms. Significant interactions with CSA emerged for MGLL at the gene level (p = .009), and for rs604300 within MGLL (DeltaR2 = .007, p < .001), the latter of which survived SNP-level Bonferroni correction and was significant in an additional sample with similar directional effects (N = 859; DeltaR2 = .005, p = .026). Furthermore, in a third sample (N = 312), there was evidence that rs604300 genotype interacts with early life adversity to predict threat-related basolateral amygdala habituation, a neural phenotype linked to the eCB system and addiction (DeltaR2 = .013, p = .047). Rs604300 may be related to epigenetic modulation of MGLL expression. These results are consistent with rodent models implicating 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid metabolized by the enzyme encoded by MGLL, in the etiology of stress adaptation related to cannabis dependence, but require further replication. Title: Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents Griebel G, Pichat P, Beeske S, Leroy T, Redon N, Jacquet A, Francon D, Bert L, Even L and Escoubet J <21 more author(s)> Griebel G, Pichat P, Beeske S, Leroy T, Redon N, Jacquet A, Francon D, Bert L, Even L, Lopez-Grancha M, Tolstykh T, Sun F, Yu Q, Brittain S, Arlt H, He T, Zhang B, Wiederschain D, Bertrand T, Houtmann J, Rak A, Vallee F, Michot N, Auge F, Menet V, Bergis OE, George P, Avenet P, Mikol V, Didier M, Escoubet J (- 21) Ref: Sci Rep, 5:7642, 2015 : PubMed ESTHER: Griebel_2015_Sci.Rep_5_7642 PubMedSearch: Griebel 2015 Sci.Rep 5 7642 PubMedID: 25560837 Gene_locus related to this paper: mouse-ABHD6 Inhibitor(s) related to this paper: 64D Abstract Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents. Title: Effects of harmine, an acetylcholinesterase inhibitor, on spatial learning and memory of APP/PS1 transgenic mice and scopolamine-induced memory impairment mice He D, Wu H, Wei Y, Liu W, Huang F, Shi H, Zhang B, Wu X, Wang C Ref: European Journal of Pharmacology, 768:96, 2015 : PubMed ESTHER: He_2015_Eur.J.Pharmacol_768_96 PubMedSearch: He 2015 Eur.J.Pharmacol 768 96 PubMedID: 26526348 Inhibitor(s) related to this paper: Harmine Abstract Harmine, a beta-carboline alkaloid present in Peganum harmala with a wide spectrum of pharmacological activities, has been shown to exert strong inhibition against acetylcholinesterase in vitro. However, whether it can rescue the impaired cognition has not been elucidated yet. In current study, we examined its effects on scopolamine-induced memory impairment mice and APP/PS1 transgenic mice, one of the models for Alzheimer's disease, using Morris Water Maze test. In addition, whether harmine could penetrate blood brain barrier, interact with and inhibit acetylcholinesterase, and activate downstream signaling network was also investigated. Our results showed that harmine (20mg/kg) administered by oral gavage for 2 weeks could effectively enhance the spatial cognition of C57BL/6 mice impaired by intraperitoneal injection of scopolamine (1mg/kg). Meanwhile, long-term consumption of harmine (20mg/kg) for 10 weeks also slightly benefited the impaired memory of APP/PS1 mice. Furthermore, harmine could pass through blood brain barrier, penetrate into the brain parenchyma shortly after oral administration, and modulate the expression of Egr-1, c-Jun and c-Fos. Molecular docking assay disclosed that harmine molecule could directly dock into the catalytic active site of acetylcholinesterase, which was partially confirmed by its in vivo inhibitory activity on acetylcholinesterase. Taken together, all these results suggested that harmine could ameliorate impaired memory by enhancement of cholinergic neurotransmission via inhibiting the activity of acetylcholinesterase, which may contribute to its clinical use in the therapy of neurological diseases characterized with acetylcholinesterase deficiency. Title: Reward and Toxicity of Cocaine Metabolites Generated by Cocaine Hydrolase Murthy V, Geng L, Gao Y, Zhang B, Miller JD, Reyes S, Brimijoin S Ref: Cellular Molecular Neurobiology, 35:819, 2015 : PubMed ESTHER: Murthy_2015_Cell.Mol.Neurobiol_35_819 PubMedSearch: Murthy 2015 Cell.Mol.Neurobiol 35 819 PubMedID: 25814464 Inhibitor(s) related to this paper: Cocaine Abstract Butyrylcholinesterase (BChE) gene therapy is emerging as a promising concept for treatment of cocaine addiction. BChE levels after gene transfer can rise 1000-fold above those in untreated mice, making this enzyme the second most abundant plasma protein. For months or years, gene transfer of a BChE mutated into a cocaine hydrolase (CocH) can maintain enzyme levels that destroy cocaine within seconds after appearance in the blood stream, allowing little to reach the brain. Rapid enzyme action causes a sharp rise in plasma levels of two cocaine metabolites, benzoic acid (BA) and ecgonine methyl ester (EME), a smooth muscle relaxant that is mildly hypotensive and, at best, only weakly rewarding. The present study, utilizing Balb/c mice, tested reward effects and cardiovascular effects of administering EME and BA together at molar levels equivalent to those generated by a given dose of cocaine. Reward was evaluated by conditioned place preference. In this paradigm, cocaine (20 mg/kg) induced a robust positive response but the equivalent combined dose of EME + BA failed to induce either place preference or aversion. Likewise, mice that had undergone gene transfer with mouse CocH (mCocH) showed no place preference or aversion after repeated treatments with a near-lethal 80 mg/kg cocaine dose. Furthermore, a single administration of that same high cocaine dose failed to affect blood pressure as measured using the noninvasive tail-cuff method. These observations confirm that the drug metabolites generated after CocH gene transfer therapy are safe even after a dose of cocaine that would ordinarily be lethal. Title: Anticancer drugs induce hypomethylation of the acetylcholinesterase promoter via a phosphorylated-p38-DNMT1-AChE pathway in apoptotic hepatocellular carcinoma cells Xi Q, Gao N, Yang Y, Ye W, Zhang B, Wu J, Jiang G, Zhang X Ref: International Journal of Biochemistryistry & Cell Biology, 68:21, 2015 : PubMed ESTHER: Xi_2015_Int.J.Biochem.Cell.Biol_68_21 PubMedSearch: Xi 2015 Int.J.Biochem.Cell.Biol 68 21 PubMedID: 26299326 Abstract Apoptosis, also known as programmed cell death, plays an essential role in eliminating excessive, damaged or harmful cells. Previous work has demonstrated that anticancer drugs induce cell apoptosis by inducing cytotoxicity. In recent years, several reports demonstrated modulated expression of DNA methyltransferases 1 (DNMT1) and acetylcholinesterase (AChE) in a variety of tumors. In this study, we showed that the expression of DNMT1 was decreased and the methylation of CpGs in the promoter of AChE was reduced in anticancer drugs-induced apoptotic hepatocellular carcinoma cells. Silencing of DNMT1 expression by AZA or RNA interference (RNAi) restored AChE production and inhibition of AChE expression by RNAi protected HCC cells from anticancer drugs-induced apoptosis. Furthermore, we demonstrated that the regulation of AChE by DNMT1 was involved in the phosphorylated p38 pathway in anticancer drugs-induced apoptosis. In addition, immunohistochemical staining showed that P-p38, DNMT1 and AChE were aberrantly expressed in a subset of HCC tumors. Taken together, we demonstrated the regulation of AChE by DNMT1 and further, we found that this regulation was involved in the phosphorylated p38 pathway in anticancer drugs-induced apoptosis. Title: CYP2C8 rs17110453 and EPHX2 rs751141 two-locus interaction increases susceptibility to ischemic stroke Yi X, Zhang B, Wang C, Liao D, Lin J, Chi L Ref: Gene, 565:85, 2015 : PubMed ESTHER: Yi_2015_Gene_565_85 PubMedSearch: Yi 2015 Gene 565 85 PubMedID: 25839935 Abstract AIMS: Ischemic stroke (IS) is a multifactorial disease caused by a combination of environmental risk factors and genetic susceptibilities. However, few studies have assessed the effects of gene-gene interactions among cytochrome P450 (CYP) pathway genes on the risk of stroke. The present study investigated the association of seven variants of six CYP pathway genes with IS in a Chinese population. MAIN Title: Neuroligins Sculpt Cerebellar Purkinje-Cell Circuits by Differential Control of Distinct Classes of Synapses Zhang B, Chen LY, Liu X, Maxeiner S, Lee SJ, Gokce O, Sudhof TC Ref: Neuron, 87:781, 2015 : PubMed ESTHER: Zhang_2015_Neuron_87_781 PubMedSearch: Zhang 2015 Neuron 87 781 PubMedID: 26291161 Abstract Neuroligins are postsynaptic cell-adhesion molecules that bind presynaptic neurexins and are genetically linked to autism. Neuroligins are proposed to organize synaptogenesis and/or synaptic transmission, but no systematic analysis of neuroligins in a defined circuit is available. Here, we show that conditional deletion of all neuroligins in cerebellar Purkinje cells caused loss of distal climbing-fiber synapses and weakened climbing-fiber but not parallel-fiber synapses, consistent with alternative use of neuroligins and cerebellins as neurexin ligands for the excitatory climbing-fiber versus parallel-fiber synapses. Moreover, deletion of neuroligins increased the size of inhibitory basket/stellate-cell synapses but simultaneously severely impaired their function. Multiple neuroligin isoforms differentially contributed to climbing-fiber and basket/stellate-cell synapse functions, such that inhibitory synapse-specific neuroligin-2 was unexpectedly essential for maintaining normal climbing-fiber synapse numbers. Using systematic analyses of all neuroligins in a defined neural circuit, our data thus show that neuroligins differentially contribute to various Purkinje-cell synapses in the cerebellum in vivo. Title: Omarigliptin (MK-3102): a novel long-acting DPP-4 inhibitor for once-weekly treatment of type 2 diabetes Biftu T, Sinha-Roy R, Chen P, Qian X, Feng D, Kuethe JT, Scapin G, Gao YD, Yan Y and Weber AE <19 more author(s)> Biftu T, Sinha-Roy R, Chen P, Qian X, Feng D, Kuethe JT, Scapin G, Gao YD, Yan Y, Krueger D, Bak A, Eiermann G, He J, Cox J, Hicks J, Lyons K, He H, Salituro G, Tong S, Patel S, Doss G, Petrov A, Wu J, Xu SS, Sewall C, Zhang X, Zhang B, Thornberry NA, Weber AE (- 19) Ref: Journal of Medicinal Chemistry, 57:3205, 2014 : PubMed ESTHER: Biftu_2014_J.Med.Chem_57_3205 PubMedSearch: Biftu 2014 J.Med.Chem 57 3205 PubMedID: 24660890 Gene_locus related to this paper: human-DPP4 Inhibitor(s) related to this paper: Omarigliptin Abstract In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development. Title: The associations between endothelial lipase 584C/T polymorphism and HDL-C level and coronary heart disease susceptibility: a meta-analysis Cai G, Huang Z, Zhang B, Weng W, Shi G Ref: Lipids Health Dis, 13:85, 2014 : PubMed ESTHER: Cai_2014_Lipids.Health.Dis_13_85 PubMedSearch: Cai 2014 Lipids.Health.Dis 13 85 PubMedID: 24886585 Gene_locus related to this paper: human-LIPG Abstract BACKGROUND: Studies had investigated the relationships between endothelial lipase (EL) 584C/T polymorphism and high density lipoprotein cholesterol (HDL-C) level and coronary heart disease (CHD), but the results were controversial. To investigate a more authentic associations between EL 584C/T polymorphism and HDL-C level, and the risk of CHD, we performed this meta-analysis. Title: Phaeodactylibacter xiamenensis gen. nov., sp. nov., a member of the family Saprospiraceae isolated from the marine alga Phaeodactylum tricornutum Chen Z, Lei X, Lai Q, Li Y, Zhang B, Zhang J, Zhang H, Yang L, Zheng W and Zheng T <3 more author(s)> Chen Z, Lei X, Lai Q, Li Y, Zhang B, Zhang J, Zhang H, Yang L, Zheng W, Tian Y, Yu Z, Xu H, Zheng T (- 3) Ref: Int J Syst Evol Microbiol, 64:3496, 2014 : PubMed ESTHER: Chen_2014_Int.J.Syst.Evol.Microbiol_64_3496 PubMedSearch: Chen 2014 Int.J.Syst.Evol.Microbiol 64 3496 PubMedID: 25052393 Gene_locus related to this paper: 9bact-a0a098s2s4, 9bact-a0a098s0v5 Abstract A novel Gram-staining-negative, aerobic, rod-shaped, non-motile, reddish-orange and chemoheterotrophic bacteria, designated strain KD52(T), was isolated from a culture of the alga Phaeodactylum tricornutum from Xiamen, Fujian Province, China. 16S rRNA gene sequence comparison showed that strain KD52(T) was a member of the family Saprospiraceae, forming a distinct lineage with 'Portibacter lacus' KCTC 23747. The 16S rRNA gene sequence similarity between strain KD52(T) and the type strains of species of the family Saprospiraceae ranged from 86% to 89%. Growth occurred at 20-37 degrees C (optimum, 28 degrees C), in the presence of 1-9% (w/v) NaCl (optimum, 2.5%) and at pH 5-8.5 (optimum, pH 6.0). The dominant fatty acids (>10%) of strain KD52(T) were iso-C15:0 (33.1%), iso-C15:1 G (14.8%) and summed feature 3 (comprising C16:1omega7c and/or C16:1omega6c, 13.8%). The major polar lipids were diphosphatidylglycerol, three unidentified phospholipids, four unknown lipids and one unidentified aminolipid. The DNA G+C content was 51 mol% and the major respiratory quinone was menaquinone-7 (MK-7). On the basis of phenotypic data and phylogenetic inference, strain KD52(T) represents a novel species of a new genus, for which the name Phaeodactylibacter xiamenensis gen. nov., sp. nov., is proposed. The type strain is KD52(T) ( = MCCC 1F01213(T) = KCTC 32575(T)). Title: Effect of Cocaine on Ion Channels and Glutamatergic EPSCs in Noradrenergic Locus Coeruleus Neurons Liu LN, Zhu FP, Song MY, Kang XJ, Shang SJ, Zhang XY, Xu HD, Teng SS, Liu B and Xu ZQ <10 more author(s)> Liu LN, Zhu FP, Song MY, Kang XJ, Shang SJ, Zhang XY, Xu HD, Teng SS, Liu B, Kuo ST, Liu W, Li ML, Zhou L, Jiao RY, Wang CH, Wang SR, Yang H, Zhang B, Zhou Z, Xu ZQ (- 10) Ref: Journal of Molecular Neuroscience, 53:345, 2014 : PubMed ESTHER: Liu_2014_J.Mol.Neurosci_53_345 PubMedSearch: Liu 2014 J.Mol.Neurosci 53 345 PubMedID: 24214104 Abstract The locus coeruleus (LC) is an important brainstem area involved in cocaine addiction. However, evidence to elucidate how cocaine modulates the activity of LC neurons remains incomplete. Here, we performed whole recordings in brain slices to evaluate the effects of cocaine on the sodium (Na(+)), potassium (K(+)), calcium (Ca(2+)) channels, and glutamatergic synaptic transmission in the locus coeruleus neurons. Local application of cocaine significantly and reversibly reduced the spontaneous firing rate but did not affect action potential amplitude, rising time, decay time, or half width of noradrenergic locus coeruleus neurons. Moreover, cocaine attenuated the sodium current but did not affect potassium and calcium currents. The N-methyl-D-aspartate receptor mediated excitatory postsynaptic currents were reduced by neuropeptide galanin but not cocaine. All those data demonstrate that cocaine has inhibitory effect on the spontaneous activities and sodium current in locus coeruleus neurons. Therefore, neuromodulation of sodium channel in locus coeruleus neurons may play an important role in drug addiction. Title: AChE inhibition: One dominant factor for swimming behavior changes of Daphnia magna under DDVP exposure Ren Z, Zhang X, Wang X, Qi P, Zhang B, Zeng Y, Fu R, Miao M Ref: Chemosphere, 120C:252, 2014 : PubMed ESTHER: Ren_2014_Chemosphere_120C_252 PubMedSearch: Ren 2014 Chemosphere 120C 252 PubMedID: 25112705 Abstract As a key enzyme that hydrolyzes the neurotransmitter acetylcholine in cholinergic synapses of both vertebrates and invertebrates, acetylcholinesterase (AChE) is strongly inhibited by organophosphates. AChE inhibition may induce the decrease of swimming ability. According to previous research, swimming behavior of different aquatic organisms could be affected by different chemicals, and there is a shortage of research on direct correlation analysis between swimming behavior and biochemical indicators. Therefore, swimming behavior and whole-body AChE activity of Daphnia magna under dichlorvos (DDVP) exposure were identified in order to clarify the relationship between behavioral responses and AChE inhibition in this study. In the beginning, AChE activity was similar in all treatments with the control. During all exposures, the tendency of AChE activity inhibition was the same as the behavioral responses of D. magna. The AChE activity of individuals without movement would decrease to about zero in several minutes. The correlation analysis between swimming behavior of D. magna and AChE activity showed that the stepwise behavioral response was mainly decided by AChE activity. All of these results suggested that the toxicity characteristics of DDVP as an inhibitor of AChE on the swimming behavior of organisms were the same, and the AChE activity inhibition could induce loss of the nerve conduction ability, causing hyperactivity, loss of coordination, convulsions, paralysis and other kinds of behavioral changes, which was illustrated by the stepwise behavioral responses under different environmental stresses. Title: A natural antisense transcript regulates acetylcholinesterase gene expression via epigenetic modification in Hepatocellular Carcinoma Xi Q, Gao N, Zhang X, Zhang B, Ye W, Wu J Ref: International Journal of Biochemistry & Cell Biology, 55C:242, 2014 : PubMed ESTHER: Xi_2014_Int.J.Biochem.Cell.Biol_55C_242 PubMedSearch: Xi 2014 Int.J.Biochem.Cell.Biol 55C 242 PubMedID: 25240585 Abstract In recent years, widespread antisense transcripts have been identified systematically in mammalian cells and are known to regulate gene expression, although their functional significance remains largely unknown. Previous work has identified that acetylcholinesterase (AChE) is expressed aberrantly in various malignant tumors and function as a tumor growth suppressor. However, the mechanism of AChE gene regulation in tumors remains unclear. In this study, we show that the AChE antisense RNA (AChE-AS) play an important role in AChE expression regulation. An inverse relationship was identified between AChE-AS and AChE expression in hepatocellular carcinoma and hepatoma cells. The silenced AChE-AS corresponds to elevated expression of AChE. Furthermore, we demonstrated that reduced AChE-AS increased H3K4 methylation and decreased H3K9 methylation in the AChE promoter region. As expected, elevated AChE levels induced by inhibition of AChE-AS enhanced anticarcinogen-induced apoptosis. These observations demonstrated that AChE-AS modulates AChE expression and exerts an anti-apoptotic effect through direct repression of AChE expression in HCC cells. Thus, natural antisense RNA may play an important role in AChE regulation via affecting the epigenetic modification in the AChE promoter region. Title: Protective effects of perindopril on d-galactose and aluminum trichloride induced neurotoxicity via the apoptosis of mitochondria-mediated intrinsic pathway in the hippocampus of mice Yang W, Shi L, Chen L, Zhang B, Ma K, Liu Y, Qian Y Ref: Brain Research Bulletin, 109:46, 2014 : PubMed ESTHER: Yang_2014_Brain.Res.Bull_109_46 PubMedSearch: Yang 2014 Brain.Res.Bull 109 46 PubMedID: 25290208 Abstract Perindopril, an angiotensin converting enzyme inhibitor, has been reported to improve learning and memory in a mouse or rat model of Alzheimer's disease (AD) induced by injection of beta-amyloid protein. However, the exact mechanism of perindopril on the cognitive deficits is not fully understood. Our previous data have indicated that perindopril improves learning and memory in a mouse model of AD induced by d-galactose (d-gal) and aluminum trichloride (AlCl3) via inhibition of acetylcholinesterase activity and oxidative stress. Whether perindopril also inhibit apoptosis to prevent cognitive decline remains unknown in mice. Therefore, the present study explored the protective effects of perindopril in the hippocampus of mice further. Perindopril (0.5mg/kg/day) was administered intragastrically for 60 days after the mice were given a d-gal (150mg/kg/day) and AlCl3 (10mg/kg/day) intraperitoneally for 90 days. Then the expression of Bcl-2, Bax, Fas, FasL, caspase-3, caspase-8 and caspase-9 were analyzed by RT-PCR and western blotting in the hippocampus. Perindopril significantly decreased caspase-3 and caspase-9 activities, and elevated Bcl-2/Bax ratio in the hippocampus. However, the expression of Fas, FasL and caspase-8 did not change in the hippocampus whether treatment with d-gal and AlCl3 or perindopril. Taken together, the above findings indicated that perindopril inhibited apoptosis in the hippocampus may be another mechanism by which perindopril improves learning and memory functions in d-gal and AlCl3 treated mice. Title: Hsa-miR-132 Regulates Apoptosis in Non-Small Cell Lung Cancer Independent of Acetylcholinesterase Zhang B, Lu L, Zhang X, Ye W, Wu J, Xi Q Ref: Journal of Molecular Neuroscience, 53:335, 2014 : PubMed ESTHER: Zhang_2014_J.Mol.Neurosci_53_335 PubMedSearch: Zhang 2014 J.Mol.Neurosci 53 335 PubMedID: 24158730 Abstract MiR-132 is enriched in the central nerve system and is thought to be involved in neuronal development, maturation and function, and to be associated with several neurological disorders including Alzheimer's disease. In addition to its documented neuronal functions, an emerging role for miR-132 in tumorigenesis has been suggested. Recently, hsa-miR-132 was shown to be modulated in different tumor types. However, its role in non-small cell lung cancer (NSCLC) remains unclear. Here, we show that hsa-miR-132 can initiate apoptosis in NSCLC cells to dramatically attenuate tumor formation in nude mice independent of its effect on the proliferation/apoptosis-associated gene, acetylcholinesterase (AChE). Interestingly, hsa-miR-132 has no pro-apoptotic effect in normal pulmonary trachea epithelium. Taken together, these results suggest that hsa-miR-132 represses NSCLC growth by inducing apoptosis independent of AChE. Title: Genome sequence and transcriptome analyses of the thermophilic zygomycete fungus Rhizomucor miehei Zhou P, Zhang G, Chen S, Jiang Z, Tang Y, Henrissat B, Yan Q, Yang S, Chen CF and Du Z <1 more author(s)> Zhou P, Zhang G, Chen S, Jiang Z, Tang Y, Henrissat B, Yan Q, Yang S, Chen CF, Zhang B, Du Z (- 1) Ref: BMC Genomics, 15:294, 2014 : PubMed ESTHER: Zhou_2014_BMC.Genomics_15_294 PubMedSearch: Zhou 2014 BMC.Genomics 15 294 PubMedID: 24746234 Abstract BACKGROUND: The zygomycete fungi like Rhizomucor miehei have been extensively exploited for the production of various enzymes. As a thermophilic fungus, R. miehei is capable of growing at temperatures that approach the upper limits for all eukaryotes. To date, over hundreds of fungal genomes are publicly available. However, Zygomycetes have been rarely investigated both genetically and genomically. Title: Genome Sequence of Streptomyces violaceusniger Strain SPC6, a Halotolerant Streptomycete That Exhibits Rapid Growth and Development Chen X, Zhang B, Zhang W, Wu X, Zhang M, Chen T, Liu G, Dyson P Ref: Genome Announc, 1:, 2013 : PubMed ESTHER: Chen_2013_Genome.Announc_1_e00494 PubMedSearch: Chen 2013 Genome.Announc 1 e00494 PubMedID: 23868127 Gene_locus related to this paper: 9actn-a0a1d3dv58 Abstract Streptomyces violaceusniger strain SPC6 is a halotolerant streptomycete isolated from the Linze desert in China. The strain has a very high growth rate and a short life cycle for a streptomycete. For surface-grown cultures, the period from spore germination to formation of colonies with mature spore chains is only 2 days at 37 degrees C. Additionally, the strain is remarkably resistant to osmotic, heat, and UV stress compared with other streptomycetes. Analysis of the draft genome sequence indicates that the strain has the smallest reported genome (6.4 Mb) of any streptomycete. The availability of this genome sequence allows us to investigate the genetic basis of adaptation for growth in an extremely arid environment. Title: Draft genome of the wheat A-genome progenitor Triticum urartu Ling HQ, Zhao S, Liu D, Wang J, Sun H, Zhang C, Fan H, Li D, Dong L and Zhang A <39 more author(s)> Ling HQ, Zhao S, Liu D, Wang J, Sun H, Zhang C, Fan H, Li D, Dong L, Tao Y, Gao C, Wu H, Li Y, Cui Y, Guo X, Zheng S, Wang B, Yu K, Liang Q, Yang W, Lou X, Chen J, Feng M, Jian J, Zhang X, Luo G, Jiang Y, Liu J, Wang Z, Sha Y, Zhang B, Tang D, Shen Q, Xue P, Zou S, Wang X, Liu X, Wang F, Yang Y, An X, Dong Z, Zhang K, Luo MC, Dvorak J, Tong Y, Yang H, Li Z, Wang D, Zhang A (- 39) Ref: Nature, 496:87, 2013 : PubMed ESTHER: Ling_2013_Nature_496_87 PubMedSearch: Ling 2013 Nature 496 87 PubMedID: 23535596 Gene_locus related to this paper: triua-m8a764, triua-m8ag96, triua-m7zp69, wheat-w5d1z6, wheat-w5d232, wheat-w5bnf5, triua-t1nm05, wheat-w5cae4, triua-m7ytf7, wheat-w5f1j8, triua-m8ad49, wheat-a0a077s1q2, wheat-a0a3b6c2m6, triua-m7zi26, wheat-a0a3b6at77 Abstract Bread wheat (Triticum aestivum, AABBDD) is one of the most widely cultivated and consumed food crops in the world. However, the complex polyploid nature of its genome makes genetic and functional analyses extremely challenging. The A genome, as a basic genome of bread wheat and other polyploid wheats, for example, T. turgidum (AABB), T. timopheevii (AAGG) and T. zhukovskyi (AAGGA(m)A(m)), is central to wheat evolution, domestication and genetic improvement. The progenitor species of the A genome is the diploid wild einkorn wheat T. urartu, which resembles cultivated wheat more extensively than do Aegilops speltoides (the ancestor of the B genome) and Ae. tauschii (the donor of the D genome), especially in the morphology and development of spike and seed. Here we present the generation, assembly and analysis of a whole-genome shotgun draft sequence of the T. urartu genome. We identified protein-coding gene models, performed genome structure analyses and assessed its utility for analysing agronomically important genes and for developing molecular markers. Our T. urartu genome assembly provides a diploid reference for analysis of polyploid wheat genomes and is a valuable resource for the genetic improvement of wheat. Title: Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26 Lu G, Hu Y, Wang Q, Qi J, Gao F, Li Y, Zhang Y, Zhang W, Yuan Y and Gao GF <4 more author(s)> Lu G, Hu Y, Wang Q, Qi J, Gao F, Li Y, Zhang Y, Zhang W, Yuan Y, Bao J, Zhang B, Shi Y, Yan J, Gao GF (- 4) Ref: Nature, 500:227, 2013 : PubMed ESTHER: Lu_2013_Nature_500_227 PubMedSearch: Lu 2013 Nature 500 227 PubMedID: 23831647 Gene_locus related to this paper: human-DPP4 Abstract The newly emergent Middle East respiratory syndrome coronavirus (MERS-CoV) can cause severe pulmonary disease in humans, representing the second example of a highly pathogenic coronavirus, the first being SARS-CoV. CD26 (also known as dipeptidyl peptidase 4, DPP4) was recently identified as the cellular receptor for MERS-CoV. The engagement of the MERS-CoV spike protein with CD26 mediates viral attachment to host cells and virus-cell fusion, thereby initiating infection. Here we delineate the molecular basis of this specific interaction by presenting the first crystal structures of both the free receptor binding domain (RBD) of the MERS-CoV spike protein and its complex with CD26. Furthermore, binding between the RBD and CD26 is measured using real-time surface plasmon resonance with a dissociation constant of 16.7 nM. The viral RBD is composed of a core subdomain homologous to that of the SARS-CoV spike protein, and a unique strand-dominated external receptor binding motif that recognizes blades IV and V of the CD26 beta-propeller. The atomic details at the interface between the two binding entities reveal a surprising protein-protein contact mediated mainly by hydrophilic residues. Sequence alignment indicates, among betacoronaviruses, a possible structural conservation for the region homologous to the MERS-CoV RBD core, but a high variation in the external receptor binding motif region for virus-specific pathogenesis such as receptor recognition. Title: Synaptic acetylcholinesterase targeted by microRNA-212 functions as a tumor suppressor in non-small cell lung cancer Lu L, Zhang X, Zhang B, Wu J Ref: International Journal of Biochemistry & Cell Biology, 45:2530, 2013 : PubMed ESTHER: Lu_2013_Int.J.Biochem.Cell.Biol_45_2530 PubMedSearch: Lu 2013 Int.J.Biochem.Cell.Biol 45 2530 PubMedID: 23974008 Abstract Acetylcholinesterase expression is modulated in various types of tumor, which suggests it is associated with tumor development; however, the mechanism of acetylcholinesterase gene regulation in tumors remains unclear. Here, we report that acetylcholinesterase is aberrantly expressed in non-small cell lung cancer and is an evolutionarily conserved functional target of miR-212. Acetylcholinesterase expression was negatively regulated by miR-212 in vitro and was inversely correlated with miR-212 expression in vivo. In addition, acetylcholinesterase levels were increased, and miR-212 levels decreased, in non-small cell lung cancer cells during cisplatin-induced apoptosis. We further determined that acetylcholinesterase acted as a pro-apoptotic gene in non-small cell lung cells; and attenuated the growth of xenografts in nude mice when upregulated. In contrast, elevated miR-212 levels preserved the protective effect of acetylcholinesterase silencing by RNA interference against cisplatin-induced apoptosis, whereas restoration of miR-212-resistant synaptic acetylcholinesterase expression inhibited the miR-212 anti-apoptotic function. The results demonstrated that miR-212 exerted an anti-apoptotic effect through direct repression of synaptic acetylcholinesterase expression in non-small cell lung cancer cells. Taken together, our study revealed that synaptic acetylcholinesterase may be a tumor suppressor and is modulated by miR-212 in non-small cell lung cancer. Title: sym-Triazines for Directed Multitarget Modulation of Cholinesterases and Amyloid-beta in Alzheimer's Disease Veloso AJ, Dhar D, Chow AM, Zhang B, Tang DW, Ganesh HV, Mikhaylichenko S, Brown IR, Kerman K Ref: ACS Chem Neurosci, 4:339, 2013 : PubMed ESTHER: Veloso_2013_ACS.Chem.Neurosci_4_339 PubMedSearch: Veloso 2013 ACS.Chem.Neurosci 4 339 PubMedID: 23421685 Abstract Alzheimer's disease (AD) is a complex neurodegenerative disorder marked by numerous causative factors of disease progression, termed pathologies. We report here the synthesis of a small library of novel sym-triazine compounds designed for targeted modulation of multiple pathologies related to AD, specifically human acetylcholinesterase (AChE), butyrylcholinesterase (BCHE), and Abeta aggregation. Rational targeting of AChE was achieved by the incorporation of acetylcholine substrate analogues into a sym-triazine core in either a mono-, di-, or trisubstituted regime. A subset of these derivatives demonstrated improved activity compared to several commercially available cholinesterase inhibitors. High AChE/BCHE selectivity was characteristic of all derivatives, and AChE steady-state kinetics indicated a mixed-type inhibition mechanism. Further integration of multiple hydrophobic phenyl units allowed for improved beta-sheet intercalation into amyloid aggregates. Several highly effective structures exhibited fibril inhibition greater than the previously reported beta-sheet-disrupting penta-peptide, iAbeta5p, evaluated by thioflavin T fluorescence spectroscopy and transmission electron microscopy. Highly effective sym-triazines were shown to be well tolerated by differentiated human neuronal cells, as demonstrated by the absence of adverse effects on cellular viability at a wide range of concentrations. Parallel targeting of multiple pathologies using sym-triazines is presented here as an effective strategy to address the complex, multifactorial nature of AD progression. Title: Cholesteryl ester storage disease: protean presentations of lysosomal Acid lipase deficiency Zhang B, Porto AF Ref: J Pediatr Gastroenterol Nutr, 56:682, 2013 : PubMed ESTHER: Zhang_2013_J.Pediatr.Gastroenterol.Nutr_56_682 PubMedSearch: Zhang 2013 J.Pediatr.Gastroenterol.Nutr 56 682 PubMedID: 23403440 Abstract OBJECTIVE: : LIPA gene mutations result in deficiency of lysosomal acid lipase and present phenotypically as Wolman disease or cholesteryl ester storage disease (CESD) depending on the level of deficiency. Patients with CESD may often be misdiagnosed because symptoms may be nonspecific. Symptoms may present in infancy if there is complete loss of lysosomal acid lipase or in early childhood or adulthood when there is partial loss. The purpose of the present study is to review the literature for pediatric cases of CESD to better understand the phenotype of CESD. Title: Impulse-dependent extracellular resting dopamine concentration in rat striatum in vivo Zuo PL, Yao W, Sun L, Kuo ST, Li Q, Wang SR, Dou HQ, Xu HD, Zhang CX and Zhang B <2 more author(s)> Zuo PL, Yao W, Sun L, Kuo ST, Li Q, Wang SR, Dou HQ, Xu HD, Zhang CX, Kang XJ, Zhou Z, Zhang B (- 2) Ref: Neurochem Int, 62:50, 2013 : PubMed ESTHER: Zuo_2013_Neurochem.Int_62_50 PubMedSearch: Zuo 2013 Neurochem.Int 62 50 PubMedID: 23159778 Abstract The ambient resting dopamine (DA) concentration in brain regulates cognition and motivation. Despite its importance, resting DA level in vivo remains elusive. Here, by high-frequency stimulation of the medial forebrain bundle and immediately following the stimulus-induced DA overflow, we recorded a DA "undershoot" which is a temporal reduction of DA concentration to a level below the baseline. Based on the DA undershoot, we predicted a resting DA concentration of approximately 73nM in rat striatum in vivo. Simulation studies suggested that removing basal DA by DAT during the post-stimulation inhibition of tonic DA release caused the DA undershoot, and the resting concentration of DA modulated the kinetics of the evoked DA transient. The DA undershoot was eliminated by either blocking D2 receptors with haloperidol or blocking the DA transporter (DAT) with cocaine. Therefore, the impulse-dependent resting DA concentration is in the tens of nanomolar range and is modulated by the presynaptic D2 receptors and the DAT in vivo. Title: Complete genome sequence of the metabolically versatile halophilic archaeon Haloferax mediterranei, a poly(3-hydroxybutyrate-co-3-hydroxyvalerate) producer Han J, Zhang F, Hou J, Liu X, Li M, Liu H, Cai L, Zhang B, Chen Y and Xiang H <2 more author(s)> Han J, Zhang F, Hou J, Liu X, Li M, Liu H, Cai L, Zhang B, Chen Y, Zhou J, Hu S, Xiang H (- 2) Ref: Journal of Bacteriology, 194:4463, 2012 : PubMed ESTHER: Han_2012_J.Bacteriol_194_4463 PubMedSearch: Han 2012 J.Bacteriol 194 4463 PubMedID: 22843593 Abstract Haloferax mediterranei, an extremely halophilic archaeon, has shown promise for production of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) from unrelated cheap carbon sources. Here we report the complete genome (3,904,707 bp) of H. mediterranei CGMCC 1.2087, consisting of one chromosome and three megaplasmids. Title: Wnt proteins regulate acetylcholine receptor clustering in muscle cells Zhang B, Liang C, Bates R, Yin Y, Xiong WC, Mei L Ref: Mol Brain, 5:7, 2012 : PubMed ESTHER: Zhang_2012_Mol.Brain_5_7 PubMedSearch: Zhang 2012 Mol.Brain 5 7 PubMedID: 22309736 Abstract BACKGROUND: The neuromuscular junction (NMJ) is a cholinergic synapse that rapidly conveys signals from motoneurons to muscle cells and exhibits a high degree of subcellular specialization characteristic of chemical synapses. NMJ formation requires agrin and its coreceptors LRP4 and MuSK. Increasing evidence indicates that Wnt signaling regulates NMJ formation in Drosophila, C. elegans and zebrafish. Title: Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis Zhang B, Tzartos JS, Belimezi M, Ragheb S, Bealmear B, Lewis RA, Xiong WC, Lisak RP, Tzartos SJ, Mei L Ref: Archives of Neurology, 69:445, 2012 : PubMed ESTHER: Zhang_2012_Arch.Neurol_69_445 PubMedSearch: Zhang 2012 Arch.Neurol 69 445 PubMedID: 22158716 Abstract OBJECTIVES: To determine whether patients with myasthenia gravis (MG) have serum antibodies to lipoprotein-related protein 4 (LRP4), a newly identified receptor for agrin that is essential for neuromuscular junction formation, and to establish whether such antibodies contribute to MG pathogenesis. DESIGN: Serum samples from patients with MG with known status of serum antibodies to the acetylcholine receptor (AChR) and muscle-specific kinase (MuSK) and serum samples from control subjects (healthy individuals and individuals with other diseases) were tested for antibodies to LRP4. Serum samples with such antibodies were tested to determine whether they had the ability to inhibit 2 different functions of LRP4 at the neuromuscular junction. SETTING: Serum samples were collected at the Hellenic Pasteur Institute and Wayne State University. Samples were tested for LRP4 autoantibodies at Georgia Health Sciences University. Other immunoreactivities of the samples were tested at the Hellenic Pasteur Institute, Athens, Greece, or processed through University Laboratories of the Detroit Medical Center, Michigan. Patients The study included 217 patients with MG, 76 patients with other neurologic or psychiatric diseases, and 45 healthy control subjects. Title: Acetylcholinesterase is associated with apoptosis in beta cells and contributes to insulin-dependent diabetes mellitus pathogenesis Zhang B, Yang L, Yu L, Lin B, Hou Y, Wu J, Huang Q, Han Y, Guo L and Zhang X <2 more author(s)> Zhang B, Yang L, Yu L, Lin B, Hou Y, Wu J, Huang Q, Han Y, Guo L, Ouyang Q, Lu L, Zhang X (- 2) Ref: Acta Biochim Biophys Sin (Shanghai), 44:207, 2012 : PubMed ESTHER: Zhang_2012_Acta.Biochim.Biophys.Sin.(Shanghai)_44_207 PubMedSearch: Zhang 2012 Acta.Biochim.Biophys.Sin.(Shanghai) 44 207 PubMedID: 22236578 Abstract Acetylcholinesterase (AChE) expression is pivotal during apoptosis. Indeed, AChE inhibitors partially protect cells from apoptosis. Insulin-dependent diabetes mellitus (IDDM) is characterized in part by pancreatic beta-cell apoptosis. Here, we investigated the role of AChE in the development of IDDM and analyzed protective effects of AChE inhibitors. Multiple low-dose streptozotocin (MLD-STZ) administration resulted in IDDM in a mouse model. Western blot analysis, cytochemical staining, and immunofluorescence staining were used to detect AChE expression in MIN6 cells, primary beta cells, and apoptotic pancreatic beta cells of MLD-STZ-treated mice. AChE inhibitors were administered intraperitoneally to the MLD-STZ mice for 30 days. Blood glucose, plasma insulin, and creatine levels were measured, and glucose tolerance tests were performed. The effects of AChE inhibitors on MIN6 cells were also evaluated. AChE expression was induced in the apoptotic MIN6 cells and primary beta cells in vitro and pancreatic islets in vivo when treated with STZ. Induction and progressive accumulation of AChE in the pancreatic islets were associated with apoptotic beta cells during IDDM development. The administration of AChE inhibitors effectively decreased hyperglycemia and incidence of diabetes, and restored plasma insulin levels and plasma creatine clearance in the MLD-STZ mice. AChE inhibitors partially protected MIN6 cells from the damage caused by STZ treatment. Induction and accumulation of AChE in pancreatic islets and the protective effects of AChE inhibitors on the onset and development of IDDM indicate a close relationship between AChE and IDDM. Title: Structural basis of agrin-LRP4-MuSK signaling Zong Y, Zhang B, Gu S, Lee K, Zhou J, Yao G, Figueiredo D, Perry K, Mei L, Jin R Ref: Genes Dev, 26:247, 2012 : PubMed ESTHER: Zong_2012_Genes.Dev_26_247 PubMedSearch: Zong 2012 Genes.Dev 26 247 PubMedID: 22302937 Abstract Synapses are the fundamental units of neural circuits that enable complex behaviors. The neuromuscular junction (NMJ), a synapse formed between a motoneuron and a muscle fiber, has contributed greatly to understanding of the general principles of synaptogenesis as well as of neuromuscular disorders. NMJ formation requires neural agrin, a motoneuron-derived protein, which interacts with LRP4 (low-density lipoprotein receptor-related protein 4) to activate the receptor tyrosine kinase MuSK (muscle-specific kinase). However, little is known of how signals are transduced from agrin to MuSK. Here, we present the first crystal structure of an agrin-LRP4 complex, consisting of two agrin-LRP4 heterodimers. Formation of the initial binary complex requires the z8 loop that is specifically present in neuronal, but not muscle, agrin and that promotes the synergistic formation of the tetramer through two additional interfaces. We show that the tetrameric complex is essential for neuronal agrin-induced acetylcholine receptor (AChR) clustering. Collectively, these results provide new insight into the agrin-LRP4-MuSK signaling cascade and NMJ formation and represent a novel mechanism for activation of receptor tyrosine kinases. Title: Complete genome sequence of Bifidobacterium longum subsp. longum BBMN68, a new strain from a healthy chinese centenarian Hao Y, Huang D, Guo H, Xiao M, An H, Zhao L, Zuo F, Zhang B, Hu S and Ren F <2 more author(s)> Hao Y, Huang D, Guo H, Xiao M, An H, Zhao L, Zuo F, Zhang B, Hu S, Song S, Chen S, Ren F (- 2) Ref: Journal of Bacteriology, 193:787, 2011 : PubMed ESTHER: Hao_2011_J.Bacteriol_193_787 PubMedSearch: Hao 2011 J.Bacteriol 193 787 PubMedID: 21097614 Gene_locus related to this paper: biflo-BL0073, biflo-BL0336, biflo-BL0581, biflo-BL0582, biflo-BL0682, biflo-BL0787, biflo-BL0807, biflo-BL1109, biflo-BL1514, biflo-PAP, biflo-PTRB Abstract Bifidobacterium longum subsp. longum BBMN68 was isolated from the feces of a healthy centenarian living in an area of BaMa, Guangxi, China, known for longevity. Here we report the main genome features of B. longum strain BBMN68 and the identification of several predicted proteins associated with the ecological niche of longevity. Title: Cluster K mycobacteriophages: insights into the evolutionary origins of mycobacteriophage TM4 Pope WH, Ferreira CM, Jacobs-Sera D, Benjamin RC, Davis AJ, DeJong RJ, Elgin SC, Guilfoile FR, Forsyth MH and Hatfull GF <29 more author(s)> Pope WH, Ferreira CM, Jacobs-Sera D, Benjamin RC, Davis AJ, DeJong RJ, Elgin SC, Guilfoile FR, Forsyth MH, Harris AD, Harvey SE, Hughes LE, Hynes PM, Jackson AS, Jalal MD, MacMurray EA, Manley CM, McDonough MJ, Mosier JL, Osterbann LJ, Rabinowitz HS, Rhyan CN, Russell DA, Saha MS, Shaffer CD, Simon SE, Sims EF, Tovar IG, Weisser EG, Wertz JT, Weston-Hafer KA, Williamson KE, Zhang B, Cresawn SG, Jain P, Piuri M, Jacobs WR, Jr., Hendrix RW, Hatfull GF (- 29) Ref: PLoS ONE, 6:e26750, 2011 : PubMed ESTHER: Pope_2011_PLoS.ONE_6_E26750 PubMedSearch: Pope 2011 PLoS.ONE 6 E26750 PubMedID: 22053209 Gene_locus related to this paper: 9caud-g1d5a5 Abstract Five newly isolated mycobacteriophages--Angelica, CrimD, Adephagia, Anaya, and Pixie--have similar genomic architectures to mycobacteriophage TM4, a previously characterized phage that is widely used in mycobacterial genetics. The nucleotide sequence similarities warrant grouping these into Cluster K, with subdivision into three subclusters: K1, K2, and K3. Although the overall genome architectures of these phages are similar, TM4 appears to have lost at least two segments of its genome, a central region containing the integration apparatus, and a segment at the right end. This suggests that TM4 is a recent derivative of a temperate parent, resolving a long-standing conundrum about its biology, in that it was reportedly recovered from a lysogenic strain of Mycobacterium avium, but it is not capable of forming lysogens in any mycobacterial host. Like TM4, all of the Cluster K phages infect both fast- and slow-growing mycobacteria, and all of them--with the exception of TM4--form stable lysogens in both Mycobacterium smegmatis and Mycobacterium tuberculosis; immunity assays show that all five of these phages share the same immune specificity. TM4 infects these lysogens suggesting that it was either derived from a heteroimmune temperate parent or that it has acquired a virulent phenotype. We have also characterized a widely-used conditionally replicating derivative of TM4 and identified mutations conferring the temperature-sensitive phenotype. All of the Cluster K phages contain a series of well conserved 13 bp repeats associated with the translation initiation sites of a subset of the genes; approximately one half of these contain an additional sequence feature composed of imperfectly conserved 17 bp inverted repeats separated by a variable spacer. The K1 phages integrate into the host tmRNA and the Cluster K phages represent potential new tools for the genetics of M. tuberculosis and related species. Title: Expanding the diversity of mycobacteriophages: insights into genome architecture and evolution Pope WH, Jacobs-Sera D, Russell DA, Peebles CL, Al-Atrache Z, Alcoser TA, Alexander LM, Alfano MB, Alford ST and Hatfull GF <182 more author(s)> Pope WH, Jacobs-Sera D, Russell DA, Peebles CL, Al-Atrache Z, Alcoser TA, Alexander LM, Alfano MB, Alford ST, Amy NE, Anderson MD, Anderson AG, Ang AA, Ares M, Jr., Barber AJ, Barker LP, Barrett JM, Barshop WD, Bauerle CM, Bayles IM, Belfield KL, Best AA, Borjon A, Jr., Bowman CA, Boyer CA, Bradley KW, Bradley VA, Broadway LN, Budwal K, Busby KN, Campbell IW, Campbell AM, Carey A, Caruso SM, Chew RD, Cockburn CL, Cohen LB, Corajod JM, Cresawn SG, Davis KR, Deng L, Denver DR, Dixon BR, Ekram S, Elgin SC, Engelsen AE, English BE, Erb ML, Estrada C, Filliger LZ, Findley AM, Forbes L, Forsyth MH, Fox TM, Fritz MJ, Garcia R, George ZD, Georges AE, Gissendanner CR, Goff S, Goldstein R, Gordon KC, Green RD, Guerra SL, Guiney-Olsen KR, Guiza BG, Haghighat L, Hagopian GV, Harmon CJ, Harmson JS, Hartzog GA, Harvey SE, He S, He KJ, Healy KE, Higinbotham ER, Hildebrandt EN, Ho JH, Hogan GM, Hohenstein VG, Holz NA, Huang VJ, Hufford EL, Hynes PM, Jackson AS, Jansen EC, Jarvik J, Jasinto PG, Jordan TC, Kasza T, Katelyn MA, Kelsey JS, Kerrigan LA, Khaw D, Kim J, Knutter JZ, Ko CC, Larkin GV, Laroche JR, Latif A, Leuba KD, Leuba SI, Lewis LO, Loesser-Casey KE, Long CA, Lopez AJ, Lowery N, Lu TQ, Mac V, Masters IR, McCloud JJ, McDonough MJ, Medenbach AJ, Menon A, Miller R, Morgan BK, Ng PC, Nguyen E, Nguyen KT, Nguyen ET, Nicholson KM, Parnell LA, Peirce CE, Perz AM, Peterson LJ, Pferdehirt RE, Philip SV, Pogliano K, Pogliano J, Polley T, Puopolo EJ, Rabinowitz HS, Resiss MJ, Rhyan CN, Robinson YM, Rodriguez LL, Rose AC, Rubin JD, Ruby JA, Saha MS, Sandoz JW, Savitskaya J, Schipper DJ, Schnitzler CE, Schott AR, Segal JB, Shaffer CD, Sheldon KE, Shepard EM, Shepardson JW, Shroff MK, Simmons JM, Simms EF, Simpson BM, Sinclair KM, Sjoholm RL, Slette IJ, Spaulding BC, Straub CL, Stukey J, Sughrue T, Tang TY, Tatyana LM, Taylor SB, Taylor BJ, Temple LM, Thompson JV, Tokarz MP, Trapani SE, Troum AP, Tsay J, Tubbs AT, Walton JM, Wang DH, Wang H, Warner JR, Weisser EG, Wendler SC, Weston-Hafer KA, Whelan HM, Williamson KE, Willis AN, Wirtshafter HS, Wong TW, Wu P, Yang Y, Yee BC, Zaidins DA, Zhang B, Zuniga MY, Hendrix RW, Hatfull GF (- 182) Ref: PLoS ONE, 6:e16329, 2011 : PubMed ESTHER: Pope_2011_PLoS.ONE_6_E16329 PubMedSearch: Pope 2011 PLoS.ONE 6 E16329 PubMedID: 21298013 Gene_locus related to this paper: 9caud-g1jvt5, 9caud-e0ypf9 Abstract Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists. Title: Genome sequence and analysis of the tuber crop potato Xu X, Pan S, Cheng S, Zhang B, Mu D, Ni P, Zhang G, Yang S, Li R and Visser RG <87 more author(s)> Xu X, Pan S, Cheng S, Zhang B, Mu D, Ni P, Zhang G, Yang S, Li R, Wang J, Orjeda G, Guzman F, Torres M, Lozano R, Ponce O, Martinez D, De la Cruz G, Chakrabarti SK, Patil VU, Skryabin KG, Kuznetsov BB, Ravin NV, Kolganova TV, Beletsky AV, Mardanov AV, Di Genova A, Bolser DM, Martin DM, Li G, Yang Y, Kuang H, Hu Q, Xiong X, Bishop GJ, Sagredo B, Mejia N, Zagorski W, Gromadka R, Gawor J, Szczesny P, Huang S, Zhang Z, Liang C, He J, Li Y, He Y, Xu J, Zhang Y, Xie B, Du Y, Qu D, Bonierbale M, Ghislain M, Herrera Mdel R, Giuliano G, Pietrella M, Perrotta G, Facella P, O'Brien K, Feingold SE, Barreiro LE, Massa GA, Diambra L, Whitty BR, Vaillancourt B, Lin H, Massa AN, Geoffroy M, Lundback S, DellaPenna D, Buell CR, Sharma SK, Marshall DF, Waugh R, Bryan GJ, Destefanis M, Nagy I, Milbourne D, Thomson SJ, Fiers M, Jacobs JM, Nielsen KL, Sonderkaer M, Iovene M, Torres GA, Jiang J, Veilleux RE, Bachem CW, De Boer J, Borm T, Kloosterman B, van Eck H, Datema E, Hekkert B, Goverse A, van Ham RC, Visser RG (- 87) Ref: Nature, 475:189, 2011 : PubMed ESTHER: Xu_2011_Nature_475_189 PubMedSearch: Xu 2011 Nature 475 189 PubMedID: 21743474 Gene_locus related to this paper: soltu-q2tqv0, soltu-q4h433, soltu-m0zl00, soltu-m1aw23, soltu-m0zxh5, soltu-m1d3q4, soltu-m1bz14, soltu-m1d3q6, sollc-k4b1g3, soltu-m0zzn8, soltu-m1ba60, sollc-k4bf33, soltu-m1c8d8, soltu-m1ced9, soltu-m1a385, soltu-m1bz15, soltu-m1a7s9, soltu-m1bc84, soltu-m1bpd1, sollc-k4bm34, soltu-m1a487, soltu-m1a5u0, soltu-m1cjx7, soltu-m1bvq8, soltu-m1baq1, soltu-m1cfh4, soltu-m1azl4, soltu-m0ztj0, soltu-m1d6d0 Abstract Potato (Solanum tuberosum L.) is the world's most important non-grain food crop and is central to global food security. It is clonally propagated, highly heterozygous, autotetraploid, and suffers acute inbreeding depression. Here we use a homozygous doubled-monoploid potato clone to sequence and assemble 86% of the 844-megabase genome. We predict 39,031 protein-coding genes and present evidence for at least two genome duplication events indicative of a palaeopolyploid origin. As the first genome sequence of an asterid, the potato genome reveals 2,642 genes specific to this large angiosperm clade. We also sequenced a heterozygous diploid clone and show that gene presence/absence variants and other potentially deleterious mutations occur frequently and are a likely cause of inbreeding depression. Gene family expansion, tissue-specific expression and recruitment of genes to new pathways contributed to the evolution of tuber development. The potato genome sequence provides a platform for genetic improvement of this vital crop. Title: Codon optimization, expression and enzymatic comparison of Rhizopus oryzae lipases pro-ROL and m-ROL in Pichia pastoris Yang J, Yan X, Huang R, Zhang B Ref: Sheng Wu Gong Cheng Xue Bao, 27:1780, 2011 : PubMed ESTHER: Yang_2011_Sheng.Wu.Gong.Cheng.Xue.Bao_27_1780 PubMedSearch: Yang 2011 Sheng.Wu.Gong.Cheng.Xue.Bao 27 1780 PubMedID: 22506419 Abstract Rhizopus oryzae lipase (ROL) is not only a biocatalyst used in a broad range of biotechnological fields, but also a model to investigate the function of intramolecular chaperone in the post-translational processing of lipase. In this study, we cloned and expressed the mature lipase gene (m-ROL) containing the pre-sequence (pro-ROL) of R. oryzae HU3005 in Pichia pastoris GS115 and characterized their enzymatic activities. m-ROL exhibited higher hydrolysis activity towards middle-chain substrates (C10 and C12) at pH 9.0, whereas pro-ROL preferred short-chain substrates (C4) and displayed maximal activity at pH 8.0. Moreover, pro-ROL possessed better thermal stability than m-ROL. This enzymatic discrepancy between m-ROL and p-ROL may be due to the pre-sequence that affects the folding and conformation of the mature lipase domain. To improve the expression level of m-ROL in P. pastoris, overlap extension PCR was conducted to substitute eight less-frequently used codons of m-ROL with frequently used codons. After methanol-induced expression for 72 h, the activity and protein content of the codon optimized m-ROL reached 132.7 U/mL and 50.4 mg/L, while the activity of the parental m-ROL and pro-ROL are 28.7 U/mL and 14.4 mg/L, 29.6 U/mL and 14.1 mg/L, respectively. Title: Monoacylglycerol lipase (MAGL) knockdown inhibits tumor cells growth in colorectal cancer Ye L, Zhang B, Seviour EG, Tao KX, Liu XH, Ling Y, Chen JY, Wang GB Ref: Cancer Letters, 307:6, 2011 : PubMed ESTHER: Ye_2011_Cancer.Lett_307_6 PubMedSearch: Ye 2011 Cancer.Lett 307 6 PubMedID: 21543155 Abstract OBJECTIVES: Obesity has been reported to increase the risk of colorectal cancer, which may due to aberrant lipid metabolism. And recently findings of monoacylglycerol lipase provide a novel evidence in the correlation of obesity and cancer. So in this study, we investigated the effect of MAGL in regulation of tumor growth in colorectal cancer. METHODS: MAGL expression in tumor tissues was estimated, and then JZL184 and siRNA were used to knockdown the expression of MAGL in colorectal cancer cells. Cell viability and invasion were detected to estimate the influence of MAGL knocked down in vitro and vivo. Then cell proliferation, apoptosis, cell cycle transition and screening of candidate genes were performed for further exploring of the effect mediated by MAGL knocked down. RESULTS: It was noted that the expression of MAGL was highly elevated in tumor tissues, however, it was found only significantly correlated with the BMI index. Tumor cells' growth and invasion was significantly inhibited in vitro and in vivo induced by pharmacological and siRNA mediated MAGL knocked down. Cell proliferation was reduced and apoptosis was increased. And two target genes Cyclin D1 and Bcl-2 seemed to be repressed by MAGL knocked down. CONCLUSIONS: This study demonstrated colorectal cancer cells growth can be inhibited via knockdown of MAGL, which manipulate tumor cells proliferation and apoptosis by downregulation of Cyclin D1 and Bcl-2. It provides a novel therapeutic target in treatment of colorectal cancer and a further support for the correlation of obesity and colorectal cancer. Title: Genome sequence of the milbemycin-producing bacterium Streptomyces bingchenggensis Wang XJ, Yan YJ, Zhang B, An J, Wang JJ, Tian J, Jiang L, Chen YH, Huang SX and Xiang WS <5 more author(s)> Wang XJ, Yan YJ, Zhang B, An J, Wang JJ, Tian J, Jiang L, Chen YH, Huang SX, Yin M, Zhang J, Gao AL, Liu CX, Zhu ZX, Xiang WS (- 5) Ref: Journal of Bacteriology, 192:4526, 2010 : PubMed ESTHER: Wang_2010_J.Bacteriol_192_4526 PubMedSearch: Wang 2010 J.Bacteriol 192 4526 PubMedID: 20581206 Gene_locus related to this paper: strbb-d7bqj5, strbb-d7br78, strbb-d7bt68, strbb-d7bu74, strbb-d7bwt1, strbb-d7bzy9, strbb-d7c1k2, strbb-d7c2f2, strbb-d7c3x7, strbb-d7c6p4, strbb-d7c968, strbb-d7c973, strbb-d7cbn6, strbb-d7cds1, strbb-d7cet7, strbb-d7cf67, strbb-d7cgw9, strbb-d7bqa3, strbb-d7bw96 Abstract Streptomyces bingchenggensis is a soil-dwelling bacterium producing the commercially important anthelmintic macrolide milbemycins. Besides milbemycins, the insecticidal polyether antibiotic nanchangmycin and some other antibiotics have also been isolated from this strain. Here we report the complete genome sequence of S. bingchenggensis. The availability of the genome sequence of S. bingchenggensis should enable us to understand the biosynthesis of these structurally intricate antibiotics better and facilitate rational improvement of this strain to increase their titers. Title: [Ischemic hepatitis in hepatitis B related liver cirrhotic patients with upper gastrointestinal hemorrhage: clinical features and prognostic implications] Fan CL, Duan J, Dong PL, Ou-Yang Y, Zhang B, Ping CX, Ding HG Ref: Zhonghua Gan Zang Bing Za Zhi, 17:258, 2009 : PubMed ESTHER: Fan_2009_Zhonghua.Gan.Zang.Bing.Za.Zhi_17_258 PubMedSearch: Fan 2009 Zhonghua.Gan.Zang.Bing.Za.Zhi 17 258 PubMedID: 19403022 Abstract OBJECTIVE: To investigate the incidence, clinical features and prognostic implications of ischemic hepatitis in hepatitis B related liver cirrhotic patients with upper gastrointestinal hemorrhage. METHODS: By retrospective review of the medical records of all 264 inpatients with upper gastrointestinal hemorrhage of hepatitis B related liver cirrhosis from January 1st 2007 to November 30th 2008, 11 patients with ischemic hepatitis (IH) were identified. The clinical features and prognostic implications were compared between the IH patients and 30 patients without ischemic hepatitis (control group). RESULTS: The incidence of ischemic hepatitis was 4.17% in hepatitis B related liver cirrhotic patients with upper gastrointestinal hemorrhage. The patients in IH group were younger than those in control group, the average age was (43.1+/-5.7) in IH group and (52.3+/-11.1) in control group (P=0.013). The serum alanine aminotransferase and aspartate aminotransferase were increased more than 20-fold above the upper limit of normal values, and returned to normal values within 10 days. Compared to the control group, total bilirubin, lactate dehydrogenase, alkaline phosphates, gamma-glutamyltransferase, blood urea nitrogen, creatinine, and white blood cells were increased, while serum cholinesterase was decreased in IH group (P<0.05). The fatality rate of ischemic hepatitis was much higher than that of control group (54.5% vs 16.7%, P=0.041). The main causes of death in IH group were infection, hepatorenal syndrome and hepatic encephalopathy. The patients in IH group lost 200 to 3600 milliliter blood, and hemorrhagic shock occurred in 63.6% (7/11) of IH patients. Therefore the bleeding volume was not correlated with the occurrence rate of ischemic hepatitis. CONCLUSION: Ischemic hepatitis may occur secondary to upper gastrointestinal hemorrhage in hepatitis B related liver cirrhosis. The risk factors of ischemic hepatitis in cirrhositic patients with upper gastrointestinal hemorrhage are young and with hemorrhagic shock, and poor liver function. It is important to use antibiotics in time to improve the prognosis of these patients. Title: The genome of the cucumber, Cucumis sativus L Huang S, Li R, Zhang Z, Li L, Gu X, Fan W, Lucas WJ, Wang X, Xie B and Du Y <77 more author(s)> Huang S, Li R, Zhang Z, Li L, Gu X, Fan W, Lucas WJ, Wang X, Xie B, Ni P, Ren Y, Zhu H, Li J, Lin K, Jin W, Fei Z, Li G, Staub J, Kilian A, van der Vossen EA, Wu Y, Guo J, He J, Jia Z, Tian G, Lu Y, Ruan J, Qian W, Wang M, Huang Q, Li B, Xuan Z, Cao J, Asan, Wu Z, Zhang J, Cai Q, Bai Y, Zhao B, Han Y, Li Y, Li X, Wang S, Shi Q, Liu S, Cho WK, Kim JY, Xu Y, Heller-Uszynska K, Miao H, Cheng Z, Zhang S, Wu J, Yang Y, Kang H, Li M, Liang H, Ren X, Shi Z, Wen M, Jian M, Yang H, Zhang G, Yang Z, Chen R, Ma L, Liu H, Zhou Y, Zhao J, Fang X, Fang L, Liu D, Zheng H, Zhang Y, Qin N, Li Z, Yang G, Yang S, Bolund L, Kristiansen K, Li S, Zhang X, Wang J, Sun R, Zhang B, Jiang S, Du Y (- 77) Ref: Nat Genet, 41:1275, 2009 : PubMed ESTHER: Huang_2009_Nat.Genet_41_1275 PubMedSearch: Huang 2009 Nat.Genet 41 1275 PubMedID: 19881527 Gene_locus related to this paper: cucsa-a0a0a0ktw5, cucsa-a0a0a0lnt6, cucsa-a0a0a0kpn7, cucsa-a0a0a0lvt9, cucsa-a0a0a0kdx8, cucsa-a0a0a0m228, cucsa-a0a0a0kz31, cucsa-a0a0a0k5t5, cucsa-a0a0a0kfs7, cucsa-a0a0a0kjj7, cucsa-a0a0a0kzs7, cucsa-a0a0a0l0a6, cucsa-a0a0a0l4w4, cucsa-a0a0a0lpz0, cucsa-a0a0a0ls66 Abstract Cucumber is an economically important crop as well as a model system for sex determination studies and plant vascular biology. Here we report the draft genome sequence of Cucumis sativus var. sativus L., assembled using a novel combination of traditional Sanger and next-generation Illumina GA sequencing technologies to obtain 72.2-fold genome coverage. The absence of recent whole-genome duplication, along with the presence of few tandem duplications, explains the small number of genes in the cucumber. Our study establishes that five of the cucumber's seven chromosomes arose from fusions of ten ancestral chromosomes after divergence from Cucumis melo. The sequenced cucumber genome affords insight into traits such as its sex expression, disease resistance, biosynthesis of cucurbitacin and 'fresh green' odor. We also identify 686 gene clusters related to phloem function. The cucumber genome provides a valuable resource for developing elite cultivars and for studying the evolution and function of the plant vascular system. Title: Discovery of a highly potent, selective, and bioavailable soluble epoxide hydrolase inhibitor with excellent ex vivo target engagement Shen HC, Ding FX, Wang S, Deng Q, Zhang X, Chen Y, Zhou G, Xu S, Chen HS and Colletti SL <14 more author(s)> Shen HC, Ding FX, Wang S, Deng Q, Zhang X, Chen Y, Zhou G, Xu S, Chen HS, Tong X, Tong V, Mitra K, Kumar S, Tsai C, Stevenson AS, Pai LY, Alonso-Galicia M, Chen X, Soisson SM, Roy S, Zhang B, Tata JR, Berger JP, Colletti SL (- 14) Ref: Journal of Medicinal Chemistry, 52:5009, 2009 : PubMed ESTHER: Shen_2009_J.Med.Chem_52_5009 PubMedSearch: Shen 2009 J.Med.Chem 52 5009 PubMedID: 19645482 Abstract 4-Substituted piperidine-derived trisubstituted ureas are reported as highly potent and selective inhibitors for sEH. The SAR outlines approaches to improve activity against sEH and reduce ion channel and CYP liability. With minimal off-target activity and a good PK profile, the benchmark 2d exhibited remarkable in vitro and ex vivo target engagement. The eutomer entA-2d also elicited vasodilation effect in rat mesenteric artery. Title: Cloning and expression of Pseudomonas fluorescens 26-2 lipase gene in Pichia pastoris and characterizing for transesterification Yang J, Zhang B, Yan Y Ref: Appl Biochem Biotechnol, 159:355, 2009 : PubMed ESTHER: Yang_2009_Appl.Biochem.Biotechnol_159_355 PubMedSearch: Yang 2009 Appl.Biochem.Biotechnol 159 355 PubMedID: 19005622 Abstract Pseudomonas lipases are important biocatalysts widely used in a variety of industrial fields. An extracellular lipase gene lipA with 1,854-bp open reading frame was cloned from Pseudomonas fluorescens 26-2. The multialignment assay of the putative amino acid and the secondary structure prediction revealed this enzyme could be classified into the lipolytic subfamily I.3 and secreted via adenosine-triphosphate-binding cassette pathway. The lipA gene was integrated into Pichia pastoris GS115, and the methanol-inducible recombinants with Mut(S) and Mut(+) phenotypes were acquired. The characteristics and the transesterification capacity shown by this enzyme suggested it is a useful biocatalyst for biodiesel preparation. Title: Neuromuscular blockade, reversal agent use, and operating room time: retrospective analysis of US inpatient surgeries Zhang B, Hepner DL, Tran MH, Friedman M, Korn JR, Menzin J Ref: Curr Med Res Opin, 25:943, 2009 : PubMed ESTHER: Zhang_2009_Curr.Med.Res.Opin_25_943 PubMedSearch: Zhang 2009 Curr.Med.Res.Opin 25 943 PubMedID: 19257799 Abstract PURPOSE: Reducing operating room (OR) time is of interest to hospital administrators because of high costs of OR utilization. Neuromuscular blocking agents (NMBAs) induce muscle relaxation during surgery. Several acetylcholinesterase inhibitors are used to reverse neuromuscular blockade to shorten recovery time. This study explored the relationship between elapsed OR time and the use of specific NMBAs and reversal agents among patients undergoing selected surgeries based on data from two large hospitals. Specifically, this study sought to test the hypothesis that the application of reversal agents in surgeries using a neuromuscular block would be associated with a decrease in elapsed OR time. METHODS: This retrospective cohort study used clinical data from two large hospitals. The authors selected seven types of surgical cases involving thoracic, cardiac, vascular, abdominal, peripheral, urological, and neurological systems. Eligible cases were elective surgeries performed under general anesthesia and using one or more NMBAs (including rocuronium, vecuronium, cisatracurium, and/or pancuronium). Multivariate linear regressions were conducted to examine the relationships among neuromuscular blockade, reversal agent use (including neostigmine, pyridostigmine, and edrophonium), and elapsed OR time by controlling for age, gender, and patient comorbidities. RESULTS: A total of 9670 surgeries were included in this analysis. The mean elapsed OR time across all surgeries was 227 min, and vecuronium was the most commonly used NMBA. Approximately 67% of all surgeries used a reversal agent. After controlling for confounding factors, use of a reversal agent was shown to be associated with the reduction of elapsed OR time in six of seven types of surgery. The magnitude of this effect ranged from 12 to 46 min of OR time saved. The exception was thoracic surgeries, for which use of a reversal agent was shown to be associated with longer OR time (approximately 26 min). Multivariate regression analyses revealed that the type of NMBA used was also a significant predictor of elapsed time for all surgeries (except cardiac). CONCLUSIONS: This analysis has shown that use of selected neuromuscular blockade reversal agents may lead to more efficient OR resource use. Title: Variations in DNA elucidate molecular networks that cause disease Chen Y, Zhu J, Lum PY, Yang X, Pinto S, MacNeil DJ, Zhang C, Lamb J, Edwards S and Schadt EE <12 more author(s)> Chen Y, Zhu J, Lum PY, Yang X, Pinto S, MacNeil DJ, Zhang C, Lamb J, Edwards S, Sieberts SK, Leonardson A, Castellini LW, Wang S, Champy MF, Zhang B, Emilsson V, Doss S, Ghazalpour A, Horvath S, Drake TA, Lusis AJ, Schadt EE (- 12) Ref: Nature, 452:429, 2008 : PubMed ESTHER: Chen_2008_Nature_452_429 PubMedSearch: Chen 2008 Nature 452 429 PubMedID: 18344982 Abstract Identifying variations in DNA that increase susceptibility to disease is one of the primary aims of genetic studies using a forward genetics approach. However, identification of disease-susceptibility genes by means of such studies provides limited functional information on how genes lead to disease. In fact, in most cases there is an absence of functional information altogether, preventing a definitive identification of the susceptibility gene or genes. Here we develop an alternative to the classic forward genetics approach for dissecting complex disease traits where, instead of identifying susceptibility genes directly affected by variations in DNA, we identify gene networks that are perturbed by susceptibility loci and that in turn lead to disease. Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. Our analysis provides direct experimental support that complex traits such as obesity are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors. Title: Complete genome of Phenylobacterium zucineum--a novel facultative intracellular bacterium isolated from human erythroleukemia cell line K562 Luo Y, Xu X, Ding Z, Liu Z, Zhang B, Yan Z, Sun J, Hu S, Hu X Ref: BMC Genomics, 9:386, 2008 : PubMed ESTHER: Luo_2008_BMC.Genomics_9_386 PubMedSearch: Luo 2008 BMC.Genomics 9 386 PubMedID: 18700039 Gene_locus related to this paper: phezh-b4r8z3, phezh-b4r801, phezh-b4r876, phezh-b4ras1, phezh-b4ras4, phezh-b4ray3, phezh-b4rb44, phezh-b4rd51, phezh-b4re02, phezh-b4rfb7, phezh-b4rfk3, phezh-b4rfq9, phezh-b4rfw5, phezh-b4rgf2, phezh-b4rh78, phezh-b4rh88, phezh-b4rhb1, phezh-b4rhb2, phezh-dhma, phezh-b4r875, phezh-b4rfb8, phezh-b4rbt7 Abstract BACKGROUND: Phenylobacterium zucineum is a recently identified facultative intracellular species isolated from the human leukemia cell line K562. Unlike the known intracellular pathogens, P. zucineum maintains a stable association with its host cell without affecting the growth and morphology of the latter. RESULTS: Here, we report the whole genome sequence of the type strain HLK1T. The genome consists of a circular chromosome (3,996,255 bp) and a circular plasmid (382,976 bp). It encodes 3,861 putative proteins, 42 tRNAs, and a 16S-23S-5S rRNA operon. Comparative genomic analysis revealed that it is phylogenetically closest to Caulobacter crescentus, a model species for cell cycle research. Notably, P. zucineum has a gene that is strikingly similar, both structurally and functionally, to the cell cycle master regulator CtrA of C. crescentus, and most of the genes directly regulated by CtrA in the latter have orthologs in the former. CONCLUSION: This work presents the first complete bacterial genome in the genus Phenylobacterium. Comparative genomic analysis indicated that the CtrA regulon is well conserved between C. crescentus and P. zucineum. Title: Environmental adaptation: genomic analysis of the piezotolerant and psychrotolerant deep-sea iron reducing bacterium Shewanella piezotolerans WP3 Wang F, Wang J, Jian H, Zhang B, Li S, Zeng X, Gao L, Bartlett DH, Yu J and Xiao X <1 more author(s)> Wang F, Wang J, Jian H, Zhang B, Li S, Zeng X, Gao L, Bartlett DH, Yu J, Hu S, Xiao X (- 1) Ref: PLoS ONE, 3:e1937, 2008 : PubMed ESTHER: Wang_2008_PLoS.ONE_3_E1937 PubMedSearch: Wang 2008 PLoS.ONE 3 E1937 PubMedID: 18398463 Gene_locus related to this paper: shepw-b8ci75, shepw-b8cib3, shepw-b8ciu7, shepw-b8cld5, shepw-b8cll2, shepw-b8clm3, shepw-b8cls4, shepw-b8ct86, shepw-b8ctf0, shepw-b8ctt3, shepw-b8cuq7, shepw-b8cuu6, shepw-b8cuz1, shepw-b8cvm0, shepw-b8cqh1, shepw-b8cgv9, shepw-b8chj5, shepw-b8cpv3, shepw-b8civ4, shepw-b8cn18 Abstract Shewanella species are widespread in various environments. Here, the genome sequence of Shewanella piezotolerans WP3, a piezotolerant and psychrotolerant iron reducing bacterium from deep-sea sediment was determined with related functional analysis to study its environmental adaptation mechanisms. The genome of WP3 consists of 5,396,476 base pairs (bp) with 4,944 open reading frames (ORFs). It possesses numerous genes or gene clusters which help it to cope with extreme living conditions such as genes for two sets of flagellum systems, structural RNA modification, eicosapentaenoic acid (EPA) biosynthesis and osmolyte transport and synthesis. And WP3 contains 55 open reading frames encoding putative c-type cytochromes which are substantial to its wide environmental adaptation ability. The mtr-omc gene cluster involved in the insoluble metal reduction in the Shewanella genus was identified and compared. The two sets of flagellum systems were found to be differentially regulated under low temperature and high pressure; the lateral flagellum system was found essential for its motility and living at low temperature. Title: LRP4 serves as a coreceptor of agrin Zhang B, Luo S, Wang Q, Suzuki T, Xiong WC, Mei L Ref: Neuron, 60:285, 2008 : PubMed ESTHER: Zhang_2008_Neuron_60_285 PubMedSearch: Zhang 2008 Neuron 60 285 PubMedID: 18957220 Abstract Neuromuscular junction (NMJ) formation requires agrin, a factor released from motoneurons, and MuSK, a transmembrane tyrosine kinase that is activated by agrin. However, how signal is transduced from agrin to MuSK remains unclear. We report that LRP4, a low-density lipoprotein receptor (LDLR)-related protein, is expressed specifically in myotubes and binds to neuronal agrin. Its expression enables agrin binding and MuSK signaling in cells that otherwise do not respond to agrin. Suppression of LRP4 expression in muscle cells attenuates agrin binding, agrin-induced MuSK tyrosine phosphorylation, and AChR clustering. LRP4 also forms a complex with MuSK in a manner that is stimulated by agrin. Finally, we showed that LRP4 becomes tyrosine-phosphorylated in agrin-stimulated muscle cells. These observations indicate that LRP4 is a coreceptor of agrin that is necessary for MuSK signaling and AChR clustering and identify a potential target protein whose mutation and/or autoimmunization may cause muscular dystrophies. Title: (3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)- 1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes Biftu T, Feng D, Qian X, Liang GB, Kieczykowski G, Eiermann G, He H, Leiting B, Lyons K and Weber AE <10 more author(s)> Biftu T, Feng D, Qian X, Liang GB, Kieczykowski G, Eiermann G, He H, Leiting B, Lyons K, Petrov A, Sinha-Roy R, Zhang B, Scapin G, Patel S, Gao YD, Singh S, Wu J, Zhang X, Thornberry NA, Weber AE (- 10) Ref: Bioorganic & Medicinal Chemistry Lett, 17:49, 2007 : PubMed ESTHER: Biftu_2007_Bioorg.Med.Chem.Lett_17_49 PubMedSearch: Biftu 2007 Bioorg.Med.Chem.Lett 17 49 PubMedID: 17055272 Gene_locus related to this paper: human-DPP4 Inhibitor(s) related to this paper: Diazepanone-Analog-18, Diazepanone-Analog-1 Abstract Replacement of the triazolopiperazine ring of sitagliptin (DPP-4 IC(50)=18nM) with 3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one gave dipeptidyl peptidase IV (DPP-4) inhibitor 1 which is potent (DPP-4 IC(50)=2.6nM), selective, and efficacious in an oral glucose tolerance test in mice. It was selected for extensive preclinical development as a potential back-up candidate to sitagliptin. Title: Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin Biftu T, Scapin G, Singh S, Feng D, Becker JW, Eiermann G, He H, Lyons K, Patel S and Weber AE <7 more author(s)> Biftu T, Scapin G, Singh S, Feng D, Becker JW, Eiermann G, He H, Lyons K, Patel S, Petrov A, Sinha-Roy R, Zhang B, Wu J, Zhang X, Doss GA, Thornberry NA, Weber AE (- 7) Ref: Bioorganic & Medicinal Chemistry Lett, 17:3384, 2007 : PubMed ESTHER: Biftu_2007_Bioorg.Med.Chem.Lett_17_3384 PubMedSearch: Biftu 2007 Bioorg.Med.Chem.Lett 17 3384 PubMedID: 17433672 Gene_locus related to this paper: human-DPP4 Inhibitor(s) related to this paper: CHEMBL233360 Abstract Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central beta-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC(50)=21 nM) with excellent in vivo activity and pharmacokinetic profile. Title: Optimization of 1,4-diazepan-2-one containing dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes Liang GB, Qian X, Feng D, Biftu T, Eiermann G, He H, Leiting B, Lyons K, Petrov A and Weber AE <5 more author(s)> Liang GB, Qian X, Feng D, Biftu T, Eiermann G, He H, Leiting B, Lyons K, Petrov A, Sinha-Roy R, Zhang B, Wu J, Zhang X, Thornberry NA, Weber AE (- 5) Ref: Bioorganic & Medicinal Chemistry Lett, 17:1903, 2007 : PubMed ESTHER: Liang_2007_Bioorg.Med.Chem.Lett_17_1903 PubMedSearch: Liang 2007 Bioorg.Med.Chem.Lett 17 1903 PubMedID: 17291750 Inhibitor(s) related to this paper: Diazepanone-Analog-18, Diazepanone-Analog-1 Abstract Following the discovery of N-acyl-1,4-diazepan-2-one as a novel pharmacophore for potent and selective DPP-4 inhibitors, optimization of this new lead with different substitution on the seven-membered ring resulted in several highly potent and selective, orally bioavailable, and efficacious DPP-4 inhibitors, such as 3R-methyl-1-cyclopropyl-1,4-diazepan-2-one derivative 9i (DPP-4 IC(50)=8.0 nM) and 3R,6R-dimethyl-1,4-diazepan-2-one derivative 14a (DPP-4 IC(50)=9.7 nM). Title: The role of the cytoskeleton in neuromuscular junction formation Dobbins GC, Zhang B, Xiong WC, Mei L Ref: Journal of Molecular Neuroscience, 30:115, 2006 : PubMed ESTHER: Dobbins_2006_J.Mol.Neurosci_30_115 PubMedSearch: Dobbins 2006 J.Mol.Neurosci 30 115 PubMedID: 17192654 Abstract The cytoskeleton plays a vital role in neuromuscular junction (NMJ) formation. It is responsible for shaping synaptic membrane into folds opposed to presynaptic active zones and anchoring acetylcholine receptors (AChRs) to the crest of the junctional folds. Acetylcholine receptors (AChRs) associate with the actin cytoskeleton, the disruption of which affects spontaneous and agrin-induced AChR clusters (Prives et al., 1982; Connolly, 1984; Peng and Phelan, 1984; Bloch, 1986; Dai et al., 2000). How AChRs are tethered to the actin cytoskeleton remains unclear. Title: MuSK signaling at the neuromuscular junction Wang Q, Zhang B, Xiong WC, Mei L Ref: Journal of Molecular Neuroscience, 30:223, 2006 : PubMed ESTHER: Wang_2006_J.Mol.Neurosci_30_223 PubMedSearch: Wang 2006 J.Mol.Neurosci 30 223 PubMedID: 17192681 Abstract The neuromuscular junction (NMJ) is a peripheral cholinergic synapse that conveys signals from motor neurons to muscle cells (Sanes and Lichtman, 1999; Sanes and Lichtman, 2001). The formation of the NMJ requires communication between motoneurons and muscle fibers. Three molecules are essential for NMJ formation: agrin, MuSK, and rapsyn. MuSK appears to be involved in every aspect of NMJ development and maintenance. The paper reviews agrin-MuSK cascades and its potential cross talk with Wnt signaling pathways. Title: High-resolution functional proteomics by active-site peptide profiling Okerberg ES, Wu J, Zhang B, Samii B, Blackford K, Winn DT, Shreder KR, Burbaum JJ, Patricelli MP Ref: Proc Natl Acad Sci U S A, 102:4996, 2005 : PubMed ESTHER: Okerberg_2005_Proc.Natl.Acad.Sci.U.S.A_102_4996 PubMedSearch: Okerberg 2005 Proc.Natl.Acad.Sci.U.S.A 102 4996 PubMedID: 15795380 Abstract Characterization and functional annotation of the large number of proteins predicted from genome sequencing projects poses a major scientific challenge. Whereas several proteomics techniques have been developed to quantify the abundance of proteins, these methods provide little information regarding protein function. Here, we present a gel-free platform that permits ultrasensitive, quantitative, and high-resolution analyses of protein activities in proteomes, including highly problematic samples such as undiluted plasma. We demonstrate the value of this platform for the discovery of both disease-related enzyme activities and specific inhibitors that target these proteins. Title: The Genomes of Oryza sativa: a history of duplications Yu J, Wang J, Lin W, Li S, Li H, Zhou J, Ni P, Dong W, Hu S and Yang H <88 more author(s)> Yu J, Wang J, Lin W, Li S, Li H, Zhou J, Ni P, Dong W, Hu S, Zeng C, Zhang J, Zhang Y, Li R, Xu Z, Li X, Zheng H, Cong L, Lin L, Yin J, Geng J, Li G, Shi J, Liu J, Lv H, Li J, Deng Y, Ran L, Shi X, Wang X, Wu Q, Li C, Ren X, Li D, Liu D, Zhang X, Ji Z, Zhao W, Sun Y, Zhang Z, Bao J, Han Y, Dong L, Ji J, Chen P, Wu S, Xiao Y, Bu D, Tan J, Yang L, Ye C, Xu J, Zhou Y, Yu Y, Zhang B, Zhuang S, Wei H, Liu B, Lei M, Yu H, Li Y, Xu H, Wei S, He X, Fang L, Huang X, Su Z, Tong W, Tong Z, Ye J, Wang L, Lei T, Chen C, Chen H, Huang H, Zhang F, Li N, Zhao C, Huang Y, Li L, Xi Y, Qi Q, Li W, Hu W, Tian X, Jiao Y, Liang X, Jin J, Gao L, Zheng W, Hao B, Liu S, Wang W, Yuan L, Cao M, McDermott J, Samudrala R, Wong GK, Yang H (- 88) Ref: PLoS Biol, 3:e38, 2005 : PubMed ESTHER: Yu_2005_PLoS.Biol_3_e38 PubMedSearch: Yu 2005 PLoS.Biol 3 e38 PubMedID: 15685292 Gene_locus related to this paper: orysa-Q7XTC5, orysa-Q852M6, orysa-Q8GSE8, orysa-Q9S7P1, orysa-Q9FYP7, orysa-Q5ZBH3, orysa-Q5ZA26, orysa-Q5JLP6, orysa-Q8H5P9, orysa-Q8H5P5, orysa-Q7F1Y5, orysa-Q949C9, orysa-cbp1, orysa-cbp3, orysa-cbpx, orysa-Q33B71, orysa-Q8GSJ3, orysa-LPL1, orysa-Q6YSZ8, orysa-Q8S5X5, orysa-Q8LIG3, orysa-Q6K7F5, orysa-Q7F1B1, orysa-Q8H4S9, orysa-Q69UB1, orysa-Q9FW17, orysa-Q337C3, orysa-Q7F959, orysa-Q84QZ6, orysa-Q84QY7, orysa-Q851E3, orysa-Q6YTH5, orysa-Q0JK71, orysa-Q8S1D9, orysa-Q5N8V4, orysa-Q0JCY4, orysa-Q8GTK2, orysa-B9EWJ8, orysa-Q8H3K6, orysa-Q6ZDG8, orysa-Q6ZDG6, orysa-Q6ZDG5, orysa-Q6ZDG4, orysa-Q5NAI4, orysa-Q658B2, orysa-Q5JMQ8, orysa-Q5QMD9, orysa-Q5N7L1, orysa-Q8RYV9, orysa-Q8H3R3, orysa-Q5SNH3, orysa-Q8W0F0, orysa-pir7a, orysa-pir7b, orysa-q2qlm4, orysa-q2qm78, orysa-q2qm82, orysa-q2qn31, orysa-q2qnj4, orysa-q2qnt9, orysa-q2qur1, orysa-q2qx94, orysa-q2qyi1, orysa-q2qyj1, orysa-q2r051, orysa-q2r077, orysa-q2ram0, orysa-q2rat1, orysa-q2rbb3, orysa-Q4VWY7, orysa-q5na00, orysa-q5nbu1, orysa-Q5QLC0, orysa-q5smv5, orysa-Q5VP27, orysa-q5vrt2, orysa-q5w6c5, orysa-q5z5a3, orysa-q5z9i2, orysa-q5z417, orysa-q5z901, orysa-Q5ZAM8, orysa-Q5ZBI5, orysa-Q5ZCR3, orysa-q6atz0, orysa-q6ave2, orysa-q6f358, orysa-q6h6s1, orysa-q6h7i6, orysa-q6i5q3, orysa-q6i5u7, orysa-q6j657, orysa-q6k3d9, orysa-q6k4q2, orysa-q6k880, orysa-q6l5b6, orysa-Q6L5F5, orysa-q6l556, orysj-q6yse8, orysa-q6yy42, orysa-q6yzk1, orysa-q6z8b1, orysa-q6z995, orysa-q6zc62, orysa-q6zia4, orysa-q6zjq6, orysa-q7x7y5, orysa-Q7XC50, orysa-q7xej4, orysa-q7xem8, orysa-q7xkj9, orysa-q7xr62, orysa-q7xr63, orysa-q7xr64, orysa-q7xsg1, orysa-q7xsq2, orysa-q7xts6, orysa-q7xv53, orysa-Q7XVB5, orysa-Q8L562, orysa-Q8LQS5, orysa-Q8RZ40, orysa-Q8RZ79, orysa-Q8S0U8, orysa-Q8S0V0, orysa-Q8S125, orysa-Q8SAY7, orysa-Q8SAY9, orysa-Q8W3C6, orysa-Q8W3F2, orysa-Q8W3F4, orysa-Q8W3F6, orysa-Q9LHX5, orysa-q33aq0, orysa-q53lh1, orysa-q53m20, orysa-q53nd8, orysa-q60e79, orysa-q60ew8, orysa-q67iz2, orysa-q67iz3, orysa-q67iz7, orysa-q67iz8, orysa-q67j02, orysa-q67j05, orysa-q67j07, orysa-q67j09, orysa-q67j10, orysa-q67tr6, orysa-q67tv0, orysa-q67uz1, orysa-q67v34, orysa-q67wz5, orysa-q69j38, orysa-q69k08, orysa-q69md7, orysa-q69me0, orysa-q69pf3, orysa-q69ti3, orysa-q69xr2, orysa-q69y12, orysa-q69y21, orysa-q75hy2, orysa-q75i01, orysa-Q94JD7, orysa-Q0J0A4, orysa-q651a8, orysa-q651z3, orysa-q652g4, orysa-q688m0, orysa-q688m8, orysa-q688m9, orysa-Q6H8G1, orysi-a2wn01, orysi-a2xc83, orysi-a2yh83, orysi-a2z179, orysi-a2zef2, orysi-b8a7e6, orysi-b8a7e7, orysi-b8bfe5, orysi-b8bhp9, orysj-a3b9l8, orysj-b9eub8, orysj-b9eya5, orysj-b9fi05, orysj-b9fkb0, orysj-b9fn42, orysj-b9gbb7, orysj-cgep, orysj-PLA7, orysj-q0d4u5, orysj-q0djj0, orysj-q0jaf0, orysj-q5jl22, orysj-q5jlw7, orysj-q5z419, orysj-q6h7q9, orysj-q6yvk6, orysj-q6z6i1, orysj-q7f8x1, orysj-q7xcx3, orysj-q9fwm6, orysj-q10j20, orysj-q10ss2, orysj-q69uw6, orysj-q94d71, orysj-q338c0, orysi-b8bly4, orysj-b9gbs4, orysi-a2zb88, orysj-b9gbs1, orysi-b8b698, orysj-pla4, orysj-pla1 Abstract We report improved whole-genome shotgun sequences for the genomes of indica and japonica rice, both with multimegabase contiguity, or almost 1,000-fold improvement over the drafts of 2002. Tested against a nonredundant collection of 19,079 full-length cDNAs, 97.7% of the genes are aligned, without fragmentation, to the mapped super-scaffolds of one or the other genome. We introduce a gene identification procedure for plants that does not rely on similarity to known genes to remove erroneous predictions resulting from transposable elements. Using the available EST data to adjust for residual errors in the predictions, the estimated gene count is at least 38,000-40,000. Only 2%-3% of the genes are unique to any one subspecies, comparable to the amount of sequence that might still be missing. Despite this lack of variation in gene content, there is enormous variation in the intergenic regions. At least a quarter of the two sequences could not be aligned, and where they could be aligned, single nucleotide polymorphism (SNP) rates varied from as little as 3.0 SNP/kb in the coding regions to 27.6 SNP/kb in the transposable elements. A more inclusive new approach for analyzing duplication history is introduced here. It reveals an ancient whole-genome duplication, a recent segmental duplication on Chromosomes 11 and 12, and massive ongoing individual gene duplications. We find 18 distinct pairs of duplicated segments that cover 65.7% of the genome; 17 of these pairs date back to a common time before the divergence of the grasses. More important, ongoing individual gene duplications provide a never-ending source of raw material for gene genesis and are major contributors to the differences between members of the grass family. Title: Effects of a traditional Chinese medicine, Qing Nao Yi Zhi Fang, on glutamate excitotoxicity in rat fetal cerebral neuronal cells in primary culture Zhang J, Li L, Chen X, Zhang B, Wang Y, Yamamoto K Ref: Neuroscience Letters, 290:21, 2000 : PubMed ESTHER: Zhang_2000_Neurosci.Lett_290_21 PubMedSearch: Zhang 2000 Neurosci.Lett 290 21 PubMedID: 10925165 Abstract Qing Nao Yi Zhi Fang (QNYZ), a traditional Chinese medicine, has been developed as a drug to be used for the prevention and treatment of vascular dementia. However, the mechanisms by which this drug affects vascular dementia remain unknown. We examined the effects of QNYZ serum on glutamate excitotoxicity in rat fetal cerebral neuronal cells in primary culture. Exposure of neuronal cells to glutamate leads to a decrease in the activities of cholinesterase, superoxide dismutase, and streptoavidin peroxidase, and an increase in lactate dehydrogenase release. These enzyme activities were restored to the levels in untreated cells by the addition of QNYZ serum. QNYZ serum suppressed the increased nitric oxide production induced by glutamate and prevented glutamate-mediated apoptosis. QNYZ serum also improved mitochondrial energy metabolism after glutamate exposure. These findings suggest that QNYZ has protective effects against glutamate-mediated excitotoxicity in neuronal cells during ischemic brain injury. Title: Short-term effects of a high-sucrose diet on plasma lipid, lipoprotein cholesterol, tissue lipoprotein lipase and hepatic triglyceride lipase in rats Saku K, Okamoto T, Takeda Y, Jimi S, Zhang B, Bai H, Liu R, Arakawa K Ref: Artery, 22:36, 1996 : PubMed ESTHER: Saku_1996_Artery_22_36 PubMedSearch: Saku 1996 Artery 22 36 PubMedID: 8781709 Abstract Short-term (2 weeks) effects of a high-sucrose diet on plasma lipids, lipoproteins, tissue lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities were investigated in rats. Three days of sucrose feeding significantly increased plasma TG (42 +/- 3 mg/dl vs. 56 +/- 2 mg/dl, p = 0.032), while TC increased significantly after 10 days of the diet (50 +/- 2 mg/dl vs. 62 +/- 2 mg/dl, p = 0.0001). HDL-C increased significantly after 3 days of sucrose feeding (36.2 +/- 0.9 mg/dl vs. 42.4 +/- 2.7 mg/dl, p = 0.011). Although LDL-C tended to decrease on days 3, 7 and 10, these changes were not significant. The plasma glucose level did not change during the study. Increased LPL activity in adipose tissue and decreased enzyme activities in skeletal and heart muscles were observed. Adipose tissue LPL returned to the baseline value after 14 days of the diet treatment, while LPL in skeletal and heart muscles remained at the decreased level. HTGL and HTGL/total liver lipase activities were significantly increased after 14 days of the diet. The different responses of lipase activities in various tissues may help to regulate serum lipid and lipoprotein levels in sucrose-fed rats. | |||||||
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