Author Report for: Zhu GNo contact information in database for Zhu G
Li W, Zhang Y, Wu Y, Zhu G, Liu X, Song Y, Ma B, Lin S, Ge G and Xie P <1 more author(s)> Li W, Zhang Y, Wu Y, Zhu G, Liu X, Song Y, Ma B, Lin S, Ge G, Jiao X, Xie P (- 1) Ref: Eur Journal of Medicinal Chemistry, 259:115708, 2023 : PubMed ESTHER: Li_2023_Eur.J.Med.Chem_259_115708 PubMedSearch: Li 2023 Eur.J.Med.Chem 259 115708 PubMedID: 37544184 Inhibitor(s) related to this paper: BysspectinA-cpd20wderivative Abstract Human carboxylesterase 2A (hCES2A), the most abundant carboxylesterase in the human gut, plays a crucial role in the metabolic clearance and activation of various ester-bearing drugs, environmental toxins and carcinogens. Inhibition of intestinal hCES2A can alleviate irinotecan-induced gut toxicity and modulate the oral bioavailability of hCES2A-substrate drugs. Bysspectin A, a natural product isolated from the endophytic fungus Byssochlamys spectabilis, has been identified as a highly selective hCES2A inhibitor. Herein, two sets of bysspectin A derivatives have been designed and synthesized, utilizing a Cu-catalyzed domino Sonogashira-cyclization as the key step. Following two rounds of structure activity relationship (SAR) studies and structural optimizations, compound 20w was identified as the most potent hCES2A inhibitor, with an IC(50) value of 1.6 nM, an approximately 1000-fold improvement over bysspectin A. Further investigation showed that 20w potently inhibited hCES2A in a mixed inhibition manner, while this agent could also potently inhibit intracellular hCES2A in living cells and exhibited suitable metabolic stability. In summary, our findings demonstrate that a new bysspectin A derivative (20w) is a promising candidate for the development of clinically used hCES2A inhibitor. Title: Discovery of seven-membered ring berberine analogues as highly potent and specific hCES2A inhibitors Yang Y, Xiong Y, Zhu G, Sun M, Zou K, Zhao Y, Zhang Y, Xu Z, Li Y and Ge G <3 more author(s)> Yang Y, Xiong Y, Zhu G, Sun M, Zou K, Zhao Y, Zhang Y, Xu Z, Li Y, Zhu W, Jia Q, Li B, Ge G (- 3) Ref: Chemico-Biological Interactions, 378:110501, 2023 : PubMed ESTHER: Yang_2023_Chem.Biol.Interact_378_110501 PubMedSearch: Yang 2023 Chem.Biol.Interact 378 110501 PubMedID: 37080375 Abstract Human carboxylesterase 2A (hCES2A) is a key serine hydrolase responsible for the metabolic clearance of large number of compounds bearing the ester- or amide-bond(s). Inhibition of hCES2A can relieve the chemotherapy-induced toxicity and alter the pharmacokinetic bahaviors of some orally administrate esters-containing agents. However, most of the hCES2A inhibitors show poor cell-membrane permeability and poor specificity. Herein, guided by the structure activity relationships (SAR) of fifteen natural alkaloids against hCES2A, fifteen new seven-membered ring berberine analogues were designed and synthesized, and their anti-hCES2A activities were evaluated. Among all tested compounds, compound 28 showed potent anti-hCES2A effect (IC(50) = 1.66 microM) and excellent selectivity over hCES1A (IC(50) > 100 microM). The SAR analysis revealed that the seven-membered ring of these berberine analogues was a crucial moiety for hCES2A inhibition, while the secondary amine group of the ring-C is important for improving their specificity over other serine hydrolases. Inhibition kinetic analyses and molecular dynamic simulation demonstrated that 28 strongly inhibited hCES2A in a mixed-inhibition manner, with an estimated K(i) value of 1.035 microM. Moreover, 28 could inhibit intracellular hCES2A in living HepG2 cells and exhibited suitable metabolic stability. Collectively, the SAR of seven-membered ring berberine analogues as hCES2A inhibitors were studied, while compound 28 acted as a promising candidate for developing highly selective hCES2A inhibitors. Title: High Peroxidase-Mimicking Metal-Organic Frameworks Decorated with Platinum Nanozymes for the Colorimetric Detection of Acetylcholine Chloride and Organophosphorus Pesticides via Enzyme Cascade Reaction Yi Y, Zhou X, Liao D, Hou J, Liu H, Zhu G Ref: Inorg Chem, :, 2023 : PubMed ESTHER: Yi_2023_Inorg.Chem__ PubMedSearch: Yi 2023 Inorg.Chem PubMedID: 37583283 Abstract The sensitive detection of acetylcholinesterase (AChE) and organophosphorus pesticides (OPs) is very important for the protection of human health. Herein, a hybrid material, Pt NPs/Fe-MOF, consisting of a metal-organic framework (MIL-88B-NH(2), Fe-MOF) decorated with platinum nanoparticles (Pt NPs), was prepared first and exhibited remarkably improved and excellent peroxidase-mimicking activity compared to the Fe-MOF material resulting from the synergistic catalysis effect between Fe-MOF and Pt NPs, which can effectively catalyze 3,3',5,5'-tetramethylbenzidine (TMB) oxidation to generate a blue product (oxidized TMB, oxTMB). Interestingly, in the presence of AChE and acetylcholinesterase, the peroxidase-mimicking activity from Pt NPs/Fe-MOF was inhibited obviously, and thus, a colorimetric sensing platform for AChE can be constructed; more importantly, after the addition of OPs, this nanozyme activity can be recovered, inducing the further successful construction of a sensitive colorimetric sensing platform for OPs. The related sensing mechanism and condition optimization were studied, and the as-prepared Pt NPs/Fe-MOF nanozyme-based colorimetric method for AChE and OP detection displayed superior analytical performances with wide linearities and low detection limits. Furthermore, the designed method offers satisfactory real application ability. We expect the as-proposed Pt NPs/Fe-MOF nanozyme-based colorimetric sensing platform for AChE and OPs via the enzyme cascade reaction to show great potential application. Title: The roles of serine hydrolases and serum albumin in alisol B 23-acetate hydrolysis in humans Zhang T, Zhang F, Zhang Y, Li H, Zhu G, Weng T, Huang C, Wang P, He Y and Ge G <1 more author(s)> Zhang T, Zhang F, Zhang Y, Li H, Zhu G, Weng T, Huang C, Wang P, He Y, Hu J, Ge G (- 1) Ref: Front Pharmacol, 14:1160665, 2023 : PubMed ESTHER: Zhang_2023_Front.Pharmacol_14_1160665 PubMedSearch: Zhang 2023 Front.Pharmacol 14 1160665 PubMedID: 37089921 Abstract Introduction: Alisol B 23-acetate (AB23A), a major bioactive constituent in the Chinese herb Zexie (Rhizoma Alismatis), has been found with multiple pharmacological activities. AB23A can be readily hydrolyzed to alisol B in mammals, but the hydrolytic pathways of AB23A in humans and the key enzymes responsible for AB23A hydrolysis are still unrevealed. This study aims to reveal the metabolic organs and the crucial enzymes responsible for AB23A hydrolysis in human biological systems, as well as to decipher the impact of AB23A hydrolysis on its biological effects. Methods: The hydrolytic pathways of AB23A in human plasma and tissue preparations were carefully investigated by using Q-Exactive quadrupole-Orbitrap mass spectrometer and LC-UV, while the key enzymes responsible for AB23A hydrolysis were studied via performing a set of assays including reaction phenotyping assays, chemical inhibition assays, and enzyme kinetics analyses. Finally, the agonist effects of both AB23A and its hydrolytic metabolite(s) on FXR were tested at the cellular level. Results: AB23A could be readily hydrolyzed to form alisol B in human plasma, intestinal and hepatic preparations, while human butyrylcholinesterase (hBchE) and human carboxylesterases played key roles in AB23A hydrolysis in human plasma and tissue preparations, respectively. It was also found that human serum albumin (hSA) could catalyze AB23A hydrolysis, while multiple lysine residues of hSA were covalently modified by AB23A, suggesting that hSA catalyzed AB23A hydrolysis via its pseudo-esterase activity. Biological tests revealed that both AB23A and alisol B exhibited similar FXR agonist effects, indicating AB23A hydrolysis did not affect its FXR agonist effect. Discussion: This study deciphers the hydrolytic pathways of AB23A in human biological systems, which is very helpful for deep understanding of the metabolic rates of AB23A in humans, and useful for developing novel prodrugs of alisol B with desirable pharmacokinetic behaviors. Title: Single and Combined Effects of Chlorpyrifos and Glyphosate on the Brain of Common Carp: Based on Biochemical and Molecular Perspective Zhang D, Ding W, Liu W, Li L, Zhu G, Ma J Ref: Int J Mol Sci, 24:, 2023 : PubMed ESTHER: Zhang_2023_Int.J.Mol.Sci_24_ PubMedSearch: Zhang 2023 Int.J.Mol.Sci 24 PubMedID: 37629125 Abstract Chlorpyrifos (CPF) and glyphosate (GLY) are the most widely used organophosphate insecticide and herbicide worldwide, respectively; co-occurrence of CPF and GLY in aquatic environments occurs where they inevitably have potential hazards to fish. However, the potential mechanisms of CPF and GLY to induce toxicity have not been fully explored. To identify the adverse impacts of CPF and GLY on fish, either alone or in combination (MIX), CPF (25 microg/L) and GLY (3.5 mg/L) were set up according to an environmentally relevant concentration to expose to common carp for 21 days. After exposure, CPF and GLY decreased the activities of acetylcholinesterase and Na(+)/K(+)-ATPase, altered monoamine oxidase levels, decreased antioxidant enzyme activities (superoxide dismutase, catalase, glutathione S-transferase and glutamic reductase), and induced the accumulation of malondialdehyde in the carp brain. The parameters in the MIX groups had a greater impact compared to that in the CPF or GLY group, suggesting that both single and combined exposure could affect neurological signaling systems and cause oxidative stress and lipid peroxidation damage in carp brains, and that MIX exposure increases the impact of each pollutant. RNA-seq results showed that single or combined exposure to CPF and GLY induced global transcriptomic changes in fish brains, and the number of differentially expressed genes in MIX-treated carp brains were globally increased compared to either the CPF or GLY groups, suggesting that the effects of co-exposure were greater than single exposure. Further analysis results revealed that the global transcriptomic changes participated in oxidative stress, immune dysfunction, and apoptosis of fish brains, and identified that the P13k-Akt signaling pathway participates in both single and combined exposure of CPF- and GLY-induced toxicity. Taken together, our results demonstrated that the interaction of CPF and GLY might be synergic and provided novel insights into the molecular mechanisms of fish brains coping with CPF and GLY. Title: Preclinical mouse model of a misfolded PNLIP variant develops chronic pancreatitis Zhu G, Wilhelm SJ, George LG, Cassidy BM, Zino S, Luke CJ, Hanna M, Stone S, Phan N and Xiao X <3 more author(s)> Zhu G, Wilhelm SJ, George LG, Cassidy BM, Zino S, Luke CJ, Hanna M, Stone S, Phan N, Matiwala N, Ballentine SJ, Lowe ME, Xiao X (- 3) Ref: Gut, :, 2023 : PubMed ESTHER: Zhu_2023_Gut__ PubMedSearch: Zhu 2023 Gut PubMedID: 36631248 Abstract OBJECTIVE: Increasing evidence implicates mutation-induced protein misfolding and endoplasm reticulum (ER) stress in the pathophysiology of chronic pancreatitis (CP). The paucity of animal models harbouring genetic risk variants has hampered our understanding of how misfolded proteins trigger CP. We previously showed that pancreatic triglyceride lipase (PNLIP) p.T221M, a variant associated with steatorrhoea and possibly CP in humans, misfolds and elicits ER stress in vitro suggesting proteotoxicity as a potential disease mechanism. Our objective was to create a mouse model to determine if PNLIP p.T221M causes CP and to define the mechanism. DESIGN: We created a mouse model of Pnlip p.T221M and characterised the structural and biochemical changes in the pancreas aged 1-12 months. We used multiple methods including histochemistry, immunostaining, transmission electron microscopy, biochemical assays, immunoblotting and qPCR. RESULTS: We demonstrated the hallmarks of human CP in Pnlip p.T221M homozygous mice including progressive pancreatic atrophy, acinar cell loss, fibrosis, fatty change, immune cell infiltration and reduced exocrine function. Heterozygotes also developed CP although at a slower rate. Immunoblot showed that pancreatic PNLIP T221M misfolded as insoluble aggregates. The level of aggregates in homozygotes declined with age and was much lower in heterozygotes at all ages. The Pnlip p.T221M pancreas had increased ER stress evidenced by dilated ER, increased Hspa5 (BiP) mRNA abundance and a maladaptive unfolded protein response leading to upregulation of Ddit3 (CHOP), nuclear factor-kappaB and cell death. CONCLUSION: Expression of PNLIP p.T221M in a preclinical mouse model results in CP caused by ER stress and proteotoxicity of misfolded mutant PNLIP. Title: Novel donepezil-chalcone-rivastigmine hybrids as potential multifunctional anti-Alzheimer's agents: Design, synthesis, in vitro biological evaluation, in vivo and in silico studies Sang Z, Bai P, Ban Y, Wang K, Wu A, Mi J, Hu J, Xu R, Zhu G and Tang L <4 more author(s)> Sang Z, Bai P, Ban Y, Wang K, Wu A, Mi J, Hu J, Xu R, Zhu G, Wang J, Zhang J, Wang C, Tan Z, Tang L (- 4) Ref: Bioorg Chem, 127:106007, 2022 : PubMed ESTHER: Sang_2022_Bioorg.Chem_127_106007 PubMedSearch: Sang 2022 Bioorg.Chem 127 106007 PubMedID: 35849893 Abstract Alzheimer's disease (AD) is a chronic, progressive brain neurodegenerative disorder. Up to now, there is no effective drug to halt or reverse the progress of AD. Given the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy is considered as the promising therapy. Herein, a series of novel donepezil-chalone-rivastigmine hybrids was rationally designed and synthesized by fusing donepezil, chalone and rivastigmine. The in vitro bioactivity results displayed that compound 10c was a reversible huAChE (IC(50) = 0.87 microM) and huBuChE (IC(50) = 3.3 microM) inhibitor. It also presented significant anti-inflammation effects by suppressing the level of IL-6 and TNF-alpha production, and significantly inhibited self-mediated Abeta(1-42) aggregation (60.6%) and huAChE-mediated induced Abeta(1-40) aggregation (46.2%). In addition, 10c showed significant neuroprotective effect on Abeta(1-42)-induced PC12 cell injury and activated UPS pathway in HT22 cells to degrade tau and amyloid precursor protein (APP). Furthermore, compound 10c presented good stabilty in artificial gastrointestinal fluids and liver microsomes in vitro. The pharmacokinetic study showed that compound 10c was rapidly absorbed in rats and distributed in rat brain after intragastric administration. The PET-CT imaging demonstrated that [(11)C]10c could quickly enter the brain and washed out gradually in vivo. Further, compound 10c at a dose of 5 mg/kg improved scopolamine-induced memory impairment, deserving further investigations. Title: Co-Inheritance of Variation in All-Cause Mortality and Biochemical Risk Factors Whitfield JB, Colodro-Conde L, Zhu G, Timmers P, Joshi PK, Montgomery GW, Martin NG Ref: Twin Res Hum Genet, :1, 2022 : PubMed ESTHER: Whitfield_2022_Twin.Res.Hum.Genet__1 PubMedSearch: Whitfield 2022 Twin.Res.Hum.Genet 1 PubMedID: 35818962 Abstract Biomarkers may be useful endophenotypes for genetic studies if they share genetic sources of variation with the outcome, for example, with all-cause mortality. Australian adult study participants who had reported their parental survival information were included in the study: 14,169 participants had polygenic risk scores (PRS) from genotyping and up to 13,365 had biomarker results. We assessed associations between participants' biomarker results and parental survival, and between biomarker results and eight parental survival PRS at varying p-value cut-offs. Survival in parents was associated with participants' serum bilirubin, C-reactive protein, HDL cholesterol, triglycerides and uric acid, and with LDL cholesterol for participants' fathers but not for their mothers. PRS for all-cause mortality were associated with liver function tests (alkaline phosphatase, butyrylcholinesterase, gamma-glutamyl transferase), metabolic tests (LDL and HDL cholesterol, triglycerides, uric acid), and acute-phase reactants (C-reactive protein, globulins). Association between offspring biomarker results and parental survival demonstrates the existence of familial effects common to both, while associations between biomarker results and PRS for mortality favor at least a partial genetic cause of this covariation. Identification of genetic loci affecting mortality-associated biomarkers offers a route to the identification of additional loci affecting mortality. Title: Design, synthesis, and evaluation of novel O-alkyl ferulamide derivatives as multifunctional ligands for treating Alzheimer's disease Zhu G, Bai P, Wang K, Mi J, Yang J, Hu J, Ban Y, Xu R, Chen R and Sang Z <2 more author(s)> Zhu G, Bai P, Wang K, Mi J, Yang J, Hu J, Ban Y, Xu R, Chen R, Wang C, Tang L, Sang Z (- 2) Ref: J Enzyme Inhib Med Chem, 37:1375, 2022 : PubMed ESTHER: Zhu_2022_J.Enzyme.Inhib.Med.Chem_37_1375 PubMedSearch: Zhu 2022 J.Enzyme.Inhib.Med.Chem 37 1375 PubMedID: 35549612 Abstract Herein, a series of novel O-alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities in vitro showed that compounds 5a, 5d, 5e, 5f, and 5h indicated significantly selective MAO-B inhibitory potency (IC(50) = 0.32, 0.56, 0.54, 0.73, and 0.86 microM, respectively) and moderate antioxidant activity. Moreover, compounds 5a, 5d, 5e, 5f, and 5h showed potent anti-inflammatory properties, remarkable effects on self-induced Abeta(1-42) aggregation, and potent neuroprotective effect on Abeta(1-42)-induced PC12 cell injury. Furthermore, compounds 5a, 5d, 5e, 5f, and 5h presented good blood-brain barrier permeation in vitro and drug-like properties. More interesting, the PET/CT images with [(11)C]5f demonstrated that [(11)C]5f could penetrate the BBB with a high brain uptake and exhibited good brain clearance kinetic property. Therefore, compound 5f would be a promising multi-functional agent for the treatment of AD. Title: A natural symbiotic bacterium drives mosquito refractoriness to Plasmodium infection via secretion of an antimalarial lipase Gao H, Bai L, Jiang Y, Huang W, Wang L, Li S, Zhu G, Wang D, Huang Z and Wang S <5 more author(s)> Gao H, Bai L, Jiang Y, Huang W, Wang L, Li S, Zhu G, Wang D, Huang Z, Li X, Cao J, Jiang L, Jacobs-Lorena M, Zhan S, Wang S (- 5) Ref: Nat Microbiol, :, 2021 : PubMed ESTHER: Gao_2021_Nat.Microbiol__ PubMedSearch: Gao 2021 Nat.Microbiol PubMedID: 33958765 Abstract The stalling global progress in the fight against malaria prompts the urgent need to develop new intervention strategies. Whilst engineered symbiotic bacteria have been shown to confer mosquito resistance to parasite infection, a major challenge for field implementation is to address regulatory concerns. Here, we report the identification of a Plasmodium-blocking symbiotic bacterium, Serratia ureilytica Su_YN1, isolated from the midgut of wild Anopheles sinensis in China that inhibits malaria parasites via secretion of an antimalarial lipase. Analysis of Plasmodium vivax epidemic data indicates that local malaria cases in Tengchong (Yunnan province, China) are significantly lower than imported cases and importantly, that the local vector A. sinensis is more resistant to infection by P. vivax than A. sinensis from other regions. Analysis of the gut symbiotic bacteria of mosquitoes from Yunnan province led to the identification of S. ureilytica Su_YN1. This bacterium renders mosquitoes resistant to infection by the human parasite Plasmodium falciparum or the rodent parasite Plasmodium berghei via secretion of a lipase that selectively kills parasites at various stages. Importantly, Su_YN1 rapidly disseminates through mosquito populations by vertical and horizontal transmission, providing a potential tool for blocking malaria transmission in the field. Title: Chemical Composition and Biological Activities of Essential Oils from the Leaves, Stems, and Roots of Kadsura coccinea Zhao T, Ma C, Zhu G Ref: Molecules, 26:, 2021 : PubMed ESTHER: Zhao_2021_Molecules_26_ PubMedSearch: Zhao 2021 Molecules 26 PubMedID: 34684838 Abstract The chemical composition and biological activities of the essential oils from the leaves, stems, and roots of Kadsura coccinea (K. coccinea) were investigated. The essential oils were extracted by hydro distillation and analyzed by gas chromatography mass spectrometry (GC-MS) and gas chromatography with flame ionization detector (GC-FID). Antioxidant activities of the essential oils were examined with DPPH radical scavenging assay, ABTS cation radical scavenging assay, and ferric reducing antioxidant power assay. Antimicrobial activities were evaluated by determining minimum inhibitory concentrations (MIC) and minimum microbiocidal concentrations (MMC). Acetylcholinesterase and butyrylcholinesterase inhibitory activity of the essential oils were also tested. A total of 46, 44, and 47 components were identified in the leaf, stem, and root oils, representing 95.66%, 97.35%, and 92.72% of total composition, respectively. The major compounds of three essential oils were alpha-pinene (16.60-42.02%), beta-pinene (10.03-18.82%), camphene (1.56-10.95%), borneol (0.50-7.71%), delta-cadinene (1.52-7.06%), and beta-elemene (1.86-4.45%). The essential oils were found to have weak antioxidant activities and cholinesterase inhibition activities. The essential oils showed more inhibitory effects against Staphylococcus aureus (S. aureus) than those of other strains. The highest antimicrobial activity was observed in the root oil against S. aureus, with MIC of 0.78 mg/mL. Therefore, K. coccinea essential oils might be considered as a natural antibacterial agent against S. aureus with potential application in food and pharmaceutical industries. Title: Structure and Function of Pancreatic Lipase-Related Protein 2 and Its Relationship With Pathological States Zhu G, Fang Q, Zhu F, Huang D, Yang C Ref: Front Genet, 12:693538, 2021 : PubMed ESTHER: Zhu_2021_Front.Genet_12_693538 PubMedSearch: Zhu 2021 Front.Genet 12 693538 PubMedID: 34290745 Gene_locus related to this paper: human-PNLIPRP2 Abstract Pancreatic lipase is critical for the digestion and absorption of dietary fats. The most abundant lipolytic enzymes secreted by the pancreas are pancreatic triglyceride lipase (PTL or PNLIP) and its family members, pancreatic lipase-related protein 1 (PNLIPRP1or PLRP1) and pancreatic lipase-related protein 2 (PNLIPRP2 or PLRP2). Unlike the family's other members, PNLIPRP2 plays an elemental role in lipid digestion, especially for newborns. Therefore, if genetic factors cause gene mutation, or other factors lead to non-expression, it may have an effect on fat digestion and absorption, on the susceptibility to pancreas and intestinal pathogens. In this review, we will summarize what is known about the structure and function of PNLIPRP2 and the levels of PNLIPRP2 and associated various pathological states. Title: Crosstalk of cholinergic pathway on thyroid disrupting effects of the insecticide chlorpyrifos in zebrafish (Danio rerio) Qiao K, Hu T, Jiang Y, Huang J, Hu J, Gui W, Ye Q, Li S, Zhu G Ref: Sci Total Environ, :143769, 2020 : PubMed ESTHER: Qiao_2020_Sci.Total.Environ__143769 PubMedSearch: Qiao 2020 Sci.Total.Environ 143769 PubMedID: 33221011 Gene_locus related to this paper: danre-ACHE Abstract Chlorpyrifos is a widely used organophosphate insecticide and ubiquitously detected in the environment. However, little attention has been paid to its endocrine disrupting effect to non-target organisms. In the present study, zebrafish was exposed to 13 and 65 g/L of chlorpyrifos for 7 and 10 days to determine the induced neurotoxicity and the alteration of thyroid metabolism. The 120 h LC(50) and LC(10) of chlorpyrifos was estimated as 1.35 mg/L and 0.62 mg/L based on the acute embryo toxicity assay, respectively. The acetylcholinesterase (AChE) inhibitory was detected by 13 g/L chlorpyrifos and could be reversed by the co-exposure of 100 and 1000 g/L anticholinergic agent atropine. For thyroid hormone level, 13 and 65 g/L of chlorpyrifos induced increased free T(3) levels in 10 dpf (days post-fertilization). The expression of thyroid related genes in 7 and 10 dpf exposed zebrafish were measured by the quantitative Real-Time PCR (qRT-PCR) assay. The mRNA expression of tshba, thrb, crhb, ttr, tpo, ugt1ab and slc5a5 had significant change. However, the alterations of thyroid hormone and mRNA expression could be partly rescued by the addition of atropine. The molecular docking of chlorpyrifos and T(3) to the thyroid receptor beta in zebrafish using homology modelling and CDOCKER procedures shown weaker binding ability of chlorpyrifos compared to T(3). Therefore, we concluded that the disturbance of thyroid signaling in zebrafish might arise from the developmental neurotoxicity induced by chlorpyrifos. Title: Design, synthesis and biological evaluation of novel O-carbamoyl ferulamide derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease Sang Z, Wang K, Bai P, Wu A, Shi J, Liu W, Zhu G, Wang Y, Lan Y and Tan Z <4 more author(s)> Sang Z, Wang K, Bai P, Wu A, Shi J, Liu W, Zhu G, Wang Y, Lan Y, Chen Z, Zhao Y, Qiao Z, Wang C, Tan Z (- 4) Ref: Eur Journal of Medicinal Chemistry, 194:112265, 2020 : PubMed ESTHER: Sang_2020_Eur.J.Med.Chem_194_112265 PubMedSearch: Sang 2020 Eur.J.Med.Chem 194 112265 PubMedID: 32240904 Abstract A novel series of O-carbamoyl ferulamide derivatives were designed by multitarget-directed ligands (MTDLs) strategy, the derivatives were synthesized and evaluated to treat Alzheimer's disease (AD). In vitro biological evaluation demonstrated that compound 4f was the best pseudo-irreversible hBChE (human butyrylcholinesterase) inhibitor with an IC50 value of 0.97 muM 4f was a potent selective MAO-B (monoamine oxidase-B) inhibitor (IC50 = 5.3 muM), and could inhibit (58.2%) and disaggregate (43.3%) self-mediated Abeta aggregation. 4f also could reduce the levels of pathological tau and APP clearance, and displayed a wide safe range hepatotoxicity on LO2 cells. The in vivo studies revealed that 4f exhibited fascinating dyskinesia recovery rate and response efficiency on AlCl3-mediated zebrafish, and demonstrated significant protective effect on vascular injury caused by Abeta1-40. PET-CT imaging demonstrated that [(11)C]4f exhibited high BBB penetration (especially could reach to hippocampus and striatum of brain) and had a fast brain uptake after intravenous bolus injection. Furthermore, compound 4f could improve scopolamine-induced cognitive impairment. Further, the metabolism in vitro of 4f was also investigated, and presented 3 metabolites in rat liver microsome metabolism, 4 metabolites in human liver microsome, and 4 metabolites in rat intestinal flora, providing previous data for the preclinical study. Therefore, these results implied that compound 4f was an advanced multi-function agent and deserved further preclinical study against mild-to-serve Alzheimer's disease. Title: Characterization of a novel hyper-thermostable and chlorpyrifos-hydrolyzing carboxylesterase EstC: A representative of the new esterase family XIX Wang B, Wu S, Chang X, Chen J, Ma J, Wang P, Zhu G Ref: Pestic Biochem Physiol, 170:104704, 2020 : PubMed ESTHER: Wang_2020_Pestic.Biochem.Physiol_170_104704 PubMedSearch: Wang 2020 Pestic.Biochem.Physiol 170 104704 PubMedID: 32980065 Gene_locus related to this paper: strco-estli Inhibitor(s) related to this paper: Chlorpyrifos Abstract Carboxylesterases have widely been used in a series of industrial applications, especially, the detoxification of pesticide residues. In the present study, EstC, a novel carboxylesterase from Streptomyces lividans TK24, was successfully heterogeneously expressed, purified and characterized. Phylogenetic analysis showed that EstC can be assigned as the first member of a novel family XIX. Multiple sequence alignment indicated that EstC has highly conserved structural features, including a catalytic triad formed by Ser155, Asp248 and His278, as well as a canonical Gly-His-Ser-Ala-Gly pentapeptide. Biochemical characterization indicated that EstC exhibited maximal activity at pH 9.0 (Tris-HCl buffer) and 55 degC. It also showed higher activity towards short-chain substrates, with the highest activity for p-nitrophenyl acetate (pNPA2) (K(m) = 0.31 +/- 0.02 mM, k(cat)/K(m) = 1923.35 +/- 9.62 s(-1) mM(-1)) compared to other pNP esters used in this experiment. Notably, EstC showed hyper-thermostability and good alkali stability. The activity of EstC had no significant changes when it was incubated under 55 degC for 100 h and reached half-life after incubation at 100 degC for 8 h. Beyond that, EstC also showed stability at pH ranging from 6.0 to 11.0 and about 90% residual activity still reserved after treatment at pH 8.0 or 9.0 for 26 h, especially. Furthermore, EstC had outstanding potential for bioremediation of chlorpyrifos-contaminated environment. The recombinant enzyme (0.5 U mL(-1)) could hydrolyze 79.89% chlorpyrifos (5 mg L(-1)) at 37 degC within 80 min. These properties will make EstC have a potential application value in various industrial productions and detoxification of chlorpyrifos residues. Title: Molecular and Biochemical Characterization of a Type II Thioesterase From the Zoonotic Protozoan Parasite Cryptosporidium parvum Guo F, Zhang H, Eltahan R, Zhu G Ref: Front Cell Infect Microbiol, 9:199, 2019 : PubMed ESTHER: Guo_2019_Front.Cell.Infect.Microbiol_9_199 PubMedSearch: Guo 2019 Front.Cell.Infect.Microbiol 9 199 PubMedID: 31231619 Gene_locus related to this paper: crypi-q5cyh5 Abstract Cryptosporidium parvum is a globally important zoonotic parasite capable of causing severe to deadly diarrhea in humans and animals. Its small genome (~9.1 Mb) encodes not only a highly streamlined metabolism, but also a 25-kb, 3-module fatty acid synthase (CpFAS1) and a 40-kb, 7-module polyketide synthase (CpPKS1). The two megasynthases contain a C-terminal reductase domain to release the final products with predicted chain lengths of >/=C22 for CpFAS1 or C28 to C38 for CpPKS1.The parasite genome also encodes a discrete thioesterase ortholog, suggesting its role to be an alternative tool in releasing the final products from CpFAS1 and/or CpPKS1, or as an editor to remove non-reactive residues or aberrant intermediates, or to control starter units as seen in other parasites. In this study, we have confirmed that this C. parvum thioesterase is a type II thioesterase (thus named as CpTEII). CpTEII contains motifs and a catalytic triad characteristic to the type II thioesterase family. CpTEII is expressed during the entire parasite life cycle stages with the highest levels of expression in the later developmental stages. CpTEII showed the highest hydrolytic activity toward C10:0 decanoyl-CoA, so we speculated that CpTEII may mainly act as an editor to remove non-reactive residues and/or aberrant medium acyl chain from CpFAS1 and/or CpPKS1. However, we cannot rule out the possibility that CpTEII may also participate in the release of final products from CpFAS1 because of its moderate activity on C20:0, C:22:0 and C24:0 acyl-CoA thioesters (i.e., ~20-30% activity vs. decanoyl-CoA). Title: The development of 2-acetylphenol-donepezil hybrids as multifunctional agents for the treatment of Alzheimer's disease Zhu G, Wang K, Shi J, Zhang P, Yang D, Fan X, Zhang Z, Liu W, Sang Z Ref: Bioorganic & Medicinal Chemistry Lett, 29:126625, 2019 : PubMed ESTHER: Zhu_2019_Bioorg.Med.Chem.Lett_29_126625 PubMedSearch: Zhu 2019 Bioorg.Med.Chem.Lett 29 126625 PubMedID: 31444085 Abstract A series of 2-acetylphenol-donepezil hybrids was designed and synthesized based on multi-target-directed ligands strategy. The biological activities were evaluated by AChE/BChE inhibition and MAO-A/MAO-B inhibition. The results revealed that the tertiary amines and methylene chain length significantly affected the eeAChE inhibitory potency, in particular, compound TM-14 showed the best eeAChE inhibitory activity with IC(50) value of 2.9 microM, in addition, both kinetic analysis of AChE inhibition and docking study displayed that TM-14 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. Moreover, compound TM-14 was a selective metal chelator and could form 1:1 TM-14-Cu(2+) complex. The structure-active-relationship also indicated that the O-alkylamine fragment remarkably decreased hMAO-B inhibitory activity, compound TM-2 exhibited potent hMAO-B inhibitory activity (IC(50) = 6.8 microM), which was supported by the molecular docking study. More interestingly, compounds TM-14 and TM-2 could cross the blood-brain barrier in vitro. Therefore, the structure-active-relationship of 2-acetylphenol-donepezil hybrids could encourage the development of multifunction agents with selective AChE inhibition or selective MAO-B inhibition for the treatment of Alzheimer's disease. Title: A non-competitive surface plasmon resonance immunosensor for rapid detection of triazophos residue in environmental and agricultural samples Guo Y, Liu R, Liu Y, Xiang D, Gui W, Li M, Zhu G Ref: Sci Total Environ, 613-614:783, 2018 : PubMed ESTHER: Guo_2018_Sci.Total.Environ_613-614_783 PubMedSearch: Guo 2018 Sci.Total.Environ 613-614 783 PubMedID: 28946376 Abstract The wide application of an organophosphate pesticide triazophos raises concern on the environmental pollution and the potential risk to human health. Thus, it is crucial to regularly monitor triazophos residue in the environment and agro-products. Herein we described a non-competitive immunoassay for trace detection of triazophos using a direct surface plasmon resonance (SPR) biosensor. Two anti-triazophos monoclonal antibodies (mAbs) were immobilized on the sensor chip and characterized by SPR-based kinetic analysis. The mAb with relatively slow dissociation rate was used for direct immunosensing of triazophos. The biosensor assay showed a high specificity and a low detection limit of 0.096ngmL-1 to triazophos, with the linear detection range of 0.98-8.29ngmL-1. Under the optimal condition, the sensor chip could be regenerated for 160cycles at least. Moreover, the sensitive method was applied to determine triazophos in the spiked environmental water and agricultural products, as well as in unknown real-life samples (including Chinese cabbage, cucumber, and apple). Desirable results demonstrated that the newly-developed immunosensor could be used as a rapid, convenient, and reliable tool to regularly monitor triazophos and meet the detection requirement of its maximum residue limits. Title: The endocannabinoid system regulates synaptic transmission in nucleus accumbens by increasing DAGL-alpha expression following short-term morphine withdrawal Wang XQ, Ma J, Cui W, Yuan WX, Zhu G, Yang Q, Heng LJ, Gao GD Ref: British Journal of Pharmacology, 173:1143, 2016 : PubMed ESTHER: Wang_2016_Br.J.Pharmacol_173_1143 PubMedSearch: Wang 2016 Br.J.Pharmacol 173 1143 PubMedID: 25296881 Abstract BACKGROUND AND PURPOSE: The endocannabinoid (eCB) system is involved in pathways that regulate drug addiction and eCB-mediated synaptic plasticity has been linked with addictive behaviours. Here, we investigated the molecular mechanisms underlying the changes in eCB-dependent synaptic plasticity in the nucleus accumbens core (NAcc) following short-term withdrawal from repeated morphine treatment. EXPERIMENTAL APPROACH: Conditioned place preference (CPP) was used to evaluate the rewarding effects of morphine in rats. Evoked inhibitory postsynaptic currents of medium spiny neurons in NAcc were measured using whole-cell patch-clamp recordings. Changes in depolarization-induced suppression of inhibition (DSI) in the NAcc were assessed to determine the effect of short-term morphine withdrawal on the eCB system. To identify the potential modulation mechanism of short-term morphine withdrawal on the eCB system, the expression of diacylglycerol lipase alpha (DGL-alpha) and monoacylglycerol lipase was detected by Western blot analysis. KEY Title: Characterization of a novel highly thermostable esterase from the Gram-positive soil bacterium Streptomyces lividans TK64 Wang B, Wang A, Cao Z, Zhu G Ref: Biotechnol Appl Biochem, 63:334, 2016 : PubMed ESTHER: Wang_2016_Biotechnol.Appl.Biochem_63_334 PubMedSearch: Wang 2016 Biotechnol.Appl.Biochem 63 334 PubMedID: 26621184 Gene_locus related to this paper: strco-SCO1265 Abstract A novel esterase gene (estW) from soil bacterium Streptomyces lividans TK64 was successfully cloned using a pair of homologous primers. The estW gene encoded a protein (EstW) of 289 amino acid residues with a predicted molecular weight of 31.43 kDa. Sequence alignment revealed that EstW show relatively high levels of homology to other lipolytic enzymes characterized from Streptomyces and phylogenetic analysis suggested EstW belongs to the bacterial lipase/esterase family I. The estW gene was expressed at a high level in Escherichia coli and the recombinant enzyme was purified to homogeneity. The purified EstW was characterized via hydrolysis of various p-nitrophenyl esters and the best substrate was found to be p-nitrophenyl acetate (pNPA). Maximal activity of the recombinant protein was observed at pH 8.0 and 50 degrees C with pNPA as the substrate. The calculated activation energy (Ea ) of the esterase reaction was 9.12 kcal/mol. Half-life of EstW at 95 degrees C was approximately 12.5 H, making it the most thermostable esterase among all of the known lipolytic enzymes from Streptomyces, and the thermostability of EstW was similar to those of some enzymes characterized from the thermophilic bacteria. EstW exhibited relatively high tolerance to several detergents and required no cations for its maximal activity. The unique properties of EstW, namely its high thermostability and stability in the presence of organic solvents, may render it a potential candidate for industrial applications. Title: Molecular Basis of the General Base Catalysis of an alpha/beta-Hydrolase Catalytic Triad Sun Y, Yin S, Feng Y, Li J, Zhou J, Liu C, Zhu G, Guo Z Ref: Journal of Biological Chemistry, 289:15867, 2014 : PubMed ESTHER: Sun_2014_J.Biol.Chem_289_15867 PubMedSearch: Sun 2014 J.Biol.Chem 289 15867 PubMedID: 24737327 Gene_locus related to this paper: ecoli-YFBB Inhibitor(s) related to this paper: SHCHC Abstract The serine-histidine-aspartate triad is well known for its covalent, nucleophilic catalysis in a diverse array of enzymatic transformations. Here we show that its nucleophilicity is shielded and its catalytic role is limited to being a specific general base by an open-closed conformational change in the catalysis of (1R,6R)-2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate synthase (or MenH), a typical alpha/beta-hydrolase fold enzyme in the vitamin K biosynthetic pathway. This enzyme is found to adopt an open conformation without a functional triad in its ligand-free form and a closed conformation with a fully functional catalytic triad in the presence of its reaction product. The open-to-closed conformational transition involves movement of half of the alpha-helical cap domain, which causes extensive structural changes in the alpha/beta-domain and forces the side chain of the triad histidine to adopt an energetically disfavored gauche conformation to form the functional triad. NMR analysis shows that the inactive open conformation without a triad prevails in ligand-free solution and is converted to the closed conformation with a properly formed triad by the reaction product. Mutation of the residues crucial to this open-closed transition either greatly decreases or completely eliminates the enzyme activity, supporting an important catalytic role for the structural change. These findings suggest that the open-closed conformational change tightly couples formation of the catalytic triad to substrate binding to enhance the substrate specificities and simultaneously shield the nucleophilicity of the triad, thus allowing it to expand its catalytic power beyond the nucleophilic catalysis. Title: A label-free silicon quantum dots-based photoluminescence sensor for ultrasensitive detection of pesticides Yi Y, Zhu G, Liu C, Huang Y, Zhang Y, Li H, Zhao J, Yao S Ref: Analytical Chemistry, 85:11464, 2013 : PubMed ESTHER: Yi_2013_Anal.Chem_85_11464 PubMedSearch: Yi 2013 Anal.Chem 85 11464 PubMedID: 24160846 Abstract Sensitive, rapid, and simple detection methods for the screening of extensively used organophosphorus pesticides and highly toxic nerve agents are in urgent demand. A novel label-free silicon quantum dots (SiQDs)-based sensor was designed for ultrasensitive detection of pesticides. This sensing strategy involves the reaction of acetylcholine chloride (ACh) with acetylcholinesterase (AChE) to form choline that is in turn catalytically oxidized by choline oxidase (ChOx) to produce betaine and H2O2 which can quench the photoluminescence (PL) of SiQDs. Upon the addition of pesticides, the activity of AChE is inhibited, leading to the decrease of the generated H2O2, and hence the PL of SiQDs increases. By measuring the increase in SiQDs PL, the inhibition efficiency of pesticide to AChE activity was evaluated. It was found that the inhibition efficiency was linearly dependent on the logarithm of the pesticides concentration. Consequently, pesticides, such as carbaryl, parathion, diazinon, and phorate, were determined with the SiQDs PL sensing method. The lowest detectable concentrations for carbaryl, parathion, diazinon, and phorate reached 7.25 x 10(-9), 3.25 x 10(-8), 6.76 x 10(-8), and 1.9 x 10(-7) g/L, respectively, which were much lower than those previously reported. The detecting results of pesticide residues in food samples via this method agree well with those from high-performance liquid chromatography. The simple strategy reported here should be suitable for on-site pesticides detection, especially in combination with other portable platforms. Title: Butyrylcholinesterase: association with the metabolic syndrome and identification of 2 gene loci affecting activity Valle A, O'Connor DT, Taylor P, Zhu G, Montgomery GW, Slagboom PE, Martin NG, Whitfield JB Ref: Clinical Chemistry, 52:1014, 2006 : PubMed ESTHER: Valle_2006_Clin.Chem_52_1014 PubMedSearch: Valle 2006 Clin.Chem 52 1014 PubMedID: 16574762 Abstract BACKGROUND: Plasma cholinesterase activity is known to be correlated with plasma triglycerides, HDL- and LDL-cholesterol, and other features of the metabolic syndrome. A role in triglyceride metabolism has been proposed. Genetic variants that decrease activity have been studied extensively, but the factors contributing to overall variation in the population are poorly understood. We studied plasma cholinesterase activity in a sample of 2200 adult twins to assess covariation with cardiovascular risk factors and components of the metabolic syndrome, to determine the degree of genetic effects on enzyme activity, and to search for quantitative trait loci affecting activity. METHODS AND RESULTS: Cholinesterase activity was lower in women than in men before the age of 50, but increased to activity values similar to those in males after that age. There were highly significant correlations with variables associated with the metabolic syndrome: plasma triglyceride, HDL- and LDL-cholesterol, apolipoprotein B and E, urate, and insulin concentrations; gamma-glutamyltransferase and aspartate and alanine aminotransferase activities; body mass index; and blood pressure. The heritability of plasma cholinesterase activity was 65%. Linkage analysis with data from the dizygotic twin pairs showed suggestive linkage on chromosome 3 at the location of the cholinesterase (BCHE) gene and also on chromosome 5. CONCLUSIONS: Our results confirm and extend the connection between cholinesterase, cardiovascular risk factors, and metabolic syndrome. They establish a substantial heritability for plasma cholinesterase activity that might be attributable to variation near the structural gene and at an independent locus. Title: Complete genome sequence of the apicomplexan, Cryptosporidium parvum Abrahamsen MS, Templeton TJ, Enomoto S, Abrahante JE, Zhu G, Lancto CA, Deng M, Liu C, Widmer G and Kapur V <10 more author(s)> Abrahamsen MS, Templeton TJ, Enomoto S, Abrahante JE, Zhu G, Lancto CA, Deng M, Liu C, Widmer G, Tzipori S, Buck GA, Xu P, Bankier AT, Dear PH, Konfortov BA, Spriggs HF, Iyer L, Anantharaman V, Aravind L, Kapur V (- 10) Ref: Science, 304:441, 2004 : PubMed ESTHER: Abrahamsen_2004_Science_304_441 PubMedSearch: Abrahamsen 2004 Science 304 441 PubMedID: 15044751 Gene_locus related to this paper: crypv-q5cph4, crypv-q5cpw0, crypv-q5cpw1, crypv-q5cq27, crypv-q5cq66, crypv-q5cq99, crypv-q5cqb9, crypv-q5cql0, crypv-q5cqw5, crypv-q5cr67, crypv-q5cre8, crypv-q5cs42, crypv-q5cs81, crypv-q5csw2, crypv-q5cv08, crypv-q5cv20 Abstract The apicomplexan Cryptosporidium parvum is an intestinal parasite that affects healthy humans and animals, and causes an unrelenting infection in immunocompromised individuals such as AIDS patients. We report the complete genome sequence of C. parvum, type II isolate. Genome analysis identifies extremely streamlined metabolic pathways and a reliance on the host for nutrients. In contrast to Plasmodium and Toxoplasma, the parasite lacks an apicoplast and its genome, and possesses a degenerate mitochondrion that has lost its genome. Several novel classes of cell-surface and secreted proteins with a potential role in host interactions and pathogenesis were also detected. Elucidation of the core metabolism, including enzymes with high similarities to bacterial and plant counterparts, opens new avenues for drug development. Title: Stress interacts with peripheral cholinesterase inhibitors to cause central nervous system effects Beck KD, Brennan FX, Moldow RL, Ottenweller JE, Zhu G, Servatius RJ Ref: Life Sciences, 73:41, 2003 : PubMed ESTHER: Beck_2003_Life.Sci_73_41 PubMedSearch: Beck 2003 Life.Sci 73 41 PubMedID: 12726885 Abstract Pyridostigmine bromide (PB), a peripheral cholinesterase inhibitor, has been shown to have central cholinesterase inhibition properties under certain conditions (such as when ingested with other chemical compounds or following a high level of stress). Here we tested if stressing rats, using an intermittent 1 hr tailshock protocol, affected the degree of brain acetylcholinesterase (AChE) inhibition caused by a subsequent single injection of PB (2.0 mg/kg) or neostigmine bromide (NB, 0.32 mg/kg), another peripheral carbamate cholinesterase inhibitor. Stressed rats treated with PB had lower levels of AChE activity in the basal forebrain/striatum, but not in other brain areas. Stressed rats treated with NB did not show basal forebrain/striatum AChE activity changes but did show minor reductions of AChE activity in the cortex and cerebellum. These results confirm that prior stress can change the characteristic actions of certain peripherally acting drugs, thus possibly leading to unexpected central nervous system effects. Possible causes for these effects are discussed. Title: Sequence and analysis of rice chromosome 4 Feng Q, Zhang Y, Hao P, Wang S, Fu G, Huang Y, Li Y, Zhu J, Liu Y and Han B <61 more author(s)> Feng Q, Zhang Y, Hao P, Wang S, Fu G, Huang Y, Li Y, Zhu J, Liu Y, Hu X, Jia P, Zhao Q, Ying K, Yu S, Tang Y, Weng Q, Zhang L, Lu Y, Mu J, Zhang LS, Yu Z, Fan D, Liu X, Lu T, Li C, Wu Y, Sun T, Lei H, Li T, Hu H, Guan J, Wu M, Zhang R, Zhou B, Chen Z, Chen L, Jin Z, Wang R, Yin H, Cai Z, Ren S, Lv G, Gu W, Zhu G, Tu Y, Jia J, Chen J, Kang H, Chen X, Shao C, Sun Y, Hu Q, Zhang X, Zhang W, Wang L, Ding C, Sheng H, Gu J, Chen S, Ni L, Zhu F, Chen W, Lan L, Lai Y, Cheng Z, Gu M, Jiang J, Li J, Hong G, Xue Y, Han B (- 61) Ref: Nature, 420:316, 2002 : PubMed ESTHER: Feng_2002_Nature_420_316 PubMedSearch: Feng 2002 Nature 420 316 PubMedID: 12447439 Gene_locus related to this paper: orysa-Q7XTC5, orysa-Q7F959, orysa-q7f9i3, orysa-q7x7y5, orysa-q7xkj9, orysa-q7xr62, orysa-q7xr63, orysa-q7xr64, orysa-q7xsg1, orysa-q7xsq2, orysa-Q7XTM8, orysa-q7xts6, orysa-q7xue7, orysa-q7xv53, orysa-Q7XVB5, orysa-Q7XVG5, orysj-q0jaf0, orysj-q7f8x1 Abstract Rice is the principal food for over half of the population of the world. With its genome size of 430 megabase pairs (Mb), the cultivated rice species Oryza sativa is a model plant for genome research. Here we report the sequence analysis of chromosome 4 of O. sativa, one of the first two rice chromosomes to be sequenced completely. The finished sequence spans 34.6 Mb and represents 97.3% of the chromosome. In addition, we report the longest known sequence for a plant centromere, a completely sequenced contig of 1.16 Mb corresponding to the centromeric region of chromosome 4. We predict 4,658 protein coding genes and 70 transfer RNA genes. A total of 1,681 predicted genes match available unique rice expressed sequence tags. Transposable elements have a pronounced bias towards the euchromatic regions, indicating a close correlation of their distributions to genes along the chromosome. Comparative genome analysis between cultivated rice subspecies shows that there is an overall syntenic relationship between the chromosomes and divergence at the level of single-nucleotide polymorphisms and insertions and deletions. By contrast, there is little conservation in gene order between rice and Arabidopsis. Title: Central nervous system effects from a peripherally acting cholinesterase inhibiting agent: interaction with stress or genetics Beck KD, Zhu G, Beldowicz D, Brennan FX, Ottenweller JE, Moldow RL, Servatius RJ Ref: Annals of the New York Academy of Sciences, 933:310, 2001 : PubMed ESTHER: Beck_2001_Ann.N.Y.Acad.Sci_933_310 PubMedSearch: Beck 2001 Ann.N.Y.Acad.Sci 933 310 PubMedID: 12000030 Title: Effects of carbamazepine on acetylcholine release and metabolism Mizuno K, Okada M, Murakami T, Kamata A, Zhu G, Kawata Y, Wada K, Kaneko S Ref: Epilepsy Research, 40:187, 2000 : PubMed ESTHER: Mizuno_2000_Epilepsy.Res_40_187 PubMedSearch: Mizuno 2000 Epilepsy.Res 40 187 PubMedID: 10863146 Abstract To clarify the mechanisms of action of carbamazepine (CBZ), we investigated the effects of CBZ on acetylcholine (ACh) release and metabolism in rat striatum and hippocampus. Acute administration of effective dose of CBZ (25 mg/kg) increased both striatal and hippocampal extracellular levels of ACh, whereas a supraeffective dose of CBZ (50 mg/kg) did not affect the levels and a toxic dose of CBZ (100 mg/kg) decreased the extracellular ACh levels in both brain regions. Both acute and chronic administrations of CBZ (25 and 50 mg/kg, mg/kg per day) increased intracellular ACh levels in striatum and hippocampus. The striatal intracellular ACh levels were decreased by both acute and chronic administrations of CBZ (100 mg/kg, mg/kg per day), whereas the hippocampal intracellular ACh levels were not affected. The effective CBZ concentration did not affect cholinesterase activity, whereas supraeffective CBZ concentration reduced it weakly. Effective dose of CBZ enhanced ACh release and synthesis; however, supraeffective doses of CBZ reduced ACh release and synthesis without enhancement of ACh degradation, indicating that CBZ has biphasic effects on ACh release and synthesis. Thus, the present findings, the slight stimulation of ACh function by effective dose of CBZ, are involved, at least partially, in the antiepileptic and mood stabilizing mechanisms of action of CBZ. Title: Effects of inescapable stress and treatment with pyridostigmine bromide on plasma butyrylcholinesterase and the acoustic startle response in rats Servatius RJ, Ottenweller JE, Guo W, Beldowicz D, Zhu G, Natelson BH Ref: Physiol Behav, 69:239, 2000 : PubMed ESTHER: Servatius_2000_Physiol.Behav_69_239 PubMedSearch: Servatius 2000 Physiol.Behav 69 239 PubMedID: 10869589 Inhibitor(s) related to this paper: Pyridostigmine Abstract Pyridostigmine bromide (PB) is a reversible, peripherally active inhibitor of acetylcholinesterase (AChE) activity, and is recommended by the military as a pretreatment against potential nerve gas exposure. Recent evidence suggests that exposure to inescapable stressors allows PB to cross the blood-brain barrier, and thereby affect central AChE activity in mice. Here, we evaluated the functional impact of a stress/PB treatment interaction on acoustic startle responding and plasma butyrylcholinesterase (BuChE) activity in male Sprague-Dawley rats. To model the treatment protocol used by the military, PB was delivered in the drinking water of rats for 7 consecutive days. The morning after the start of PB treatment, and for the next 6 days, half the rats were exposed to 1 h of supine restraint stress. We therefore employed a 2 x 2 (stress x PB treatment) between-groups design. Exposure to supine stress alone induced a persistent decrease in plasma BuChE activity. Further decreases in BuChE activity were not observed in rats exposed to supine restraint and PB treatment. Exposure to stress also induced an exaggerated startle response, evident on the last day of stress and 24 h after stressor cessation. Treatment with PB alone produced an exaggerated startle response over the same time period, albeit to a lesser degree. Although treatment with PB concurrent with stress did not produce further changes in either BuChE activity or acoustic startle responding, stress-induced alterations in drinking behavior (and thereby the dose of PB ingested) may have affected these results. Persistent stress-induced reductions in BuChE activity may increase the risk of adverse reactions to cholinomimetics. Title: Persistently exaggerated startle responses in rats treated with pyridostigmine bromide Servatius RJ, Ottenweller JE, Beldowicz D, Guo W, Zhu G, Natelson BH Ref: Journal of Pharmacology & Experimental Therapeutics, 287:1020, 1998 : PubMed ESTHER: Servatius_1998_J.Pharmacol.Exp.Ther_287_1020 PubMedSearch: Servatius 1998 J.Pharmacol.Exp.Ther 287 1020 PubMedID: 9864288 Inhibitor(s) related to this paper: Pyridostigmine Abstract Troops in the Persian Gulf War have registered complaints consistent with CNS dysfunction that emerged after returning from the Gulf. A common experience among Persian Gulf War veterans was exposure to pyridostigmine bromide (PB) for prophylaxis against nerve gas exposure. To determine whether PB causes emergent CNS dysfunction, Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats were given PB for 7 consecutive days in their drinking water. The WKY, but not the SD, rats exhibited a delayed-onset, persistently exaggerated startle response. The WKY rats exhibited exaggerated startle responses that appeared 15 days after the end of PB treatment and were still evident 22 days after the end of treatment. Both the duration and the magnitude of the exaggerated startle responses were related to the dosage of PB. The PB-treated rats exhibited normal short-term and long-term habituation. However, exaggerated startle responses were related to the development of enhanced short-term sensitization. Treating the rats for a second time, 7 weeks after the end of the first PB treatment, induced an exaggerated startle response that appeared sooner and dissipated faster than was evident after the first PB treatment. Inasmuch as the WKY rat has inherently low butyrylcholinesterase activity, a scavenger for PB, these results suggest that prophylactic PB may influence CNS function in individuals with low butyrylcholinesterase activity. Elaboration of the factors that mediate enhanced sensitization in the WKY rat may provide insight into some of the complaints registered by veterans of the Persian Gulf War. | |||||||
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