Sun W


Full name : Sun Wei

First name : Wei

Mail : Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500

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Country : USA

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References (73)

Title : Neuroprotective effects of cordycepin inhibit glutamate-induced apoptosis in hippocampal neurons - Sun_2024_Cell.Stress.Chaperones__
Author(s) : Sun H , Wei S , Gong Y , Ding K , Tang S , Sun W , Yuan C , Huang L , Liu Z , Chen C , Yao L
Ref : Cell Stress Chaperones , : , 2024
Abstract : Glutamate is a neurotransmitter that can cause excitatory neurotoxicity when its extracellular concentration is too high, leading to disrupted calcium balance and increased production of reactive oxygen species (ROS). Cordycepin, a nucleoside adenosine derivative, has been shown to protect against excitatory neurotoxicity induced by glutamate. To investigate its potential neuroprotective effects, the present study employed fluorescence detection and spectrophotometry techniques to analyze primary hippocampal-cultured neurons. The results showed that glutamate toxicity reduced hippocampal neuron viability, increased ROS production, and increased intracellular calcium levels. Additionally, glutamate-induced cytotoxicity activated acetylcholinesterase (AChE) and decreased glutathione (GSH) levels. However, cordycepin inhibited glutamate-induced cell death, improved cell viability, reduced ROS production, and lowered Ca(2+) levels. It also inhibited AChE activation and increased GSH levels. This study suggests that cordycepin can protect against glutamate-induced neuronal injury in cell models, and this effect was inhibited by adenosine A(1) receptor blockers, indicating that its neuroprotective effect is achieved through activation of the adenosine A(1) receptor.
ESTHER : Sun_2024_Cell.Stress.Chaperones__
PubMedSearch : Sun_2024_Cell.Stress.Chaperones__
PubMedID: 38219840

Title : MAGL inhibition relieves synovial inflammation and pain via regulating NOX4-Nrf2 redox balance in osteoarthritis - Li_2023_Free.Radic.Biol.Med_208_13
Author(s) : Li X , Tao H , Zhou J , Zhang L , Shi Y , Zhang C , Sun W , Chu M , Chen K , Gu C , Yang X , Geng D , Hao Y
Ref : Free Radic Biol Med , 208 :13 , 2023
Abstract : Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage injury, hyperplasia of bone and inflammatory lesions of synovium. Monoacylglycerol lipase (MAGL), a member of the alpha/beta hydrolase superfamily, is involved in regulation of injury protection and immune-inflammation response. Autoinflammatory response of the synovium and the release of inflammatory mediators play critical roles in occurrence of early-stage OA. Fibroblast-like synoviocytes (FLSs) are resident mesenchymal cells of the synovial tissue. Considering that MAGL inhibition regulates the inflammatory signaling cascade, it is crucial to ascertain the biological effects and specific mechanisms of MAGL in alleviating inflammatory infiltration of OA FLSs. The aim of this study was to investigate the effect of MAGL on biological function in OA FLSs. Results from in vitro experiments showed that MAGL blockade not only effectively inhibited proliferation, invasion and migration of FLSs, but also downregulated expression of inflammatory-associated proteins. Sequencing results indicated that MAGL inhibition significantly suppressed NOX4-mediated oxidative stress, thus promoting Nrf2 nuclear accumulation and inhibiting generation of intracellular reactive oxygen species (ROS). Attenuation of NOX4 further alleviated redox dysplasia and ultimately improved tumor-like phenotypes, such as abnormal proliferation, migration and migration of FLSs. In vivo results corroborated this finding, with MAGL inhibition found to modulate pain and disease progression in an OA rat model. Collectively, these results indicate that MAGL administration is an ideal therapy treating OA.
ESTHER : Li_2023_Free.Radic.Biol.Med_208_13
PubMedSearch : Li_2023_Free.Radic.Biol.Med_208_13
PubMedID: 37516370
Gene_locus related to this paper: human-MGLL

Title : Lonicera japonica polysaccharides alleviate D-galactose-induced oxidative stress and restore gut microbiota in ICR mice - Sun_2023_Int.J.Biol.Macromol__125517
Author(s) : Sun W , Zhu J , Qin G , Huang Y , Cheng S , Chen Z , Zhang Y , Shu Y , Zeng X , Guo R
Ref : Int J Biol Macromol , :125517 , 2023
Abstract : Lonicera japonica polysaccharides (LJPs) exhibit anti-aging effect in nematodes. Here, we further studied the function of LJPs on aging-related disorders in D-galactose (D-gal)-induced ICR mice. Four groups of mice including the control group, the D-gal-treated group, the intervening groups with low and high dose of LJPs (50 and 100 mg/kg/day) were raised for 8 weeks. The results showed that intragastric administration with LJPs improved the organ indexes of D-gal-treated mice. Moreover, LJPs improved the activity of superoxide dismutase (SOD), catalase (CAT) as well as glutathione peroxidase (GSH-Px) and decreasing the malondialdehyde (MDA) level in serum, liver and brain. Meanwhile, LJPs restored the content of acetylcholinesterase (AChE) in the brain. Further, LJPs reversed the liver tissue damages in aging mice. Mechanistically, LJPs alleviate oxidative stress at least partially through regulating Nrf2 signaling. Additionally, LJPs restored the gut microbiota composition of D-gal-treated mice by adjusting the Firmicutes/Bacteroidetes ratio at the phylum level and upregulating the relative abundances of Lactobacillaceae and Bifidobacteriacesa. Notably, the KEGG pathways involved in hazardous substances degradation and flavone and flavonol biosynthesis were significantly enhanced by LJPs treatment. Overall, our study uncovers the role of LJPs in modulating oxidative stress and gut microbiota in the D-gal-induced aging mice.
ESTHER : Sun_2023_Int.J.Biol.Macromol__125517
PubMedSearch : Sun_2023_Int.J.Biol.Macromol__125517
PubMedID: 37353132

Title : A Phenotypic Screen Identifies Potent DPP9 Inhibitors Capable of Killing HIV-1 Infected Cells - Moore_2022_ACS.Chem.Biol_17_2595
Author(s) : Moore KP , Schwaid AG , Tudor M , Park S , Beshore DC , Converso A , Shipe WD , Anand R , Lan P , Moningka R , Rothman DM , Sun W , Chi A , Cornella-Taracido I , Adam GC , Bahnck-Teets C , Carroll SS , Fay JF , Goh SL , Lusen J , Quan S , Rodriguez S , Xu M , Andrews CL , Song C , Filzen T , Li J , Hollenstein K , Klein DJ , Lammens A , Lim UM , Fang Z , McHale C , Li Y , Lu M , Diamond TL , Howell BJ , Zuck P , Balibar CJ
Ref : ACS Chemical Biology , 17 :2595 , 2022
Abstract : Although current antiretroviral therapy can control HIV-1 replication and prevent disease progression, it is not curative. Identifying mechanisms that can lead to eradication of persistent viral reservoirs in people living with HIV-1 (PLWH) remains an outstanding challenge to achieving cure. Utilizing a phenotypic screen, we identified a novel chemical class capable of killing HIV-1 infected peripheral blood mononuclear cells. Tool compounds ICeD-1 and ICeD-2 ("inducer of cell death-1 and 2"), optimized for potency and selectivity from screening hits, were used to deconvolute the mechanism of action using a combination of chemoproteomic, biochemical, pharmacological, and genetic approaches. We determined that these compounds function by modulating dipeptidyl peptidase 9 (DPP9) and activating the caspase recruitment domain family member 8 (CARD8) inflammasome. Efficacy of ICeD-1 and ICeD-2 was dependent on HIV-1 protease activity and synergistic with efavirenz, which promotes premature activation of HIV-1 protease at high concentrations in infected cells. This in vitro synergy lowers the efficacious cell kill concentration of efavirenz to a clinically relevant dose at concentrations of ICeD-1 or ICeD-2 that do not result in complete DPP9 inhibition. These results suggest engagement of the pyroptotic pathway as a potential approach to eliminate HIV-1 infected cells.
ESTHER : Moore_2022_ACS.Chem.Biol_17_2595
PubMedSearch : Moore_2022_ACS.Chem.Biol_17_2595
PubMedID: 36044633
Gene_locus related to this paper: human-DPP8 , human-DPP9

Title : Plant GDSL Esterases\/Lipases: Evolutionary, Physiological and Molecular Functions in Plant Development - Shen_2022_Plants.(Basel)_11_
Author(s) : Shen G , Sun W , Chen Z , Shi L , Hong J , Shi J
Ref : Plants (Basel) , 11 : , 2022
Abstract : GDSL esterases/lipases (GELPs), present throughout all living organisms, have been a very attractive research subject in plant science due mainly to constantly emerging properties and functions in plant growth and development under both normal and stressful conditions. This review summarizes the advances in research on plant GELPs in several model plants and crops, including Arabidopsis, rice, maize and tomato, while focusing on the roles of GELPs in regulating plant development and plant-environment interactions. In addition, the possible regulatory network and mechanisms of GELPs have been discussed.
ESTHER : Shen_2022_Plants.(Basel)_11_
PubMedSearch : Shen_2022_Plants.(Basel)_11_
PubMedID: 35214802

Title : Co, N co-doped porous carbon-based nanozyme as an oxidase mimic for fluorescence and colorimetric biosensing of butyrylcholinesterase activity - Sun_2022_Mikrochim.Acta_189_363
Author(s) : Sun W , Wang N , Zhou X , Sheng Y , Su X
Ref : Mikrochim Acta , 189 :363 , 2022
Abstract : A Co, N co-doped porous carbon-based nanozyme (Co-N-C nanozyme) has been fabricated. Taking advantages of the excellent oxidase catalytic activity and significant stability of Co-N-C nanozyme, we propose a fluorescence and colorimetric system based on Co-N-C nanozyme and red-emitting carbon quantum dots (RCDs) for butyrylcholinesterase (BChE) sensing. As the chromogenic substrate 3,3',5,5'-tetramethylbenzidine (TMB) was catalyzed and oxidized by Co-N-C nanozyme, the generated oxTMB had a new absorption peak at 652 nm, which resulted in the significant quenching of the fluorescence of the carbon quantum dots at 610 nm. Under the catalysis of BChE, thiocholine was generated from the hydrolysis of S-butyrylthiocholine iodide (BTCh), and the as-generated thiocholine effectively inhibited the oxidation of TMB catalyzed by Co-N-C nanozyme, leading to a decrease of the absorption of oxTMB at 652 nm and effective fluorescence recovery of RCDs. By measuring the absorbance of produced oxTMB at 652 nm and the fluorescence of RCDs at 610 nm, the fluorescence and colorimetric system both exhibited an outstanding linear response to the activity of BChE in the range 0.5 to 40 U L(-1), with a detection limit of 0.16 U L(-1) and 0.21 U L(-1), respectively. Furthermore, this established dual-channel biosensing strategy has been successfully applied to the determination of BChE in human serum samples. The present work has effectively expanded the development and application of nanozyme in biosensing.
ESTHER : Sun_2022_Mikrochim.Acta_189_363
PubMedSearch : Sun_2022_Mikrochim.Acta_189_363
PubMedID: 36044087

Title : Constructing bifunctional metal-organic framework based nanozymes with fluorescence and oxidase activity for the dual-channel detection of butyrylcholinesterase - Wang_2022_Anal.Chim.Acta_1205_339717
Author(s) : Wang N , Shi J , Liu Y , Sun W , Su X
Ref : Anal Chim Acta , 1205 :339717 , 2022
Abstract : Herein, we reported a novel strategy for the fabrication of bifunctional metal-organic framework based nanozymes (oxidized UiO-66-NH(2)@Ce), which displayed excellent oxidase mimic activity as well as fluorescence property. The bifunctional oxidized UiO-66-NH(2)@Ce possess excellent oxidase activity due to oxidase-like active Ce(4+)/Ce(3+) sites, which makes the nanozymes have strong positive charge, resulting in a stronger affinity for the negatively charged chromogenic substrate 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). Utilizing the bifunctional oxidized UiO-66-NH(2)@Ce, a sensitive fluorometric and colorimetric dual-channel detection strategy for butyrylcholinesterase (BChE) was fabricated for the first time. The oxidized UiO-66-NH(2)@Ce could catalyze the oxidation of colorless ABTS to green oxABTS, which in turn quench the fluorescence of oxidized UiO-66-NH(2)@Ce. Butyrylcholinesterase (BChE) can catalyze the hydrolysis of S-butyrylthiocholine iodide (BTCh) to produce thiocholine, which could prevent the oxidation of ABTS, resulting in the fluorescence of oxidized UiO-66-NH(2)@Ce recovered. Both the colorimetric and fluorometric dual-channel sensing platform displayed a sensitive response to BChE, and the limits of detection (LOD) for BChE could achieve as low as 0.056 and 0.050U/L, respectively. The dual-output assay for BChE detection displayed excellent application prospects.
ESTHER : Wang_2022_Anal.Chim.Acta_1205_339717
PubMedSearch : Wang_2022_Anal.Chim.Acta_1205_339717
PubMedID: 35414394

Title : Peroxisomal beta-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis - Ding_2021_Nat.Metab__
Author(s) : Ding L , Sun W , Balaz M , He A , Klug M , Wieland S , Caiazzo R , Raverdy V , Pattou F , Lefebvre P , Lodhi IJ , Staels B , Heim M , Wolfrum C
Ref : Nat Metab , : , 2021
Abstract : To liberate fatty acids (FAs) from intracellular stores, lipolysis is regulated by the activity of the lipases adipose triglyceride lipase (ATGL), hormone-sensitive lipase and monoacylglycerol lipase. Excessive FA release as a result of uncontrolled lipolysis results in lipotoxicity, which can in turn promote the progression of metabolic disorders. However, whether cells can directly sense FAs to maintain cellular lipid homeostasis is unknown. Here we report a sensing mechanism for cellular FAs based on peroxisomal degradation of FAs and coupled with reactive oxygen species (ROS) production, which in turn regulates FA release by modulating lipolysis. Changes in ROS levels are sensed by PEX2, which modulates ATGL levels through post-translational ubiquitination. We demonstrate the importance of this pathway for non-alcoholic fatty liver disease progression using genetic and pharmacological approaches to alter ROS levels in vivo, which can be utilized to increase hepatic ATGL levels and ameliorate hepatic steatosis. The discovery of this peroxisomal beta-oxidation-mediated feedback mechanism, which is conserved in multiple organs, couples the functions of peroxisomes and lipid droplets and might serve as a new way to manipulate lipolysis to treat metabolic disorders.
ESTHER : Ding_2021_Nat.Metab__
PubMedSearch : Ding_2021_Nat.Metab__
PubMedID: 34903883

Title : Berberine Ameliorates Glucose Metabolism in Diabetic Rats through the alpha7 Nicotinic Acetylcholine Receptor-Related Cholinergic Anti-Inflammatory Pathway - Wang_2021_Planta.Med__
Author(s) : Wang D , Ren Y , Sun W , Gong J , Zou X , Dong H , Xu L , Wang K , Lu F
Ref : Planta Med , : , 2021
Abstract : Berberine is an isoquinoline derivative alkaloid extracted from Chinese herbs. Recent studies have demonstrated the therapeutic effect of berberine on glucose metabolic disorders. However, its specific mechanism is still unclear. Our study aimed to research the glucose-lowering effect of berberine in diabetic rats and to reveal the possible role of the cholinergic anti-inflammatory pathway. Diabetic rats induced by administration of a high-calorie diet and streptozocin tail vein injection were assessed by the oral glucose tolerance test. Then, the diabetic rats were divided into two groups, those with or without the alpha7 nicotinic acetylcholine receptor gene downregulated, respectively, followed by treatment including berberine for 6 weeks. Results of this study show that the administration of berberine downregulated levels of fasting blood glucose and fasting insulin, and ameliorated insulin resistance in diabetic rats. Treatment with berberine inhibited acetylcholinesterase activity, and upregulated acetylcholine levels in the serum and alpha7 nicotinic acetylcholine receptor gene expression in the liver tissue. Meanwhile, berberine reversed elevated expression of cytokines interleukin-1beta and TNF-alpha in the serum and downregulated nuclear factor kappaB expression. However, berberine administration showed no glucose-lowering or anti-inflammatory effect in diabetic rats in which alpha7 nicotinic acetylcholine receptor gene expression was downregulated, and acetylcholinesterase activity was also significantly inhibited. In conclusion, berberine may ameliorate glucose metabolism by activating the alpha7 nicotinic acetylcholine receptor-mediated cholinergic anti-inflammatory pathway.
ESTHER : Wang_2021_Planta.Med__
PubMedSearch : Wang_2021_Planta.Med__
PubMedID: 33682914

Title : Discovery of memantyl urea derivatives as potent soluble epoxide hydrolase inhibitors against lipopolysaccharide-induced sepsis - Du_2021_Eur.J.Med.Chem_223_113678
Author(s) : Du F , Sun W , Morisseau C , Hammock BD , Bao X , Liu Q , Wang C , Zhang T , Yang H , Zhou J , Xiao W , Liu Z , Chen G
Ref : Eur Journal of Medicinal Chemistry , 223 :113678 , 2021
Abstract : Sepsis, a systemic inflammatory response, caused by pathogenic factors including microorganisms, has high mortality and limited therapeutic approaches. Herein, a new soluble epoxide hydrolase (sEH) inhibitor series comprising a phenyl ring connected to a memantyl moiety via a urea or amide linkage has been designed. A preferential urea pharmacophore that improved the binding properties of the compounds was identified for those series via biochemical assay in vitro and in vivo studies. Molecular docking displayed that 3,5-dimethyl on the adamantyl group in B401 could make van der Waals interactions with residues at a hydrophobic pocket of sEH active site, which might indirectly explain the subnanomolar level activities of memantyl urea derivatives in vitro better than AR-9281. Among them, compound B401 significantly improved the inhibition potency with human and murine sEH IC(50) values as 0.4 nM and 0.5 nM, respectively. Although the median survival time of C57BL/6 mice in LPS-induced sepsis model was slightly increased, the survival rate did not reach significant efficacy. Based on safety profile, metabolic stability, pharmacokinetic and in vivo efficacy, B401 demonstrated the proof of potential for this class of memantyl urea-based sEH inhibitors as therapeutic agents in sepsis.
ESTHER : Du_2021_Eur.J.Med.Chem_223_113678
PubMedSearch : Du_2021_Eur.J.Med.Chem_223_113678
PubMedID: 34218083

Title : Pig Liver Esterases Hydrolyze Endocannabinoids and Promote Inflammatory Response - Zhou_2021_Front.Immunol_12_670427
Author(s) : Zhou Q , Yan B , Sun W , Chen Q , Xiao Q , Xiao Y , Wang X , Shi D
Ref : Front Immunol , 12 :670427 , 2021
Abstract : Endocannabinoids are endogenous ligands of cannabinoid receptors and activation of these receptors has strong physiological and pathological significance. Structurally, endocannabinoids are esters (e.g., 2-arachidonoylglycerol, 2-AG) or amides (e.g., N-arachidonoylethanolamine, AEA). Hydrolysis of these compounds yields arachidonic acid (AA), a major precursor of proinflammatory mediators such as prostaglandin E(2). Carboxylesterases are known to hydrolyze esters and amides with high efficiency. CES1, a human carboxylesterase, has been shown to hydrolyze 2-AG, and shares a high sequence identity with pig carboxylesterases: PLE1 and PLE6 (pig liver esterase). The present study was designed to test the hypothesis that PLE1 and PLE6 hydrolyze endocannabinoids and promote inflammatory response. Consistent with the hypothesis, purified PLE1 and PLE6 efficaciously hydrolyzed 2-AG and AEA. PLE6 was 40-fold and 3-fold as active as PLE1 towards 2-AG and AEA, respectively. In addition, both PLE1 and PLE6 were highly sensitive to bis(4-nitrophenyl) phosphate (BNPP), an aryl phosphodiester known to predominately inhibit carboxylesterases. Based on the study with BNPP, PLEs contributed to the hydrolysis of 2-AG by 53.4 to 88.4% among various organs and cells. Critically, exogenous addition or transfection of PLE6 increased the expression and secretion of proinflammatory cytokines in response to the immunostimulant lipopolysaccharide (LPS). This increase was recapitulated in cocultured alveolar macrophages and PLE6 transfected cells in transwells. Finally, BNPP reduced inflammation trigged by LPS accompanied by reduced formation of AA and proinflammatory mediators. These findings define an innovative connection: PLE-endocannabinoid-inflammation. This mechanistic connection signifies critical roles of carboxylesterases in pathophysiological processes related to the metabolism of endocannabinoids.
ESTHER : Zhou_2021_Front.Immunol_12_670427
PubMedSearch : Zhou_2021_Front.Immunol_12_670427
PubMedID: 34079552
Gene_locus related to this paper: pig-PLE1 , pig-a0a1s6l967

Title : Melamine Disrupts Acetylcholine-Mediated Neural Information Flow in the Hippocampal CA3-CA1 Pathway - Sun_2021_Front.Behav.Neurosci_15_594907
Author(s) : Sun W , Liu P , Tang C , An L
Ref : Front Behavioral Neuroscience , 15 :594907 , 2021
Abstract : Considering the cognitive and synaptic deficits following intragastric administration of melamine, the aim of the current investigation was to test whether the hippocampal oscillations were affected. The local field potential (LFP) was recorded in the hippocampal CA3-CA1 pathway of Wistar rats during a spatial-dependent Y-maze task. The general partial directed coherence (gPDC) method was used to assess the directionality of neural information flow (NIF) between the CA3 and CA1 regions. The levels of acetylcholine (ACh) and its esterolytic protease, acetylcholinesterase (AChE), were detected in the hippocampus (HPC) following the behavioral test. The values of phase synchronization between the CA3 and CA1 regions in delta, low theta, and high theta oscillations were reduced significantly in the melamine-treated group. Moreover, the coupling directional index and the strength of CA3 driving CA1 were critically decreased in the above three frequency bands as well. Meanwhile, a reduction in ACh expression and an enhancement in AChE activity were found in the HPC of melamine-treated rats. Intrahippocampal infusion with ACh could mitigate the weakened neural coupling and directional NIF in parallel with spatial learning improvements. However, infusion of scopolamine, an acetylcholine receptor antagonist, could block the mitigative effects of ACh treatment in melamine rats. These findings provide first evidence that ACh-mediated neuronal coupling and NIF in the CA3-CA1 pathway are involved in spatial learning deficits induced by chronic melamine exposure.
ESTHER : Sun_2021_Front.Behav.Neurosci_15_594907
PubMedSearch : Sun_2021_Front.Behav.Neurosci_15_594907
PubMedID: 33679339

Title : Adipogenic activity of 2-ethylhexyl diphenyl phosphate via peroxisome proliferator-activated receptor gamma pathway - Sun_2020_Sci.Total.Environ_711_134810
Author(s) : Sun W , Duan X , Chen H , Zhang L , Sun H
Ref : Sci Total Environ , 711 :134810 , 2020
Abstract : Recent studies have shown that exposure to some organophosphates, such as triphenyl phosphate (TPHP) and diphenyl phosphate (DPHP), can affect adipogenesis in preadipocytes. 2-Ethylhexyl diphenyl phosphate (EHDPP), an organophosphate, is frequently detected in various environmental media. However, there is less information about the toxicity effects and the mechanism by which EHDPP affects preadipocytes. In the present study, we investigated whether EHDPP could induce differentiation in 3T3-L1 preadipocytes through the peroxisome proliferator-activated receptor gamma (PPARgamma) signaling pathway. The fluorescence competitive binding assay and the dual-luciferase reporter gene assay were used to assess the binding affinity and activation of PPARgamma, and the results showed that EHDPP can bind to the ligand binding domain of PPARgamma (PPARgamma-LBD) and activate PPARgamma in vitro. Exposure to EHDPP for 10 days extensively induced adipogenesis in 3T3-L1 preadipocytes as assessed by lipid accumulation and gene expression of adipogenic markers of fatty acid binding protein 4 (FABP4), lipoprotein lipase (Lpl), adiponectin (Adip), and fatty acid synthase (Fasn). Furthermore, the preadipocytes differentiation was blocked by the PPARgamma-specific antagonist GW9662, indicating that the PPARgamma signaling pathway plays an important part in 3T3-L1 cell differentiation induced by EHDPP. Taken together, EHDPP can bind to PPARgamma-LBD, activate PPARgamma receptor, and induce cell differentiation via the PPARgamma signaling pathway in 3T3-L1 preadipocytes.
ESTHER : Sun_2020_Sci.Total.Environ_711_134810
PubMedSearch : Sun_2020_Sci.Total.Environ_711_134810
PubMedID: 31812418

Title : Self-assembly of lipase hybrid nanoflowers with bifunctional Ca(2+) for improved activity and stability - Zhang_2020_Enzyme.Microb.Technol_132_109408
Author(s) : Zhang Y , Sun W , Elfeky NM , Wang Y , Zhao D , Zhou H , Wang J , Bao Y
Ref : Enzyme Microb Technol , 132 :109408 , 2020
Abstract : Lipase ZC12, a cold-adapted lipase derived from Psychrobacter sp. ZY124, can be effectively activated by Ca(2+). Inspired by this significant property, we developed a novel immobilized lipase ZC12/Ca3(PO4)2 hybrid nanoflowers (LHNs). The LHNs have been characterized as a regular hierarchical flowerlike structure nanoflowers by scanning electron microscopy (SEM). Compared with free lipase ZC12, the LHNs exerted enhanced enzymatic activity of 206% and 2.31-fold in kcat/Km value, especially high specific activity at low temperature. After 7 successive cycles, the LHNs could still maintain its initial activity, demonstrating superior durability than the free lipase ZC12. Meanwhile, its stability basically kept unchanged in a wide range of temperature and pH. Finally, fructose laurate was transformed by the LHNs with 57.39% conversion rate which is twice as much as the free lipase. To sum up, these results validated that LHNs could emerge as an efficient immobilized lipase and possess the promising potential for practical applications.
ESTHER : Zhang_2020_Enzyme.Microb.Technol_132_109408
PubMedSearch : Zhang_2020_Enzyme.Microb.Technol_132_109408
PubMedID: 31731973
Gene_locus related to this paper: 9gamm-a0a1b1ijp3

Title : Western diet induces severe nonalcoholic steatohepatitis, ductular reaction, and hepatic fibrosis in liver CGI-58 knockout mice - Yang_2020_Sci.Rep_10_4701
Author(s) : Yang P , Wang Y , Tang W , Sun W , Ma Y , Lin S , Jing J , Jiang L , Shi H , Song Z , Yu L
Ref : Sci Rep , 10 :4701 , 2020
Abstract : Humans and rodents with Comparative Gene Identification-58 (CGI-58) mutations manifest nonalcoholic fatty liver disease (NAFLD). Here we show that liver CGI-58 knockout (LivKO) mice fed a Western diet rapidly develop advanced NAFLD, including nonalcoholic steatohepatitis (NASH) and hepatic fibrosis. After 14 weeks of diet challenge, starting at 6 weeks of age, LivKO mice showed increased inflammatory cell infiltration and proinflammatory gene expression in the liver, which was associated with elevated plasma levels of aminotransferases. Hepatic ductular reactions, pericellular fibrosis, and bridging fibrosis were observed only in the LivKO mice. Consistently, the KO mice had a significant increase in hepatic mRNAs for fibrogenic genes. In addition, LivKO mice displayed massive accumulation of lipid droplets (LDs) in hepatocytes. LDs were also observed in the cholangiocytes of the LivKO mice, but not the floxed controls. Four of the five LD coat proteins, including perilipins 2, 3, 4, and 5, were increased in the CGI-58 KO liver. CRISPR/Cas9-mediated knockout of CGI-58 in Huh7 human hepatoma cells induced LD deposition and perilipin expression, suggesting a cell autonomous effect. Our findings establish the Western diet-fed LivKO mice as an animal model of NASH and hepatic fibrosis. These animals may facilitate preclinical screening of therapeutic agents that counter against NAFLD progression.
ESTHER : Yang_2020_Sci.Rep_10_4701
PubMedSearch : Yang_2020_Sci.Rep_10_4701
PubMedID: 32170127
Gene_locus related to this paper: human-ABHD5 , mouse-abhd5

Title : ABHD5 blunts the sensitivity of colorectal cancer to fluorouracil via promoting autophagic uracil yield - Ou_2019_Nat.Commun_10_1078
Author(s) : Ou J , Peng Y , Yang W , Zhang Y , Hao J , Li F , Chen Y , Zhao Y , Xie X , Wu S , Zha L , Luo X , Xie G , Wang L , Sun W , Zhou Q , Li J , Liang H
Ref : Nat Commun , 10 :1078 , 2019
Abstract : The efficacy of Fluorouracil (FU) in the treatment of colorectal cancer (CRC) is greatly limited by drug resistance. Autophagy has been implicated in chemoresistance, but the role of selective autophagic degradation in regulating chemoresistance remains unknown. In this study, we revealed a critical role of ABHD5 in charging CRC sensitivity to FU via regulating autophagic uracil yield. We demonstrated that ABHD5 localizes to lysosome and interacts with PDIA5 to prevent PDIA5 from interacting with RNASET2 and inactivating RNASET2. ABHD5 deficiency releases PDIA5 to directly interact with RNASET2 and leave RNASET2 in an inactivate state, which impairs RNASET2-mediated autophagic uracil yield and promotes CRC cells to uptake FU as an exogenous uracil, thus increasing their sensitivity to FU. Our findings for the first time reveal a novel role of ABHD5 in regulating lysosome function, highlighting the significance of ABHD5 as a compelling biomarker predicting the sensitivity of CRCs to FU-based chemotherapy.
ESTHER : Ou_2019_Nat.Commun_10_1078
PubMedSearch : Ou_2019_Nat.Commun_10_1078
PubMedID: 30842415
Gene_locus related to this paper: human-ABHD5

Title : The Effector AGLIP1 in Rhizoctonia solani AG1 IA Triggers Cell Death in Plants and Promotes Disease Development Through Inhibiting PAMP-Triggered Immunity in Arabidopsis thaliana - Li_2019_Front.Microbiol_10_2228
Author(s) : Li S , Peng X , Wang Y , Hua K , Xing F , Zheng Y , Liu W , Sun W , Wei S
Ref : Front Microbiol , 10 :2228 , 2019
Abstract : Rhizoctonia solani, one of the most detrimental necrotrophic pathogens, causes rice sheath blight and poses a severe threat to production. Focus on the function of effectors secreted by necrotrophic pathogens during infection has grown rapidly in recent years. However, little is known about the virulence and mechanisms of these proteins. In this study, we performed functional studies on putative effectors in R. solani and revealed that AGLIP1 out of 13 putative effectors induced cell death in Nicotiana benthamiana. AGLIP1 was also demonstrated to trigger cell death in rice protoplasts. The predicted lipase active sites and signal peptide (SP) of this protein were required for the cell death-inducing ability. AGLIP1 was greatly induced during R. solani infection in rice sheath. The AGLIP1's virulence function was further demonstrated by transgenic technology. The pathogenesis-related genes induced by pathogen-associated molecular pattern and bacteria were remarkably inhibited in AGLIP1-expressing transgenic Arabidopsis lines. Ectopic expression of AGLIP1 strongly facilitated disease progression in Arabidopsis caused by the type III secretion system-defective mutant from Pseudomonas syringae pv. tomato DC3000. Collectively, these results indicate that AGLIP1 is a possible effector that plays a significant role in pathogen virulence through inhibiting basal defenses and promoting disease development in plants.
ESTHER : Li_2019_Front.Microbiol_10_2228
PubMedSearch : Li_2019_Front.Microbiol_10_2228
PubMedID: 31611861
Gene_locus related to this paper: 9agam-a0a8h2wbw6

Title : The association of the S447X mutation in LPL with Coronary artery disease: a meta-analysis - Sun_2019_Minerva.Cardioangiol_67_246
Author(s) : Sun W , Wu Y , Wen Y , Guo M , Zhang H
Ref : Minerva Cardioangiol , 67 :246 , 2019
Abstract : INTRODUCTION: To investigate the relationships between lipase gene polymorphisms and coronary artery disease (CAD) risk. EVIDENCE ACQUISITION: We searched PubMed, Embase and ISI web of science databases for articles estimated the association of S447X polymorphism with CAD. EVIDENCE SYNTESIS: Twelve-five articles were included in the meta-analysis. We found the G allele S447X polymorphism could reduce CAD risk by approximately 22% (OR=0.78, 95% CI: 0.71-0.84; fixed effects, I2=35.3%, P=0.07). Compared with non-carriers, individuals with two copies of the G allele had approximately 52% risks of CAD (OR=0.48, 95% CI: 0.29-0.68), and the individuals with GG and GC+GG had approximately 19% and 26% risks of CAD compared with those with CC genotype, respectively (GC versus CC: OR=0.81, 95% CI: 0.74-0.88; [GC+GG] versus CC: OR=0.74, 95% CI: 0.68-0.80). The G allelic significantly decreased risk of myocardial infarction (MI) (OR=0.74, 95% CI: 0.57-0.92). We found significant relationship between the variant and AMD in all the genetic models (GG versus CC: OR=0.48, 95% CI: 0.18-0.79; GC versus CC: OR=0.76, 95% CI: 0.57-0.94; [GG+GC] versus CC: OR=0.73, 95% CI: 0.64-0.83). CONCLUSIONS: The results indicated G allelic could significantly decrease CAD and MI risk.
ESTHER : Sun_2019_Minerva.Cardioangiol_67_246
PubMedSearch : Sun_2019_Minerva.Cardioangiol_67_246
PubMedID: 29687697
Gene_locus related to this paper: human-LPL

Title : Design, synthesis and biological evaluation of novel copper-chelating acetylcholinesterase inhibitors with pyridine N-benzylpiperidine fragments - Zhou_2019_Bioorg.Chem_93_103322
Author(s) : Zhou Y , Sun W , Peng J , Yan H , Zhang L , Liu X , Zuo Z
Ref : Bioorg Chem , 93 :103322 , 2019
Abstract : Cholinergic depletion is the direct cause of disability and dementia among AD patients. AChE is a classical and key target of cholinergic disorders. Some new inhibitors of AChE combining pyridine, acylhydrazone and N-benzylpiperidine fragments were developed in this work. The hit structure was optimized to yield the compound 21 with an IC50 value of 6.62nM against AChE, while almost no inhibitory effect against BChE. ADMET predictions and PAMPA permeability evaluation showed good drug-like property. The higher activity with an intermediate alkyl chain substitution indicates a new binding mode of inhibitor with AChE. This finding provides new insights into the binding mechanism and is helpful for discovery of novel high-activity AChE inhibitors.
ESTHER : Zhou_2019_Bioorg.Chem_93_103322
PubMedSearch : Zhou_2019_Bioorg.Chem_93_103322
PubMedID: 31585263

Title : De novo genome assembly of the endangered Acer yangbiense, a plant species with extremely small populations endemic to Yunnan Province, China - Yang_2019_Gigascience_8_giz085
Author(s) : Yang J , Wariss HM , Tao L , Zhang R , Yun Q , Hollingsworth P , Dao Z , Luo G , Guo H , Ma Y , Sun W
Ref : Gigascience , 8 : , 2019
Abstract : BACKGROUND: Acer yangbiense is a newly described critically endangered endemic maple tree confined to Yangbi County in Yunnan Province in Southwest China. It was included in a programme for rescuing the most threatened species in China, focusing on "plant species with extremely small populations (PSESP)". FINDINGS: We generated 64, 94, and 110 Gb of raw DNA sequences and obtained a chromosome-level genome assembly of A. yangbiense through a combination of Pacific Biosciences Single-molecule Real-time, Illumina HiSeq X, and Hi-C mapping, respectively. The final genome assembly is -666 Mb, with 13 chromosomes covering -97% of the genome and scaffold N50 sizes of 45 Mb. Further, BUSCO analysis recovered 95.5% complete BUSCO genes. The total number of repetitive elements account for 68.0% of the A. yangbiense genome. Genome annotation generated 28,320 protein-coding genes, assisted by a combination of prediction and transcriptome sequencing. In addition, a nearly 1:1 orthology ratio of dot plots of longer syntenic blocks revealed a similar evolutionary history between A. yangbiense and grape, indicating that the genome has not undergone a whole-genome duplication event after the core eudicot common hexaploidization. CONCLUSION: Here, we report a high-quality de novo genome assembly of A. yangbiense, the first genome for the genus Acer and the family Aceraceae. This will provide fundamental conservation genomics resources, as well as representing a new high-quality reference genome for the economically important Acer lineage and the wider order of Sapindales.
ESTHER : Yang_2019_Gigascience_8_giz085
PubMedSearch : Yang_2019_Gigascience_8_giz085
PubMedID: 31307060
Gene_locus related to this paper: 9rosi-a0a5c7hxy4 , 9rosi-a0a5c7h0k5 , 9rosi-a0a5n5kbl1

Title : Asperversins A and B, Two Novel Meroterpenoids with an Unusual 5\/6\/6\/6 Ring from the Marine-Derived Fungus Aspergillus versicolor - Li_2018_Mar.Drugs_16_
Author(s) : Li H , Sun W , Deng M , Qi C , Chen C , Zhu H , Luo Z , Wang J , Xue Y , Zhang Y
Ref : Mar Drugs , 16 : , 2018
Abstract : Asperversins A (1) and B (2), two novel meroterpenoids featuring an uncommon 5/6/6/6 ring system, along with five new analogues (3(-)7) and a known compound asperdemin (8), were obtained from the marine-derived fungus Aspergillus versicolor. Their structures and absolute configurations were confirmed by extensive spectroscopic analyses, single-crystal X-ray diffraction studies, and electronic circular dichroism (ECD) calculation. All new compounds were tested for their acetylcholinesterase enzyme (AChE) inhibitory activities and cytotoxic activities, of which compound 7 displayed moderate inhibitory activity against the AChE with an IC50 value of 13.6 μM.
ESTHER : Li_2018_Mar.Drugs_16_
PubMedSearch : Li_2018_Mar.Drugs_16_
PubMedID: 29882867

Title : Chemical Proteomics Reveals Soluble Epoxide Hydrolase as a Therapeutic Target for Ocular Neovascularization - Sulaiman_2018_ACS.Chem.Biol_13_45
Author(s) : Sulaiman RS , Park B , Sheik Pran Babu SP , Si Y , Kharwadkar R , Mitter SK , Lee B , Sun W , Qi X , Boulton ME , Meroueh SO , Fei X , Seo SY , Corson TW
Ref : ACS Chemical Biology , 13 :45 , 2018
Abstract : The standard-of-care therapeutics for the treatment of ocular neovascular diseases like wet age-related macular degeneration (AMD) are biologics targeting vascular endothelial growth factor signaling. There are currently no FDA approved small molecules for treating these blinding eye diseases. Therefore, therapeutic agents with novel mechanisms are critical to complement or combine with existing approaches. Here, we identified soluble epoxide hydrolase (sEH), a key enzyme for epoxy fatty acid metabolism, as a target of an antiangiogenic homoisoflavonoid, SH-11037. SH-11037 inhibits sEH in vitro and in vivo and docks to the substrate binding cleft in the sEH hydrolase domain. sEH levels and activity are up-regulated in the eyes of a choroidal neovascularization (CNV) mouse model. sEH is overexpressed in human wet AMD eyes, suggesting that sEH is relevant to neovascularization. Known sEH inhibitors delivered intraocularly suppressed CNV. Thus, by dissecting a bioactive compound's mechanism, we identified a new chemotype for sEH inhibition and characterized sEH as a target for blocking the CNV that underlies wet AMD.
ESTHER : Sulaiman_2018_ACS.Chem.Biol_13_45
PubMedSearch : Sulaiman_2018_ACS.Chem.Biol_13_45
PubMedID: 29193961

Title : Bioactive polycyclic polyprenylated acylphloroglucinols from Hypericum perforatum - Guo_2018_Org.Biomol.Chem_16_8130
Author(s) : Guo Y , Zhang N , Sun W , Duan X , Zhang Q , Zhou Q , Chen C , Zhu H , Luo Z , Liu J , Li XN , Xue Y , Zhang Y
Ref : Org Biomol Chem , 16 :8130 , 2018
Abstract : Fifteen new polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperforatones A-O (1-15), along with 3 structurally related analogues (16-18), were isolated from the stems and leaves of Hypericum perforatum. Their structures and absolute configurations were established by a combination of NMR spectroscopic analyses, experimental and calculated electronic circular dichroism (ECD), modified Mosher's methods, Rh2(OCOCF3)4- and [Mo2(OAc)4]-induced ECD, X-ray crystallography, and the assistance of quantum chemical predictions (QCP) of 13C NMR chemical shifts. Compound 5 was found to be the first PPAP decorated by a rare 2,2,4,4,5-(pentamethyltetrahydrofuran-3-yl)methanol moiety and an oxepane ring. Furthermore, the isolates were screened for their acetylcholinesterase (AChE) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitory activities. Compounds 5, 10, 11, and 15 showed desirable AChE inhibitory activities (IC50 6.9-9.2 muM) and simultaneously inhibited BACE1 (at a concentration of 5 muM) with inhibition rates of 50.3%, 34.3%, 47.2%, and 34.6%, respectively. Interestingly, compound 5 showed the most balanced inhibitory activities against both AChE and BACE1 of all the tested compounds, which means that 5 could serve as the first valuable dual-targeted PPAP for the treatment of Alzheimer's disease. Preliminary molecular docking studies of 5 with BACE1 and AChE were also performed.
ESTHER : Guo_2018_Org.Biomol.Chem_16_8130
PubMedSearch : Guo_2018_Org.Biomol.Chem_16_8130
PubMedID: 30334059

Title : Hepatotoxicity induced by radix Sophorae tonkinensis in mice and increased serum cholinesterase as a potential supplemental biomarker for liver injury - Wang_2017_Exp.Toxicol.Pathol_69_193
Author(s) : Wang L , Lu J , Sun W , Gu Y , Zhang C , Jin R , Li L , Zhang Z , Tian X
Ref : Exp Toxicol Pathol , 69 :193 , 2017
Abstract : Radix Sophorae tonkinensis (S. tonkinensis) is used in Chinese folk medicine to treat sore throats, viral hepatitis, and jaundice. However, little is known about the hepatotoxicity induced by it. This study is to investigate hepatotoxicity induced by radix S. tonkinensis and a potential supplemental biomarker for liver injury through acute toxicity, accumulative toxicity, tolerance test, and sub-chronic toxicity. The contents of cytisine (CYT), matrine (MT), and oxymatrine (OMT) in radix S. tonkinensis extracts were determined simultaneously by the method we developed. In the acute toxicity study, mice were scheduled for single oral gavage at doses of 0, 2.4, 3.2, 4.2, 5.6, 7.5g/kg of radix S. tonkinensis extracts respectively. Another three groups of mice received radix S. tonkinensis extracts orally in single doses of 0, 4.3, 5.6g/kg, while the two groups of the hepatic injury model were induced by intraperitoneal injection with 0.1% and 0.2% carbon tetrachloride (CCl4). Mortality rate, analysis of serum biochemistry, and histopathological examination were used to assess the acute toxicity. In the accumulative toxicity study, mice were treated radix S. tonkinensis extracts orally by the method of dose escalation for 20days respectively. Accumulative toxicity was assessed by mortality rate. In the tolerance test, half of the mice of test group in the accumulative toxicity were administered the dose of 4.3g/kg radix S. tonkinensis extracts, and the rest of the mice in the test group were assigned to receive the dose of 5.6g/kg radix S. tonkinensis extracts. In the sub-chronic toxicity study, mice were treated with daily doses of 0, 0.25, 1.0, 2.5g/kg radix S. tonkinensis extracts for 90days. Assessments of body weights, serum biochemical analysis, and histopathological examination were performed. An enzyme-inhibition assay for butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) of CYT, MT, and OMT was also carried out. The contents of CYT, MT, and OMT in radix S. tonkinensis extracts were 5.63mg/g, 27.63mg/g, and 16.20mg/g respectively. In the acute toxicity study, LD50 of radix S. tonkinensis extracts was 4.3g/kg. No mice were found dead in the accumulative toxicity study. In the acute toxicity and tolerance test, increased ALT, AST, and CHE levels were observed in a dose-response manner, while the severity of histological changes in liver was shown in a dose-dependent mode. In the sub-chronic toxicity, though there was a decline trend of ALT and AST levels found in 0.25g/kg, 1.0g/kg, and 2.5g/kg radix S. tonkinensis extracts as compared to control, which might be related to weight loss, the severity of histopathological changes in the liver and the increased serum CHE level was shown in a dose-response manner. MT, OMT, and CYT showed inhibitory effects on BuChE and AChE in the enzyme-inhibition assay. The results of this study indicate that radix S. tonkinensis should have hepatotoxicity, and increased serum CHE is a potential supplemental biomarker for liver injury.
ESTHER : Wang_2017_Exp.Toxicol.Pathol_69_193
PubMedSearch : Wang_2017_Exp.Toxicol.Pathol_69_193
PubMedID: 28126209

Title : Study of acetylcholinesterase activity and apoptosis in SH-SY5Y cells and mice exposed to ethanol - Sun_2017_Toxicology_384_33
Author(s) : Sun W , Chen L , Zheng W , Wei X , Wu W , Duysen EG , Jiang W
Ref : Toxicology , 384 :33 , 2017
Abstract : Ethanol is one of the most commonly abused psychotropic substances with deleterious effects on the central nervous system. Ethanol exposure during development results in the loss of neurons in brain regions and when exposed to ethanol cultured cells undergo apoptosis. To date no information is available on whether abnormally high AChE activity is characteristic of apoptosis in animals exposed to ethanol. The aims of the present study were to determine whether induction of AChE activity is associated with ethanol-induced apoptosis and to explore the mechanism of enhanced AChE activity induced by ethanol. For this purpose, in vitro and in vivo experiments were performed. AChE activity was quantified by spectrophotometry and apoptosis by flow cytometer in SH-SY5Y cells exposed to ethanol. The results showed that cells treated with 500mM ethanol for 24h had a 9-fold increase in apoptotic cells and a 6-fold increase in AChE activity compared with controls. Mice exposed acutely to 200mul of 20% ethanol daily on days 1-4 had elevated AChE activity in plasma on days 3-7. On day 4, plasma AChE activity was 2.4-fold higher than pretreatment activity. More apoptotic cells were found in the brains of treated mice compared to controls. Cells in brain sections that were positive in the TUNEL assay stained for AChE activity. In conclusion, AChE activity and apoptosis were induced in SH-SY5Y cells and mice treated with ethanol, which may indicate that increased AChE may related to apoptosis induced by ethanol. Unusually high AChE activity may be an effect marker of exposure to ethanol. The relationship between AChE and apoptosis might represent a novel mechanism of ethanol-associated neuronal injury.
ESTHER : Sun_2017_Toxicology_384_33
PubMedSearch : Sun_2017_Toxicology_384_33
PubMedID: 28427893

Title : The Synergistic Effect of Microwave Radiation and Hypergravity on Rats and the Intervention Effect of Rana Sylvatica Le Conte Oil - Sun_2017_Dose.Response_15_1559325817711511
Author(s) : Sun W , Yang Y , Yu H , Wang L , Pan S
Ref : Dose Response , 15 :1559325817711511 , 2017
Abstract : AIM: The phenomena of hypergravity and microwave radiation are widespread, which cause more and more concern for the hazards to human health. The aim of this study was to investigate the synergistic effect of microwave radiation and hypergravity on rats and observe the protective effect of Rana sylvatica Le conte oil.
METHODS: Rats were exposed to microwave radiation and hypergravity, and the rat weight, the climbing pole height, serum enzyme activities, blood urea nitrogen concentration, and total antioxidant capacity were detected.
RESULTS: The climbing pole height, the activities of choline acetyl transferase and cholinesterase, and the total antioxidant capacity decreased, whereas the activities of alanine aminotransferase, aspartate aminotransferase, areatine kinase, isocitric dehydrogenase, hydroxybutyrate dehydrogenase, and the blood urea nitrogen concentration increased in the hypergravity irradiation group as compared with the others. CONCLUSION: These results imply that the motion and nervous system of rats might be affected critically by the synergistic effect of microwave radiation and hypergravity, and it causes damage to most rat organs, such as the bone, skeletal muscle, liver, heart, and kidney, and the antioxidant effect is also damaged, while the injury resulted from it could be protected by Rana sylvatica Le conte oil.
ESTHER : Sun_2017_Dose.Response_15_1559325817711511
PubMedSearch : Sun_2017_Dose.Response_15_1559325817711511
PubMedID: 28717348

Title : Dibenzo-alpha-pyrones: a new class of larvicidal metabolites against Aedes aegypti from the endophytic fungus Hyalodendriella sp. Ponipodef12 - Mao_2017_Pest.Manag.Sci_73_1478
Author(s) : Mao Z , Lai D , Liu X , Fu X , Meng J , Wang A , Wang X , Sun W , Liu ZL , Zhou L , Liu Y
Ref : Pest Manag Sci , 73 :1478 , 2017
Abstract : BACKGROUND: In our search for new agrochemicals from endophytic fungi, the crude extract of the endophytic Hyalodendriella sp. Ponipodef12 associated with the hybrid 'Neva' of Populus deltoides Marsh x P. nigra L. was found to possess larvicidal activity against Aedes aegypti.
RESULTS: Fractionation of the extract has led to the isolation of 11 dibenzo-alpha-pyrones (1-11), including three new congeners: hyalodendriols A-C (1-3). The structures of the new compounds were elucidated by comprehensive spectroscopic analyses, including the modified Mosher's method for the assignment of the absolute configuration. Compounds 2-7 showed potent larvicidal activities against the fourth-instar larvae of A. aegypti with IC50 values ranging from 7.21 to 120.81 microg mL-1 . Among them, penicilliumolide D (6) displayed the strongest activity (IC50 = 7.21 microg mL-1 ). A structure-larvicidal activity relationship was discussed. The possible mode of action of these compounds was assessed for their acetylcholinesterase inhibitory activities. In addition, hyalodendriol C (3) displayed antibacterial activity against Bacillus subtilis and Xanthomonas vesicatoria, and exhibited strong inhibition against the spore germination of Magnaporthe oryzae. CONCLUSION: Our study revealed dibenzo-alpha-pyrones to be a new class of larvicidal metabolites against A. aegypti. (c) 2016 Society of Chemical Industry.
ESTHER : Mao_2017_Pest.Manag.Sci_73_1478
PubMedSearch : Mao_2017_Pest.Manag.Sci_73_1478
PubMedID: 27862895

Title : ABHD5 interacts with BECN1 to regulate autophagy and tumorigenesis of colon cancer independent of PNPLA2 - Peng_2016_Autophagy_12_2167
Author(s) : Peng Y , Miao H , Wu S , Yang W , Zhang Y , Xie G , Xie X , Li J , Shi C , Ye L , Sun W , Wang L , Liang H , Ou J
Ref : Autophagy , 12 :2167 , 2016
Abstract : Autophagy critically contributes to metabolic reprogramming and chromosomal stability. It has been reported that monoallelic loss of the essential autophagy gene BECN1 (encoding BECN1/Beclin 1) promotes cancer development and progression. However, the mechanism by which BECN1 is inactivated in malignancy remains largely elusive. We have previously reported a tumor suppressor role of ABHD5 (abhydrolase domain containing 5), a co-activator of PNPLA2 (patatin like phospholipase domain containing 2) in colorectal carcinoma (CRC). Here we report a noncanonical role of ABHD5 in regulating autophagy and CRC tumorigenesis. ABHD5 directly competes with CASP3 for binding to the cleavage sites of BECN1, and consequently prevents BECN1 from being cleaved by CASP3. ABHD5 deficiency provides CASP3 an advantage to cleave and inactivate BECN1, thus impairing BECN1-induced autophagic flux and augmenting genomic instability, which subsequently promotes tumorigenesis. Notably, clinical data also confirm that ABHD5 proficiency is significantly correlated with the expression levels of BECN1, LC3-II and CASP3 in human CRC tissues. Our findings suggest that ABHD5 possesses a PNPLA2-independent function in regulating autophagy and tumorigenesis, further establishing the tumor suppressor role of ABHD5, and offering an opportunity to develop new approaches aimed at preventing CRC carcinogenesis.
ESTHER : Peng_2016_Autophagy_12_2167
PubMedSearch : Peng_2016_Autophagy_12_2167
PubMedID: 27559856
Gene_locus related to this paper: human-ABHD5

Title : Third-Generation Sequencing and Analysis of Four Complete Pig Liver Esterase Gene Sequences in Clones Identified by Screening BAC Library - Zhou_2016_PLoS.One_11_e0163295
Author(s) : Zhou Q , Sun W , Liu X , Wang X , Xiao Y , Bi D , Yin J , Shi D
Ref : PLoS ONE , 11 :e0163295 , 2016
Abstract : AIM: Pig liver carboxylesterase (PLE) gene sequences in GenBank are incomplete, which has led to difficulties in studying the genetic structure and regulation mechanisms of gene expression of PLE family genes. The aim of this study was to obtain and analysis of complete gene sequences of PLE family by screening from a Rongchang pig BAC library and third-generation PacBio gene sequencing.
METHODS: After a number of existing incomplete PLE isoform gene sequences were analysed, primers were designed based on conserved regions in PLE exons, and the whole pig genome used as a template for Polymerase chain reaction (PCR) amplification. Specific primers were then selected based on the PCR amplification results. A three-step PCR screening method was used to identify PLE-positive clones by screening a Rongchang pig BAC library and PacBio third-generation sequencing was performed. BLAST comparisons and other bioinformatics methods were applied for sequence analysis.
RESULTS: Five PLE-positive BAC clones, designated BAC-10, BAC-70, BAC-75, BAC-119 and BAC-206, were identified. Sequence analysis yielded the complete sequences of four PLE genes, PLE1, PLE-B9, PLE-C4, and PLE-G2. Complete PLE gene sequences were defined as those containing regulatory sequences, exons, and introns. It was found that, not only did the PLE exon sequences of the four genes show a high degree of homology, but also that the intron sequences were highly similar. Additionally, the regulatory region of the genes contained two 720bps reverse complement sequences that may have an important function in the regulation of PLE gene expression. SIGNIFICANCE: This is the first report to confirm the complete sequences of four PLE genes. In addition, the study demonstrates that each PLE isoform is encoded by a single gene and that the various genes exhibit a high degree of sequence homology, suggesting that the PLE family evolved from a single ancestral gene. Obtaining the complete sequences of these PLE genes provides the necessary foundation for investigation of the genetic structure, function, and regulatory mechanisms of the PLE gene family.
ESTHER : Zhou_2016_PLoS.One_11_e0163295
PubMedSearch : Zhou_2016_PLoS.One_11_e0163295
PubMedID: 27695062
Gene_locus related to this paper: pig-EST1 , pig-PLE1 , pig-a0a1s6l948 , pig-a0a1s6l959 , pig-a0a1s6l967

Title : A new alkaline lipase obtained from the metagenome of marine sponge Ircinia sp - Su_2015_World.J.Microbiol.Biotechnol_31_1093
Author(s) : Su J , Zhang F , Sun W , Karuppiah V , Zhang G , Li Z , Jiang Q
Ref : World J Microbiol Biotechnol , 31 :1093 , 2015
Abstract : Microorganisms associated with marine sponges are potential resources for marine enzymes. In this study, culture-independent metagenomic approach was used to isolate lipases from the complex microbiome of the sponge Ircinia sp. obtained from the South China Sea. A metagenomic library was constructed, containing 6568 clones, and functional screening on 1 % tributyrin agar resulted in the identification of a positive lipase clone (35F4). Following sequence analysis 35F4 clone was found to contain a putative lipase gene lipA. Sequence analysis of the predicted amino acid sequence of LipA revealed that it is a member of subfamily I.1 of lipases, with 63 % amino acid similarity to the lactonizing lipase from Aeromonas veronii (WP_021231793). Based on the predicted secondary structure, LipA was predicted to be an alkaline enzyme by sequence/structure analysis. Heterologous expression of lipA in E. coli BL21 (DE3) was performed and the characterization of the recombinant enzyme LipA showed that it is an alkaline enzyme with high tolerance to organic solvents. The isolated lipase LipA was active in the broad alkaline range, with the highest activity at pH 9.0, and had a high level of stability over a pH range of 7.0-12.0. The activity of LipA was increased in the presence of 5 mM Ca(2+) and some organic solvents, e.g. methanol, acetone and isopropanol. The optimum temperature for the activity of LipA is 40 degrees C and the molecular weight of LipA was determined to be ~30 kDa by SDS-PAGE. LipA is an alkaline lipase and shows good tolerance to some organic solvents, which make it of potential utility in the detergent industry and enzyme mediated organic synthesis. The result of this study has broadened the diversity of known lipolytic genes and demonstrated that marine sponges are an important source for new enzymes.
ESTHER : Su_2015_World.J.Microbiol.Biotechnol_31_1093
PubMedSearch : Su_2015_World.J.Microbiol.Biotechnol_31_1093
PubMedID: 25921581
Gene_locus related to this paper: 9bact-m1hou7

Title : Pharmacokinetics and immunogenicity of a recombinant human butyrylcholinesterase bioscavenger in macaques following intravenous and pulmonary delivery - Rosenberg_2015_Chem.Biol.Interact_242_219
Author(s) : Rosenberg YJ , Adams RJ , Hernandez-Abanto S , Jiang X , Sun W , Mao L , Lee KD
Ref : Chemico-Biological Interactions , 242 :219 , 2015
Abstract : Recombinant (r) and native butyrylcholinesterse (BChE) are potent bioscavengers of organophosphates (OPs) such as nerve agents and pesticides and are undergoing development as antidotal treatments for OP-induced toxicity. Because of the lethal properties of such agents, regulatory approval will require extensive testing under the Animal Rule. However, human (Hu) glycoprotein biologicals, such as BChE, present a challenge for assessing immunogenicity and efficacy in heterologous animal models since any immune responses to the small species differences in amino acids or glycans between the host and biologic may alter pharmacodynamics and preclude accurate efficacy testing; possibly underestimating their potential protective value in humans. To establish accurate pharmacokinetic and efficacy data, an homologous animal model has been developed in which native and PEGylated forms of CHO-derived rMaBChE were multiply injected into homologous macaques with no induction of antibody. These now serve as controls for assessing the pharmacokinetics and immunogenicity in macaques of multiple administrations of PEGylated and unmodified human rBChE (rHuBChE) by both intravenous (IV) and pulmonary routes. The results indicate that, except for maximal concentration (Cmax), the pharmacokinetic parameters following IV injection with heterologous PEG-rHuBChE were greatly reduced even after the first injection compared with homologous PEG-rMaBChE. Anti-HuBChE antibody responses were induced in all monkeys after the second and third administrations regardless of the route of delivery; impacting rates of clearance and usually resulting in reduced endogenous MaBChE activity. These data highlight the difficulties inherent in assessing pharmacokinetics and immunogenicity in animal models, but bode well for the efficacy and safety of rHuBChE pretreatments in homologous humans.
ESTHER : Rosenberg_2015_Chem.Biol.Interact_242_219
PubMedSearch : Rosenberg_2015_Chem.Biol.Interact_242_219
PubMedID: 26415620

Title : Prophylaxis with human serum butyrylcholinesterase protects Gottingen minipigs exposed to a lethal high-dose of sarin vapor - Saxena_2015_Chem.Biol.Interact_238_161
Author(s) : Saxena A , Hastings NB , Sun W , Dabisch PA , Hulet SW , Jakubowski EM , Mioduszewski RJ , Doctor BP
Ref : Chemico-Biological Interactions , 238 :161 , 2015
Abstract : Serum-derived human butyrylcholinesterase (Hu BChE) is a stoichiometric bioscavenger that is being developed as a potential prophylactic nerve agent countermeasure. Previously, we reported the prophylactic efficacy of Hu BChE in Gottingen minipigs against a whole-body exposure to 4.1mg/m3 of sarin (GB) vapor, which produced lethality over 60min. Since the toxicity of nerve agent is concentration-dependent, in the present study, we investigated the toxic effects of an almost 3-fold higher rate of GB vapor exposure and the ability of Hu BChE to protect minipigs against this exposure. Male minipigs were subjected to: (1) air exposure; (2) GB vapor exposure; or (3) pretreatment with 7.5mg/kg of Hu BChE by i.m. injection, 24h prior to whole-body exposure to 11.4mg/m3 of GB vapor for 10min. Electrocardiogram, electroencephalogram, and pupil size were monitored throughout exposure. Blood drawn before and throughout exposure was analyzed for blood gases, electrolytes, metabolites, acetylcholinesterase and BChE activities, and amount of GB bound to red blood cells and plasma. A novel finding was that saline-treated animals exposed to GB vapor did not develop any seizures, but manifested a variety of cardiac and whole blood toxic signs and rapidly died due to respiratory failure. Strikingly, pre-treatment with 7.5mg/kg of Hu BChE not only prevented lethality, but also avoided all cardiac toxic signs manifested in the non-treated cohort. Thus, Hu BChE alone can serve as an effective prophylactic countermeasure versus a lethal high-dose exposure to GB vapor.
ESTHER : Saxena_2015_Chem.Biol.Interact_238_161
PubMedSearch : Saxena_2015_Chem.Biol.Interact_238_161
PubMedID: 26145887

Title : Quantitative Proteomics Analysis of the Hepatitis C Virus Replicon High-Permissive and Low-Permissive Cell Lines - Ye_2015_PLoS.One_10_e0142082
Author(s) : Ye F , Xin Z , Han W , Fan J , Yin B , Wu S , Yang W , Yuan J , Qiang B , Sun W , Peng X
Ref : PLoS ONE , 10 :e0142082 , 2015
Abstract : Chronic hepatitis C virus (HCV) infection is one of the leading causes of severe hepatitis. The molecular mechanisms underlying HCV replication and pathogenesis remain unclear. The development of the subgenome replicon model system significantly enhanced study of HCV. However, the permissiveness of the HCV subgenome replicon greatly differs among different hepatoma cell lines. Proteomic analysis of different permissive cell lines might provide new clues in understanding HCV replication. In this study, to detect potential candidates that might account for the differences in HCV replication. Label-free and iTRAQ labeling were used to analyze the differentially expressed protein profiles between Huh7.5.1 wt and HepG2 cells. A total of 4919 proteins were quantified in which 114 proteins were commonly identified as differentially expressed by both quantitative methods. A total of 37 differential proteins were validated by qRT-PCR. The differential expression of Glutathione S-transferase P (GSTP1), Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), carboxylesterase 1 (CES1), vimentin, Proteasome activator complex subunit1 (PSME1), and Cathepsin B (CTSB) were verified by western blot. And over-expression of CTSB or knock-down of vimentin induced significant changes to HCV RNA levels. Additionally, we demonstrated that CTSB was able to inhibit HCV replication and viral protein translation. These results highlight the potential role of CTSB and vimentin in virus replication.
ESTHER : Ye_2015_PLoS.One_10_e0142082
PubMedSearch : Ye_2015_PLoS.One_10_e0142082
PubMedID: 26544179

Title : Specific adaptation of Ustilaginoidea virens in occupying host florets revealed by comparative and functional genomics - Zhang_2014_Nat.Commun_5_3849
Author(s) : Zhang Y , Zhang K , Fang A , Han Y , Yang J , Xue M , Bao J , Hu D , Zhou B , Sun X , Li S , Wen M , Yao N , Ma LJ , Liu Y , Zhang M , Huang F , Luo C , Zhou L , Li J , Chen Z , Miao J , Wang S , Lai J , Xu JR , Hsiang T , Peng YL , Sun W
Ref : Nat Commun , 5 :3849 , 2014
Abstract : Ustilaginoidea virens (Cooke) Takah is an ascomycetous fungus that causes rice false smut, a devastating emerging disease worldwide. Here we report a 39.4 Mb draft genome sequence of U. virens that encodes 8,426 predicted genes. The genome has ~25% repetitive sequences that have been affected by repeat-induced point mutations. Evolutionarily, U. virens is close to the entomopathogenic Metarhizium spp., suggesting potential host jumping across kingdoms. U. virens possesses reduced gene inventories for polysaccharide degradation, nutrient uptake and secondary metabolism, which may result from adaptations to the specific floret infection and biotrophic lifestyles. Consistent with their potential roles in pathogenicity, genes for secreted proteins and secondary metabolism and the pathogen-host interaction database genes are highly enriched in the transcriptome during early infection. We further show that 18 candidate effectors can suppress plant hypersensitive responses. Together, our analyses offer new insights into molecular mechanisms of evolution, biotrophy and pathogenesis of U. virens.
ESTHER : Zhang_2014_Nat.Commun_5_3849
PubMedSearch : Zhang_2014_Nat.Commun_5_3849
PubMedID: 24846013
Gene_locus related to this paper: ustvr-a0a063bxn3

Title : DWARF3 participates in an SCF complex and associates with DWARF14 to suppress rice shoot branching - Zhao_2014_Plant.Cell.Physiol_55_1096
Author(s) : Zhao J , Wang T , Wang M , Liu Y , Yuan S , Gao Y , Yin L , Sun W , Peng L , Zhang W , Wan J , Li X
Ref : Plant Cell Physiol , 55 :1096 , 2014
Abstract : Strigolactones (SLs) are a novel class of plant hormones that inhibit shoot branching. Currently, two proteins in rice are thought to play crucial roles in SL signal transduction. DWARF14 (D14), an alpha/beta hydrolase, is responsible for SL perception, while DWARF3 (D3), an F-box protein with leucine-rich repeats, is essential for SL signal transduction. However, how these two proteins transmit SL signals to downstream factors remains unclear. Here, we characterized a high-tillering dwarf rice mutant, gsor300097, which is insensitive to GR24, a synthetic analog of SL. Mapping and sequencing analysis showed that gsor300097 is a novel allelic mutant of D3, in which a nonsense mutation truncates the protein from 720 to 527 amino acids. The D3 gene was strongly expressed in root, leaf, shoot base and panicle. Nuclear-localized F-box protein D3 played a role in the SCF complex by interacting with OSK1, OSK5 or OSK20 and OsCullin1. In addition, D3 associated with D14 in a GR24-dependent manner in vivo. Taken together, our findings suggested that D3 assembled into an SCF(D3) complex and associated with D14 to suppress rice shoot branching.
ESTHER : Zhao_2014_Plant.Cell.Physiol_55_1096
PubMedSearch : Zhao_2014_Plant.Cell.Physiol_55_1096
PubMedID: 24616269

Title : Cloning, homology modeling, and reaction mechanism analysis of a novel cis-epoxysuccinate hydrolase from Klebsiella sp - Cheng_2014_Biotechnol.Lett_36_2537
Author(s) : Cheng Y , Pan H , Bao W , Sun W , Xie Z , Zhang J , Zhao Y
Ref : Biotechnol Lett , 36 :2537 , 2014
Abstract : The gene encoding a novel cis-epoxysuccinate hydrolase, which hydrolyzes cis-epoxysuccinate to L (+)-tartaric acid, was cloned from Klebsiella sp. BK-58 and expressed in Escherichia coli. The ORF was 825 bp encoding a mature protein of 274 amino acids with a molecular mass of 30.1 kDa. Multiple sequence alignment showed that the enzyme belonged to the haloacid dehalogenase-like super family. Homology modeling and site-directed mutagenesis were performed to investigate the structural characteristics of the enzyme. Its overall structure consisted of a core domain formed by six-stranded parallel beta-sheets flanked by seven alpha-helices and a subdomain that had a four helix bundle structure. Residues D48, T52, R85, N165, K195, Y201, A219, H221, and D224 were catalytically important forming the active pocket between the two domains. An (18)O-labeling study suggested that the catalytic reaction of the enzyme proceeded through a two-step mechanism.
ESTHER : Cheng_2014_Biotechnol.Lett_36_2537
PubMedSearch : Cheng_2014_Biotechnol.Lett_36_2537
PubMedID: 25216644

Title : Natural Dibenzo-alpha-Pyrones and Their Bioactivities - Mao_2014_Molecules_19_5088
Author(s) : Mao Z , Sun W , Fu L , Luo H , Lai D , Zhou L
Ref : Molecules , 19 :5088 , 2014
Abstract : Natural dibenzo-alpha-pyrones are an important group of metabolites derived from fungi, mycobionts, plants and animal feces. They exhibit a variety of biological activities such as toxicity on human and animals, phytotoxicity as well as cytotoxic, antioxidant, antiallergic, antimicrobial, antinematodal, and acetylcholinesterase inhibitory properties. Dibenzo-alpha-pyrones are biosynthesized via the polyketide pathway in microorganisms or metabolized from plant-derived ellagitannins and ellagic acid by intestinal bacteria. At least 53 dibenzo-alpha-pyrones have been reported in the past few decades. This mini-review aims to briefly summarize the occurrence, biosynthesis, biotransformation, as well as their biological activities and functions. Some considerations related to synthesis, production and applications of dibenzo-alpha-pyrones are also discussed.
ESTHER : Mao_2014_Molecules_19_5088
PubMedSearch : Mao_2014_Molecules_19_5088
PubMedID: 24759070

Title : Effect of polyethylene glycol conjugation on the circulatory stability of plasma-derived human butyrylcholinesterase in mice - Sun_2013_Chem.Biol.Interact_203_172
Author(s) : Sun W , Luo C , Tipparaju P , Doctor BP , Saxena A
Ref : Chemico-Biological Interactions , 203 :172 , 2013
Abstract : Exogenously administered human serum butyrylcholinesterase (Hu BChE) was demonstrated to function as a bioscavenger of highly toxic organophosphorus (OP) compounds in several animal species. Since the enzyme is isolated from human serum, it is currently the most suitable pretreatment for human use. A dose of 200-300mg/70kg human adult is projected to provide protection from 2 X LD50 of soman. Due to the limited supply of Hu BChE, strategies aimed at reducing the dose of enzyme are being explored. In this study, we investigated the effect of modification with polyethylene glycol (PEG) on the in vivo stability of Hu BChE. Mice were given two injections of either Hu BChE or Hu BChE modified with PEG-5K or PEG-20K, six weeks apart. Pharmacokinetic parameters, such as mean residence time (MRT), maximal concentration (Cmax), elimination half-life (T1/2), and area under the plasma concentration time curve extrapolated to infinity (AUC), were determined. For the first injection, values for MRT, T1/2, Cmax, and AUC for PEG-5K-Hu BChE and PEG-20K-Hu BChE were similar to those for Hu BChE. These values for the second injection of Hu BChE as well as PEG-Hu BChEs were lower as compared to those for the first injections, likely due to antibody-mediated clearance.
ESTHER : Sun_2013_Chem.Biol.Interact_203_172
PubMedSearch : Sun_2013_Chem.Biol.Interact_203_172
PubMedID: 23220586

Title : Whole-Genome Shotgun Assembly and Analysis of the Genome of Streptomyces mobaraensis DSM 40847, a Strain for Industrial Production of Microbial Transglutaminase - Yang_2013_Genome.Announc_1_e0014313
Author(s) : Yang H , He T , Wu W , Zhu W , Lu B , Sun W
Ref : Genome Announc , 1 :e0014313 , 2013
Abstract : Here, we report the draft annotated genome sequence of Streptomyces mobaraensis strain DSM 40847, which is used in industry to produce microbial transglutaminase. The genome sequence will allow for the characterization of the molecular mechanisms underlying the beneficial properties of this organism.
ESTHER : Yang_2013_Genome.Announc_1_e0014313
PubMedSearch : Yang_2013_Genome.Announc_1_e0014313
PubMedID: 23558536
Gene_locus related to this paper: strmb-m3c6n2 , strmb-m3c3t3 , strmb-m3a818 , strmb-m3ceh8 , strmb-m3cfp8 , strmb-m3bfl5 , strmb-m3c970 , 9actn-q9fb38 , strmb-m2zv71

Title : Characterization of human serum butyrylcholinesterase in rhesus monkeys: behavioral and physiological effects - Myers_2012_Neurotoxicol.Teratol_34_323
Author(s) : Myers TM , Sun W , Naik RS , Clark MG , Doctor BP , Saxena A
Ref : Neurotoxicology & Teratology , 34 :323 , 2012
Abstract : The effects of a large dose of human serum butyrylcholinesterase (HuBChE) were evaluated in rhesus monkeys using a serial-probe recognition (SPR) task designed to assess attention and short-term memory. Each monkey received an intravenous injection of 150 mg (105,000 U or 30 mg/kg) of HuBChE 60 min prior to testing on the SPR task. Concurrent with the cognitive-behavioral assessment, blood was collected at various time points throughout the study and was analyzed for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities, anti-BChE antibody production and gross clinical pathology (i.e., complete blood count and clinical chemistry panel). HuBChE revealed a peak blood activity of 227 U/ml at 5 min after intravenous injection and a mean residence time of approximately 72 h. No cognitive-behavioral decrements of any kind in SPR performance and no toxic signs in clinical pathology were detected in any of the blood assays during the 5 weeks of observation. Anti-HuBChE antibodies peaked at about 14 days after injection, with no concomitant behavioral changes. These results demonstrate the behavioral and physiological safety of HuBChE in rhesus monkeys and support its development as a bioscavenger for the prophylaxis of chemical warfare agent toxicity in humans.
ESTHER : Myers_2012_Neurotoxicol.Teratol_34_323
PubMedSearch : Myers_2012_Neurotoxicol.Teratol_34_323
PubMedID: 22402122

Title : Developmental expression and subcellular distribution of synaptotagmin 11 in rat hippocampus - Yeo_2012_Neurosci_225_35
Author(s) : Yeo H , Kim HW , Mo J , Lee D , Han S , Hong S , Koh MJ , Sun W , Choi S , Rhyu IJ , Kim H , Lee HW
Ref : Neuroscience , 225 :35 , 2012
Abstract : Synaptotagmins are required for Ca(2+)-dependent membrane-trafficking in either neuronal synaptic vesicles or cellular membranes. Previous reports suggested that the synaptotagmin 11 (syt11) gene is involved in the development of schizophrenia based on the genomic analysis of patients. Parkin protein binds to the C2 domains of Syt11 which leads to the polyubiquitination of Syt11. However, where and how Syt11 performs its role in the brain is largely unknown. Here, we report that Syt11 is expressed mainly in the brain. In addition, exogenously expressed Syt11 in HEK293 cells can form higher molecular weight complex via its transmembrane domain. Also, Syt11 is targeted to both dendrite and axon compartments. Immunocytochemistry showed that Syt11 is juxtaposed to postsynaptic markers in both excitatory and inhibitory synapses. Both neuroligin 1 and 2, which are postsynaptic cell adhesion molecules and differentially induce excitatory and inhibitory presynapses, respectively, recruit Syt11 in neuron coculture. Immunogold electron microscopy analysis revealed that Syt11 exists mainly in presynaptic neurotransmitter vesicles and plasma membrane, and rarely in postsynaptic sites. These results suggest that Syt11 may contribute to the regulation of neurotransmitter release in the excitatory and inhibitory presynapses, and postsynapse-targeted membrane trafficking in dendrites.
ESTHER : Yeo_2012_Neurosci_225_35
PubMedSearch : Yeo_2012_Neurosci_225_35
PubMedID: 22960622

Title : Transcription and induction profiles of two esterase genes in susceptible and acaricide-resistant Tetranychus cinnabarinus - Feng_2011_Pestic.Biochem.Physiol_100_70
Author(s) : Feng Y-n , Yan J , Sun W , Zhao S , Lu W-C , Li M , He L
Ref : Pesticide Biochemistry and Physiology , 100 :70 , 2011
Abstract : The carmine spider mite Tetranychus cinnabarinus is the most serious of crop mite pests in China. Their ability to rapidly develop resistance to acaricides has caused difficulty in controlling this mite. In this study, the molecular mechanism of acaricide resistance associated with esterase genes TCE1 and TCE2 was investigated in susceptible and acaricide-resistant strains of T. cinnabarinus. The quantitative real-time PCR (qrtPCR) method was adopted to compare the expression level of two esterase genes TCE1 and TCE2 among four different strains (abamectin-resistant, AbR; fenpropathrin-resistant, FeR; omethoate-resistant, OmR and susceptible strains, S) of T. cinnabarinus. The relative expression level of TCE2 was 1.39-2.47 fold in the three resistant strains compared with the S strain. And after inducing with abamectin, fenpropathrin, and omethoate the highest expression level of TCE2 in the S was 1.64-, 2.92- and 2.24-fold compared with the control, respectively, and this difference was found to be significant. However, there was no obvious difference of the mRNA relative expression levels of TCE1 genes among the four strains, and those of TCE1 were not higher than the control throughout the study. Furthermore, the expression modes of TCE1 and TCE2 in AbR and FeR were similar with that in the S after being treated with abamectin and fenpropathrin, respectively. These results indicated that the enhanced expression of esterase gene TCE2 was associated with acaricide-resistance in T. cinnabarinus.
ESTHER : Feng_2011_Pestic.Biochem.Physiol_100_70
PubMedSearch : Feng_2011_Pestic.Biochem.Physiol_100_70

Title : Pretreatment with human serum butyrylcholinesterase alone prevents cardiac abnormalities, seizures, and death in Gottingen minipigs exposed to sarin vapor - Saxena_2011_Biochem.Pharmacol_82_1984
Author(s) : Saxena A , Sun W , Dabisch PA , Hulet SW , Hastings NB , Jakubowski EM , Mioduszewski RJ , Doctor BP
Ref : Biochemical Pharmacology , 82 :1984 , 2011
Abstract : Human serum butyrylcholinesterase (Hu BChE) is a stoichiometric bioscavenger that is being developed as a prophylactic countermeasure against organophosphorus nerve agents. This study was designed to evaluate the efficacy of Hu BChE against whole-body inhalation exposure to a lethal dose of sarin (GB) vapor. Male Gottingen minipigs were subjected to: air exposure, GB vapor exposure, or pretreatment with Hu BChE followed by GB vapor exposure. Hu BChE was administered by i.m. injection 24 h prior to exposure to 4.1 mg/m(3) of GB vapor for 60 min. Electrocardiograms (ECG), electroencephalograms (EEG), and pupil size were recorded throughout exposure. Blood drawn before and throughout exposure was analyzed for blood gases, electrolytes, metabolites, acetylcholinesterase and BChE activities, and amount of GB present. Untreated animals exposed to GB vapor exhibited cardiac abnormalities and generalized seizures, ultimately succumbing to respiratory failure. Pretreatment with 3.0 or 6.5 mg/kg of Hu BChE delayed blood gas and acid-base disturbances and the onset of cardiac and neural toxic signs, but failed to increase survivability. Pretreatment with 7.5 mg/kg of Hu BChE, however, completely prevented toxic signs, with blood chemistry and ECG and EEG parameters indistinguishable from control during and after GB exposure. GB bound in plasma was 200-fold higher than plasma from pigs that did not receive Hu BChE, suggesting that Hu BChE scavenged GB in blood and prevented it from reaching other tissues. Thus, prophylaxis with Hu BChE alone not only increased survivability, but also prevented cardiac abnormalities and neural toxicity in minipigs exposed to a lethal dose of GB vapor.
ESTHER : Saxena_2011_Biochem.Pharmacol_82_1984
PubMedSearch : Saxena_2011_Biochem.Pharmacol_82_1984
PubMedID: 21968035

Title : DPP6 establishes the A-type K(+) current gradient critical for the regulation of dendritic excitability in CA1 hippocampal neurons - Sun_2011_Neuron_71_1102
Author(s) : Sun W , Maffie JK , Lin L , Petralia RS , Rudy B , Hoffman DA
Ref : Neuron , 71 :1102 , 2011
Abstract : Subthreshold-activating A-type K(+) currents are essential for the proper functioning of the brain, where they act to delay excitation and regulate firing frequency. In CA1 hippocampal pyramidal neuron dendrites, the density of A-type K(+) current increases with distance from the soma, playing an important role in synaptic integration and plasticity. The mechanism underlying this gradient has, however, remained elusive. Here, dendritic recordings from mice lacking the Kv4 transmembrane auxiliary subunit DPP6 revealed that this protein is critical for generating the A-current gradient. Loss of DPP6 led to a decrease in A-type current, specifically in distal dendrites. Decreased current density was accompanied by a depolarizing shift in the voltage dependence of channel activation. Together these changes resulted in hyperexcitable dendrites with enhanced dendritic AP back-propagation, calcium electrogenesis, and induction of synaptic long-term potentiation. Despite enhanced dendritic excitability, firing behavior evoked by somatic current injection was mainly unaffected in DPP6-KO recordings, indicating compartmentalized regulation of neuronal excitability.
ESTHER : Sun_2011_Neuron_71_1102
PubMedSearch : Sun_2011_Neuron_71_1102
PubMedID: 21943606
Gene_locus related to this paper: human-DPP6

Title : Prophylaxis with human serum butyrylcholinesterase protects guinea pigs exposed to multiple lethal doses of soman or VX - Saxena_2011_Biochem.Pharmacol_81_164
Author(s) : Saxena A , Sun W , Fedorko JM , Koplovitz I , Doctor BP
Ref : Biochemical Pharmacology , 81 :164 , 2011
Abstract : Human serum butyrylcholinesterase (Hu BChE) is currently under advanced development as a bioscavenger for the prophylaxis of organophosphorus (OP) nerve agent toxicity in humans. It is estimated that a dose of 200mg will be required to protect a human against 2xLD(50) of soman. To provide data for initiating an investigational new drug application for the use of this enzyme as a bioscavenger in humans, we purified enzyme from Cohn fraction IV-4 paste and initiated safety and efficacy evaluations in mice, guinea pigs, and non-human primates. In mice, we demonstrated that a single dose of enzyme that is 30 times the therapeutic dose circulated in blood for at least four days and did not cause any clinical pathology in these animals. In this study, we report the results of safety and efficacy evaluations conducted in guinea pigs. Various doses of Hu BChE delivered by i.m. injections peaked at approximately 24h and had a mean residence time of 78-103h. Hu BChE did not exhibit any toxicity in guinea pigs as measured by general observation, serum chemistry, hematology, and gross and histological tissue changes. Efficacy evaluations showed that Hu BChE protected guinea pigs from an exposure of 5.5xLD(50) of soman or 8xLD(50) of VX. These results provide convincing data for the development of Hu BChE as a bioscavenger that can protect humans against all OP nerve agents.
ESTHER : Saxena_2011_Biochem.Pharmacol_81_164
PubMedSearch : Saxena_2011_Biochem.Pharmacol_81_164
PubMedID: 20846507

Title : The expression and activity of brain lipoprotein lipase is increased after acute cerebral ischemia-reperfusion in rats - Wang_2010_Neuropathology_30_131
Author(s) : Wang X , Sun W , Xu E
Ref : Neuropathology , 30 :131 , 2010
Abstract : Lipoprotein lipase (LPL) is a key enzyme involved in lipid metabolism. Previous studies have shown that the levels of brain LPL mRNA, protein and activity are up-regulated after brain and nerve injury. The aim of this study was to determine the response of expression and activity of brain LPL following acute cerebral ischemia-reperfusion. Adult male Sprague-Dawley rats were subjected to surgical occlusion of the middle cerebral artery. The expression of brain LPL was assessed by immunohistochemical staining and the enzyme activity of brain LPL was evaluated by colorimetric method. Increase of LPL immunopositive cells in the cerebral cortex around the infarction area was observed at 4, 6, 12 h ischemia, 2 h ischemia 2 h reperfusion, and 4 h ischemia 2 h reperfusion. LPL activity was significantly decreased in the ischemic side cortex at 2 h ischemia, and then significantly increased at 4 and 6 h ischemia. Our results showed that LPL immunopositive cells were increased in the cortex around the infarction area, and activity of LPL first decreased and then increased following acute cerebral ischemia-reperfusion. These results may suggest that LPL plays a potential role in the pathophysiological response of the brain to cerebral ischemia-reperfusion.
ESTHER : Wang_2010_Neuropathology_30_131
PubMedSearch : Wang_2010_Neuropathology_30_131
PubMedID: 19780982

Title : Systemic administration of the potential countermeasure huperzine reversibly inhibits central and peripheral acetylcholinesterase activity without adverse cognitive-behavioral effects - Myers_2010_Pharmacol.Biochem.Behav_94_477
Author(s) : Myers TM , Sun W , Saxena A , Doctor BP , Bonvillain AJ , Clark MG
Ref : Pharmacol Biochem Behav , 94 :477 , 2010
Abstract : Huperzine A is potentially superior to pyridostigmine bromide as a pretreatment for nerve agent intoxication because it inhibits acetylcholinesterase both peripherally and centrally, unlike pyridostigmine, which acts only peripherally. Using rhesus monkeys, we evaluated the time course of acetylcholinesterase and butyrylcholinesterase inhibition following four different doses of -(-)huperzine A: 5, 10, 20, and 40 microg/kg. Acetylcholinesterase inhibition peaked 30 min after intramuscular injection and varied dose dependently, ranging from about 30% to 75%. Subsequently, cognitive-behavioral functioning was also evaluated at each dose of huperzine A using a six-item serial-probe recognition task that assessed attention, motivation, and working memory. Huperzine did not impair performance, but physostigmine did. The results demonstrate that huperzine A can selectively and reversibly inhibit acetylcholinesterase without cognitive-behavioral side effects, thus warranting further study.
ESTHER : Myers_2010_Pharmacol.Biochem.Behav_94_477
PubMedSearch : Myers_2010_Pharmacol.Biochem.Behav_94_477
PubMedID: 19909771

Title : Safety of administration of human butyrylcholinesterase and its conjugates with soman or VX in rats - Genovese_2010_Basic.Clin.Pharmacol.Toxicol_106_428
Author(s) : Genovese RF , Sun W , Johnson CC , diTargiani RC , Doctor BP , Saxena A
Ref : Basic Clin Pharmacol Toxicol , 106 :428 , 2010
Abstract : We evaluated the effects of conjugated enzyme-nerve agent product resulting from the inhibition of bioscavenger human serum butyrylcholinesterase (Hu BChE) by nerve agents soman or VX. Rats were trained on a multiple Fixed-Ratio 32, Extinction 30 sec. (FR32, Ext30) schedule of food reinforcement and then injected (i.m.) with Hu BChE (30 mg/kg), equivalent amounts of Hu BChE-soman conjugate (GDC), Hu BChE-VX conjugate, oxotremorine (OXO) (0.316 mg/kg) or vehicle (n = 8, each group). On the day of injection and on 10 subsequent daily sessions, performance was evaluated on the FR32, Ext30 schedule. Neither conjugates nor Hu BChE produced a performance deficit under the schedule. OXO produced a substantial decrease in responding on the day of administration, with complete recovery observed on subsequent sessions. None of the treatments affected circulating acetylcholinesterase (AChE) activity when evaluated 24-72 hr after injection. The dose of Hu BChE produced a 20,000-fold increase above baseline in circulating BChE activity. Pathological evaluation of organ systems approximately 2 weeks following administration of conjugates or Hu BChE alone did not show toxicity. Taken together, these results suggest that Hu BChE - nerve agent conjugates produced following bioscavenger protection against nerve agents soman and VX do not appear to be particularly toxic. These results add to the safety assessment of Hu BChE as a bioscavenger countermeasure against nerve agent exposure.
ESTHER : Genovese_2010_Basic.Clin.Pharmacol.Toxicol_106_428
PubMedSearch : Genovese_2010_Basic.Clin.Pharmacol.Toxicol_106_428
PubMedID: 20050840

Title : Genome sequences of the human body louse and its primary endosymbiont provide insights into the permanent parasitic lifestyle - Kirkness_2010_Proc.Natl.Acad.Sci.U.S.A_107_12168
Author(s) : Kirkness EF , Haas BJ , Sun W , Braig HR , Perotti MA , Clark JM , Lee SH , Robertson HM , Kennedy RC , Elhaik E , Gerlach D , Kriventseva EV , Elsik CG , Graur D , Hill CA , Veenstra JA , Walenz B , Tubio JM , Ribeiro JM , Rozas J , Johnston JS , Reese JT , Popadic A , Tojo M , Raoult D , Reed DL , Tomoyasu Y , Kraus E , Mittapalli O , Margam VM , Li HM , Meyer JM , Johnson RM , Romero-Severson J , Vanzee JP , Alvarez-Ponce D , Vieira FG , Aguade M , Guirao-Rico S , Anzola JM , Yoon KS , Strycharz JP , Unger MF , Christley S , Lobo NF , Seufferheld MJ , Wang N , Dasch GA , Struchiner CJ , Madey G , Hannick LI , Bidwell S , Joardar V , Caler E , Shao R , Barker SC , Cameron S , Bruggner RV , Regier A , Johnson J , Viswanathan L , Utterback TR , Sutton GG , Lawson D , Waterhouse RM , Venter JC , Strausberg RL , Berenbaum MR , Collins FH , Zdobnov EM , Pittendrigh BR
Ref : Proc Natl Acad Sci U S A , 107 :12168 , 2010
Abstract : As an obligatory parasite of humans, the body louse (Pediculus humanus humanus) is an important vector for human diseases, including epidemic typhus, relapsing fever, and trench fever. Here, we present genome sequences of the body louse and its primary bacterial endosymbiont Candidatus Riesia pediculicola. The body louse has the smallest known insect genome, spanning 108 Mb. Despite its status as an obligate parasite, it retains a remarkably complete basal insect repertoire of 10,773 protein-coding genes and 57 microRNAs. Representing hemimetabolous insects, the genome of the body louse thus provides a reference for studies of holometabolous insects. Compared with other insect genomes, the body louse genome contains significantly fewer genes associated with environmental sensing and response, including odorant and gustatory receptors and detoxifying enzymes. The unique architecture of the 18 minicircular mitochondrial chromosomes of the body louse may be linked to the loss of the gene encoding the mitochondrial single-stranded DNA binding protein. The genome of the obligatory louse endosymbiont Candidatus Riesia pediculicola encodes less than 600 genes on a short, linear chromosome and a circular plasmid. The plasmid harbors a unique arrangement of genes required for the synthesis of pantothenate, an essential vitamin deficient in the louse diet. The human body louse, its primary endosymbiont, and the bacterial pathogens that it vectors all possess genomes reduced in size compared with their free-living close relatives. Thus, the body louse genome project offers unique information and tools to use in advancing understanding of coevolution among vectors, symbionts, and pathogens.
ESTHER : Kirkness_2010_Proc.Natl.Acad.Sci.U.S.A_107_12168
PubMedSearch : Kirkness_2010_Proc.Natl.Acad.Sci.U.S.A_107_12168
PubMedID: 20566863
Gene_locus related to this paper: pedhb-ACHE1 , pedhb-ACHE2 , pedhc-e0v9b5 , pedhc-e0v9b6 , pedhc-e0v9b7 , pedhc-e0vbv5 , pedhc-e0vcd0 , pedhc-e0vcl7 , pedhc-e0vd69 , pedhc-e0ve50 , pedhc-e0vel6 , pedhc-e0vel7 , pedhc-e0vf98 , pedhc-e0vfs8 , pedhc-e0vfv0 , pedhc-e0vg01 , pedhc-e0vha2 , pedhc-e0vha4 , pedhc-e0vi52 , pedhc-e0vp42 , pedhc-e0vqu6 , pedhc-e0vuj9 , pedhc-e0vup6 , pedhc-e0vv55 , pedhc-e0vwv3 , pedhc-e0vxf7 , pedhc-e0vxg1 , pedhc-e0w4a6 , pedhc-e0w4c8 , pedhc-e0w271 , pedhc-e0w444 , pedhc-e0vym0 , pedhc-e0vdk9 , pedhc-e0vk10 , pedhc-e0vgw4 , pedhc-e0vgw7 , pedhc-e0vga1 , pedhc-e0w3s1 , pedhc-e0vzt2

Title : Prenatal and early life arsenic exposure induced oxidative damage and altered activities and mRNA expressions of neurotransmitter metabolic enzymes in offspring rat brain - Xi_2010_J.Biochem.Mol.Toxicol_24_368
Author(s) : Xi S , Guo L , Qi R , Sun W , Jin Y , Sun G
Ref : J Biochem Mol Toxicol , 24 :368 , 2010
Abstract : To better understand the effect of arsenic on central nervous system by prenatal and early life exposure, the oxidative stress and neurotransmitter metabolic enzymes were determined in offspring rats' brain cortex and hippocampus. Forty-eight pregnant rats were randomly divided into four groups, each group was given free access to drinking water that contained 0, 10, 50, and 100 mg/L NaAsO(2) from gestation day 6 (GD 6) until postnatal day 42 (PND 42). Once pups were weaned, they started to drink the same arsenic (As)-containing water as the dams. The level of malondialdehyde in 100 mg/L As-exposed pup's brain on PND 0 and cortex on PND 28 and 42 were significantly higher than in the control group (p < 0.05). Reduced glutathione (GSH) levels showed a clear decreasing trend in pup's cortex and hippocampus on PND 42. Activity of acetylcholinesterase was significantly higher in 100 mg/L As-exposed pup's hippocampus than in control group on PND 28 and 42. mRNA expression of glutamate decarboxylase (GAD(65) and GAD(67)) in 100 mg/L As-exposed pup's cortex or hippocampus on PND 28 and 42 were significantly higher than in control (p < 0.05). These alterations in the neurotransmitters and reduced antioxidant defence may lead to neurobehavioral and learning and memory changes in offspring rats.
ESTHER : Xi_2010_J.Biochem.Mol.Toxicol_24_368
PubMedSearch : Xi_2010_J.Biochem.Mol.Toxicol_24_368
PubMedID: 20376865

Title : Molecular characterization of two novel esterase genes from carmine spider mite, Tetranychus cinnabarinus (Acarina: Tetranychidae) - Sun_2010_Insect.Sci_17_91
Author(s) : Sun W , Xue CH , He L , Lu WC , Li M , Cao XF , Zhao ZM
Ref : Insect Sci , 17 :91 , 2010
Abstract : Two novel esterase complementary DNAs were identified and cloned from the insecticide-susceptible strain of Tetranychus cinnabarinus (Boisduval) (Acarina: Tetranychidae), which were designated as TCE1 and TCE2, respectively. The cDNA of TCE1 gene contained an open reading frame (ORF) of 1701 bp encoding 567 amino acids, and a predicted molecular weight of 62.75 kDa, the cDNA of TCE2 contained an ORF of 1680 bp encoding 560 amino acids, and a predicted molecular weight of 63.14 kDa. TCE1 and TCE2 were submitted to GenBank, accession number EU130461 and EU130462. The well-conserved sequence motif, GXSXG, used as a signature pattern in the esterase family are present in both TCE1 and TCE2 (GQSAG in TCE1, whereas GESAG in TCE2), indicating that these two genes are predicted to be esterases. Comparison of the deduced amino acid sequence with the published mite esterase sequence coming from Boophilus microplus showed that TCE1 shares 33.98% identity and TCE2 shares 33.46% identity. TCE1 and TCE2 share 46.4% identity. Quantitative real-time polymerase chain reaction revealed that expression level of the TCE2 gene was relatively higher than that of the TCE1 in all instars examined except the protonymph, and the expression level of these two esterase genes in adults of T. cinnabarinus was significantly higher than that in any other instars, respectively. T. cinnabarinus is an important agricultural mite pest and esterases are important in the metabolisms of insects and mites; the genomic information obtained in this study will contribute to esterase molecular biological study on mite pest species.
ESTHER : Sun_2010_Insect.Sci_17_91
PubMedSearch : Sun_2010_Insect.Sci_17_91
Gene_locus related to this paper: 9acar-b3tfg6 , 9acar-q5s1p7

Title : Demonstration of in vivo stability and lack of immunogenicity of a polyethyleneglycol-conjugated recombinant CHO-derived butyrylcholinesterase bioscavenger using a homologous macaque model - Rosenberg_2010_Chem.Biol.Interact_187_279
Author(s) : Rosenberg YJ , Saxena A , Sun W , Jiang X , Chilukuri N , Luo C , Doctor BP , Lee KD
Ref : Chemico-Biological Interactions , 187 :279 , 2010
Abstract : Human serum and recombinant butyrylcholinesterase (rHuBChE) are the most advanced prophylactics against organophosphate (OP) toxicity due to nerve agent or insecticide exposure. For ethical reasons, such potential multi-use treatments cannot be tested in humans and will require extensive testing in animal models and the "Animal Rule" 21 (21 CFR 601.90) for regulatory approval. This will involve multiple injections of rHuBChE into heterologous animals, e.g. macaques, rodents with inevitable immunogenicity and subsequent elimination of the enzyme on repeat injections. In order to accurately assess pharmacokinetics, efficacy and safety of a candidate rBChE in an "antibody free" system, a homologous macaque (Ma) model has been developed. In these studies, macaques received single or multiple intravenous injections of native MaBChE as well as unmodified or PEG-conjugated forms of rMaBChE produced in CHO cells. Compared to the poor plasma retention of unmodified rBChE (MRT: <10h), three injections of 1.5-2.3mg/kg of PEG-conjugated tetrameric rBChE resulted in high circulatory stability (MRT: >134h) and lack of immunogenicity similar to native MaBChE. PEG-conjugation of the monomeric rMaBChE form also exhibited pharmacokinetic profiles comparable to the tetrameric form (MRT: >113h). However, despite the increased bioavailability of PEG-rBChE, antigenicity studies using sandwich ELISA showed that while macaque BChE was not immunogenic in macaques, PEGylation of rMaBChE did not prevent binding to anti-BChE antibodies, suggesting PEGylation may not be sufficient to mask non-human epitopes on rBChE. This homologous model can provide necessary preclinical protection data for the use of PEG-rHuBChE in humans and bodes well for a safe and efficacious CHO-derived rHuBChE therapeutic.
ESTHER : Rosenberg_2010_Chem.Biol.Interact_187_279
PubMedSearch : Rosenberg_2010_Chem.Biol.Interact_187_279
PubMedID: 20211615

Title : Pharmacokinetics and immunologic consequences of repeated administrations of purified heterologous and homologous butyrylcholinesterase in mice - Sun_2009_Life.Sci_85_657
Author(s) : Sun W , Luo C , Naik RS , Doctor BP , Saxena A
Ref : Life Sciences , 85 :657 , 2009
Abstract : AIM: To assess the consequences of repeated administrations of purified human serum butyrylcholinesterase (Hu BChE) and mouse serum (Mo) BChE into mice. MAIN METHODS: Purified Hu BChE and Mo BChE isolated from the sera of CD-1 mice were administered into Balb/c or CD-1 mice. The enzymes were delivered by i.m. injections of approximately 100U (0.15mg) on day 1 and on day 28, respectively. The effects of two injections were monitored by following blood BChE and anti-BChE IgG levels. KEY FINDINGS: Hu BChE displayed a mean residence time (MRT) of 50h, and an area under the curve (AUC) of 1220U/ml.h in Balb/c or CD-1 mice. Mo BChE exhibited an MRT of 78h and an AUC of 1815U/ml.h in Balb/c mice; the AUC increased to 2504U/ml.h in CD-1 mice. A second injection of Hu BChE in both strains exhibited a marked reduction in circulatory stability. The circulatory stability of the second injection of Mo BChE was reduced in Balb/c mice, but was almost identical to the first injection in CD-1 mice. Consistent with these observations, circulating anti-BChE IgGs were observed in mice injected with Hu BChE; low levels of anti-BChE IgGs were observed only in Balb/c mice injected with Mo BChE. No antibody response was detected in CD-1 mice following either injection of homologous Mo BChE. SIGNIFICANCE: The identical pharmacokinetic profiles and the absence of an immunologic response following a second administration of homologous BChE support the development of Hu BChE as a detoxifying drug in humans.
ESTHER : Sun_2009_Life.Sci_85_657
PubMedSearch : Sun_2009_Life.Sci_85_657
PubMedID: 19772863

Title : Adenovirus-mediated gene transfer of human butyrylcholinesterase results in persistent high-level transgene expression in vivo - Chilukuri_2008_Chem.Biol.Interact_175_327
Author(s) : Chilukuri N , Duysen EG , Parikh K , Sun W , Doctor BP , Lockridge O , Saxena A
Ref : Chemico-Biological Interactions , 175 :327 , 2008
Abstract : Human serum butyrylcholinesterase (Hu BChE) is a promising therapeutic against the toxicity of chemical warfare nerve agents, pesticide intoxication, and cocaine overdose. However, its widespread application is hampered by difficulties in large-scale production of the native protein from human plasma and/or availability as a recombinant protein suitable for use in vivo. This limitation may be resolved by in vivo delivery and expression of the Hu BChE gene. In this study, recombinant (r) adenoviruses (Ads) encoding full-length and truncated rHu BChEs were tested for in vivo expression in mice. Mice injected with these rAds intraperitoneally failed to express rHu BChE. However, a single tail vein injection of both rAds resulted in persistent high serum levels of rHu BChE in BChE knockout mice, which peaked on days 4/5 at 377+/-162U/ml for full-length rHu BChE and 574+/-143U/ml for truncated rHu BChE. These activity levels are orders of magnitude higher than 1.9U/ml of mouse BChE present in wild-type mouse serum. Thereafter, rHu BChE levels dropped rapidly and very little or no activity was detected in the serum 10 days post-virus administration. In conclusion, the present study demonstrates the potential of rAd-mediated Hu BChE gene therapy to counteract multiple lethal doses of chemical warfare nerve agent toxicity.
ESTHER : Chilukuri_2008_Chem.Biol.Interact_175_327
PubMedSearch : Chilukuri_2008_Chem.Biol.Interact_175_327
PubMedID: 18499092

Title : Effect of polyethylene glycol modification on the circulatory stability and immunogenicity of recombinant human butyrylcholinesterase - Chilukuri_2008_Chem.Biol.Interact_175_255
Author(s) : Chilukuri N , Sun W , Naik RS , Parikh K , Tang L , Doctor BP , Saxena A
Ref : Chemico-Biological Interactions , 175 :255 , 2008
Abstract : The therapeutic value of human serum butyrylcholinesterase (Hu BChE) as a bioscavenger of chemical warfare agents is due to its high reactivity with organophosphorus compounds and prolonged circulatory stability. Native Hu BChE is mostly tetrameric in form while the enzyme produced using molecular cloning technology is a mixture of tetramers, dimers, and monomers. Previous studies revealed that monomers and dimers of recombinant human (rHu) BChE cleared rapidly from the circulation of mice compared to tetrameric rHu BChE and native Hu BChE, which have mean residence times (MRTs) of 18h and 45h, respectively. It was also shown that polyethylene glycol-20K (PEG) modification of tetrameric rHu BChE prolonged its circulatory stability and bioavailability in vivo. The goal of this study was to determine if modification with PEG could prolong the circulatory stability and eliminate the immunogenicity of monomeric rHu BChE. Monomeric rHu BChE was expressed in human 293A cells using a cDNA lacking the 45 amino acid tetramerization domain from the carboxyl terminus and the adenovirus expression system. The catalytic and inhibitory properties of purified monomeric rHu BChE were similar to those for native Hu BChE and were not affected by PEG modification. As expected, monomeric rHu BChE rapidly cleared from the circulation of mice (MRT=3.2+/-0.3h) while monomeric PEG-rHu BChE demonstrated significant improvement in its bioavailability and circulatory stability in blood (MRT=31.4+/-5.4h). However, a second injection of monomeric PEG-rHu BChE, 28 days after the first, displayed a much shorter MRT=11.6+/-0.4h, and circulating anti-monomeric PEG-rHu BChE antibodies were detected in the blood of mice. These results suggest that PEG modification increased the circulatory stability of monomeric rHu BChE but failed to reduce or eliminate its immunogenicity.
ESTHER : Chilukuri_2008_Chem.Biol.Interact_175_255
PubMedSearch : Chilukuri_2008_Chem.Biol.Interact_175_255
PubMedID: 18603232

Title : Efficacy of human serum butyrylcholinesterase against sarin vapor - Saxena_2008_Chem.Biol.Interact_175_267
Author(s) : Saxena A , Sun W , Dabisch PA , Hulet SW , Hastings NB , Jakubowski EM , Mioduszewski RJ , Doctor BP
Ref : Chemico-Biological Interactions , 175 :267 , 2008
Abstract : Human serum butyrylcholinesterase (Hu BChE) is currently under advanced development as a pretreatment drug for organophosphate (OP) poisoning in humans. It was shown to protect mice, rats, guinea pigs, and monkeys against multiple LD(50) challenges of OP nerve agents by i.v. or s.c. bolus injections. Since inhalation is the most likely route of exposure to OP nerve agents on the battlefield or in public places, the aim of this study was to evaluate the efficacy of Hu BChE against whole-body inhalation exposure to sarin (GB) vapor. Male Gottingen minipigs were subjected to one of the following treatments: (1) air exposure; (2) GB vapor exposure; (3) pretreatment with 3 mg/kg of Hu BChE followed by GB vapor exposure; (4) pretreatment with 6.5 mg/kg of Hu BChE followed by GB vapor exposure; (5) pretreatment with 7.5 mg/kg of Hu BChE followed by GB vapor exposure. Hu BChE was administered by i.m. injection, 24h prior to whole-body exposure to GB vapor at a concentration of 4.1 mg/m(3) for 60 min, a dose lethal to 99% of untreated exposed pigs (LCt99). EEG, ECG, and pupil size were monitored throughout exposure, and blood drawn from a surgically implanted jugular catheter before and throughout the exposure period, was analyzed for acetylcholinesterase (AChE) and BChE activities, and the amount of GB present in plasma. All animals exposed to GB vapor alone or pretreated with 3 or 6.5 mg/kg of Hu BChE, died following exposure to GB vapor. All five animals pretreated with 7.5 mg/kg of Hu BChE survived the GB exposure. The amount of GB bound in plasma was 200-fold higher compared to that from plasma of pigs that did not receive Hu BChE, suggesting that Hu BChE was effective in scavenging GB in blood. Additionally, pretreatment with 7.5 mg/kg of Hu BChE prevented cardiac abnormalities and seizure activity observed in untreated animals and those treated with lower doses of Hu BChE.
ESTHER : Saxena_2008_Chem.Biol.Interact_175_267
PubMedSearch : Saxena_2008_Chem.Biol.Interact_175_267
PubMedID: 18597747

Title : A repeated injection of polyethyleneglycol-conjugated recombinant human butyrylcholinesterase elicits immune response in mice - Chilukuri_2008_Toxicol.Appl.Pharmacol_231_423
Author(s) : Chilukuri N , Sun W , Parikh K , Naik RS , Tang L , Doctor BP , Saxena A
Ref : Toxicol Appl Pharmacol , 231 :423 , 2008
Abstract : Human serum butyrylcholinesterase (Hu BChE) serves as an efficacious bioscavenger of highly toxic organophosphorus (OP) compounds. Since there is a concern that the supply of native Hu BChE may be limited, monomeric and tetrameric forms of recombinant Hu BChE (rHu BChE) were evaluated as replacements and found that they lacked sufficient stability in vivo. However, their in vivo stability could be significantly prolonged by conjugation with polyethyleneglycol-20K (PEG) suggesting that monomeric and tetrameric PEG-rHu BChE could function as bioscavengers. Here, the immunogenicity of PEG-rHu BChE was evaluated in mice following two injections given four weeks apart. In addition to pharmacokinetic parameters, such as mean residence time, maximal concentration, time to reach the maximal concentration, elimination half-life and area under the plasma concentration-time curve extrapolated to infinity, the presence of circulating anti-rHu BChE antibodies was also determined. Although the pharmacokinetic parameters were significantly improved for the first injection of monomeric and tetrameric PEG-rHu BChEs, they were much lower for the second injection. Anti-rHu BChE antibodies were detected in the blood of mice following the first and second enzyme injections and their levels were approximately higher by 5-fold and 2-fold in mice injected with monomeric and tetrameric PEG-rHu BChEs as compared to mice injected with unconjugated enzymes. The findings that the rapid clearance of a repeat injection of PEG-rHu BChEs in mice which coincides with the presence of circulating anti-rHu BChE antibodies suggest that PEG conjugation prolonged the circulatory stability of rHu BChE but failed to eliminate its immunogenicity in mice.
ESTHER : Chilukuri_2008_Toxicol.Appl.Pharmacol_231_423
PubMedSearch : Chilukuri_2008_Toxicol.Appl.Pharmacol_231_423
PubMedID: 18586293

Title : Long-term effects of human butyrylcholinesterase pretreatment followed by acute soman challenge in cynomolgus monkeys - Sun_2008_Chem.Biol.Interact_175_428
Author(s) : Sun W , Doctor BP , Lenz DE , Saxena A
Ref : Chemico-Biological Interactions , 175 :428 , 2008
Abstract : Human serum butyrylcholinesterase (Hu BChE) was demonstrated previously to be an effective prophylaxis that can protect animals from organophosphate nerve agents. However, in most of those studies, the maximum dose used to challenge animals was low (<2x LD(50)), and the health of these animals was monitored for only up to 2 weeks. In this study, six cynomolgus monkeys received 75 mg of Hu BChE followed by sequential doses (1.5, 2.0, 2.0 x LD(50)) of soman 10h later for a total challenge of 5.5x LD(50). Four surviving animals that did not show any signs of soman intoxication were transferred to WRAIR for the continuous evaluation of long-term health effects for 14 months. Each month, blood was drawn from these monkeys and analyzed for serum chemistry and hematology parameters, blood acetylcholinesterase (AChE) and BChE levels. Based on the serum chemistry and hematology parameters measured, no toxic effects or any organ malfunctions were observed up to 14 months following Hu BuChE protection against exposure to 5.5x LD(50) of soman. In conclusion, Hu BChE pretreatment not only effectively protects monkeys from soman-induced toxicity of the immediate acute phase but also for a long-term outcome.
ESTHER : Sun_2008_Chem.Biol.Interact_175_428
PubMedSearch : Sun_2008_Chem.Biol.Interact_175_428
PubMedID: 18674756

Title : A glimpse of streptococcal toxic shock syndrome from comparative genomics of S. suis 2 Chinese isolates - Chen_2007_PLoS.One_2_e315
Author(s) : Chen C , Tang J , Dong W , Wang C , Feng Y , Wang J , Zheng F , Pan X , Liu D , Li M , Song Y , Zhu X , Sun H , Feng T , Guo Z , Ju A , Ge J , Dong Y , Sun W , Jiang Y , Yan J , Yang H , Wang X , Gao GF , Yang R , Yu J
Ref : PLoS ONE , 2 :e315 , 2007
Abstract : BACKGROUND: Streptococcus suis serotype 2 (SS2) is an important zoonotic pathogen, causing more than 200 cases of severe human infection worldwide, with the hallmarks of meningitis, septicemia, arthritis, etc. Very recently, SS2 has been recognized as an etiological agent for streptococcal toxic shock syndrome (STSS), which was originally associated with Streptococcus pyogenes (GAS) in Streptococci. However, the molecular mechanisms underlying STSS are poorly understood. METHODS AND FINDINGS: To elucidate the genetic determinants of STSS caused by SS2, whole genome sequencing of 3 different Chinese SS2 strains was undertaken. Comparative genomics accompanied by several lines of experiments, including experimental animal infection, PCR assay, and expression analysis, were utilized to further dissect a candidate pathogenicity island (PAI). Here we show, for the first time, a novel molecular insight into Chinese isolates of highly invasive SS2, which caused two large-scale human STSS outbreaks in China. A candidate PAI of approximately 89 kb in length, which is designated 89K and specific for Chinese SS2 virulent isolates, was investigated at the genomic level. It shares the universal properties of PAIs such as distinct GC content, consistent with its pivotal role in STSS and high virulence. CONCLUSIONS: To our knowledge, this is the first PAI candidate from S. suis worldwide. Our finding thus sheds light on STSS triggered by SS2 at the genomic level, facilitates further understanding of its pathogenesis and points to directions of development on some effective strategies to combat highly pathogenic SS2 infections.
ESTHER : Chen_2007_PLoS.One_2_e315
PubMedSearch : Chen_2007_PLoS.One_2_e315
PubMedID: 17375201
Gene_locus related to this paper: strsu-a4vws4 , strsu-q302y4 , strsy-a4vus4 , strsy-a4vwf6

Title : Environmentally friendly, efficient resolution of racemic secondary alcohols by lipase-catalyzed enantioselective transesterification in ionic liquids in the presence of organic bases - Wu_2007_Chem.Biodivers_4_183
Author(s) : Wu XM , Xin JY , Sun W , Xia CG
Ref : Chem Biodivers , 4 :183 , 2007
Abstract : The lipase-catalyzed enantioselective transesterification of racemic secondary alcohols was studied using vinyl acetate as acyl donor in two imidazolium-based ionic liquids vs. hexane (Scheme), both in the absence and presence of catalytic amounts of organic bases such as triethylamine (Et(3)N) or pyridine. The organic bases generally enhanced both the rate and enantioselectivity of the reaction. Further, the system 1-butyl-3-methyl-1H-imidazolium hexafluorophosphate/Candida antarctica lipase B ([bmim][PF(6)]/CALB) could be readily recycled four times without significant loss in activity or enantioselectivity.
ESTHER : Wu_2007_Chem.Biodivers_4_183
PubMedSearch : Wu_2007_Chem.Biodivers_4_183
PubMedID: 17311231

Title : Circadian rhythms of heart rate and locomotion after treatment with low-dose acetylcholinesterase inhibitors - Scremin_2006_J.Appl.Toxicol_26_410
Author(s) : Scremin OU , Shih TM , Huynh L , Roch M , Sun W , Chialvo DR , Jenden DJ
Ref : Journal of Applied Toxicology , 26 :410 , 2006
Abstract : This study tested the hypothesis that repeated exposure to low levels of sarin, pyridostigmine bromide (PB) or their combination, at doses equivalent to those possibly experienced by veterans of the 1991 Persian Gulf War, could lead to persistent or delayed autonomic effects and thus help to explain the cause of clinical findings in this population. Male Sprague-Dawley rats were treated for 3 weeks with: saline injection (0.5 ml kg(-1), s.c., 3 times weekly) with tap drinking water (control); saline injection with PB (80 mg l(-1) in drinking water); sarin injection (62.5 microg kg(-1), s.c., 0.5 x LD(50), 3 times weekly) with tap drinking water (sarin); or sarin injection with PB in drinking water (sarin + PB). At 2, 4 or 16 weeks post-treatment, heart rate (HR) and locomotor activity (LA) were studied by radiotelemetry. Two weeks posttreatment, HR in drug-treated animals was significantly lower than in controls. A decrease in low-frequency HR power spectrum (PS) was found at 00:00 h and 08:00 h with sarin + PB and at 00:00 h with sarin, while total power was enhanced with sarin + PB at 22:00 h. Minimal effects of drug treatments on HR and HR PS were detected at 4 and 16 weeks post-treatment. No significant differences in LA between control and other groups were found. Since no consistent long-term effects were found in any of the variables studied, these experiments do not support the hypothesis that repeated administration of low doses of PB and the nerve agent sarin can induce persistent or delayed alterations in autonomic function.
ESTHER : Scremin_2006_J.Appl.Toxicol_26_410
PubMedSearch : Scremin_2006_J.Appl.Toxicol_26_410
PubMedID: 16858689

Title : Cerebral acetylcholine and choline contents and turnover following low-dose acetylcholinesterase inhibitors treatment in rats - Shih_2006_Arch.Toxicol_80_761
Author(s) : Shih TM , Scremin OU , Roch M , Huynh L , Sun W , Jenden DJ
Ref : Archives of Toxicology , 80 :761 , 2006
Abstract : Male Sprague-Dawley rats were treated for 3 weeks with (1) regular tap drinking water plus subcutaneous (s.c.) saline (0.5 ml/kg) injections three times/week, (2) pyridostigmine bromide (PB) in drinking water (80 mg/L) plus s.c. saline injections three times/week, (3) regular tap drinking water plus s.c. sarin (0.5 x LD(50)) injections three times/week, or (4) PB in drinking water plus s.c. sarin injections three times/week. Repeated doses of sarin, in the presence or absence of PB, were devoid of acute toxicity during the three-week treatment period. Two, 4, and 16 weeks post-treatment, animals were given an intravenous pulse injection of choline labeled with 4 deuterium atoms (D4Ch) followed, after 1 min, by microwave fixation of the brain in vivo. Tissue levels of endogenous acetylcholine (D0ACh), endogenous choline (D0Ch), D4Ch, and ACh synthesized from D4Ch (D4ACh) were measured by gas-chromatography mass-spectrometry in hippocampus, infundibulum, mesencephalon, neocortex, piriform cortex, and striatum. Ch uptake from blood and ACh turnover were estimated from D4Ch and D4ACh concentrations in brain tissue, respectively. Statistically significant differences among brain regions were found for D0Ch, D4Ch, D0ACh and D4ACh at 2, 4 and 16 weeks post-treatment. However, differences in the values of these parameters between control and drug treatments were found only for D0ACh and D0Ch at 2 and 4 weeks, but not at 16 weeks post-treatment. In conclusion, the results from these experiments do not support a delayed or persistent alteration in cholinergic function after exposure to low doses of PB and/or sarin.
ESTHER : Shih_2006_Arch.Toxicol_80_761
PubMedSearch : Shih_2006_Arch.Toxicol_80_761
PubMedID: 16628397

Title : Bioscavenger for protection from toxicity of organophosphorus compounds - Saxena_2006_J.Mol.Neurosci_30_145
Author(s) : Saxena A , Sun W , Luo C , Myers TM , Koplovitz I , Lenz DE , Doctor BP
Ref : Journal of Molecular Neuroscience , 30 :145 , 2006
Abstract : Current antidotal regimens for organophosphorus compound (OP) poisoning consist of a combination of pretreatment with a spontaneously reactivating AChE inhibitor such as pyridostigmine bromide, and postexposure therapy with anticholinergic drugs such as atropine sulfate and oximes such as 2-PAM chloride (Gray, 1984). Although these antidotal regimens are effective in preventing lethality of animals from OP poisoning, they do not prevent postexposure incapacitation, convulsions, performance deficits, or, in many cases, permanent brain damage (Dunn and Sidell, 1989). These problems stimulated the development of enzyme bioscavengers as a pretreatment to sequester highly toxic OPs before they reach their physiological targets. Several studies over the last two decades have demonstrated that exogenously administered human serum butyrylcholinesterase (Hu BChE) can be used successfully as a safe, efficacious, and single prophylactic treatment to counteract the toxicity of OPs. It also has potential use for first responders (civilians) reacting to terrorist nerve gas release, pesticide overexposure, or succinylcholine-induced apnea. A dose of 200 mg of Hu BChE in humans is envisioned as a prophylactic treatment that can protect from exposure of 2-5 x LD50 of nerve agents (Ashani, 2000).
ESTHER : Saxena_2006_J.Mol.Neurosci_30_145
PubMedSearch : Saxena_2006_J.Mol.Neurosci_30_145
PubMedID: 17192662

Title : Human serum butyrylcholinesterase: in vitro and in vivo stability, pharmacokinetics, and safety in mice - Saxena_2005_Chem.Biol.Interact_157-158_199
Author(s) : Saxena A , Sun W , Luo C , Doctor BP
Ref : Chemico-Biological Interactions , 157-158 :199 , 2005
Abstract : The use of exogenously administered cholinesterases (ChEs) as bioscavengers of highly toxic organophosphate (OP) nerve agents is now sufficiently well documented to make them a highly viable prophylactic treatment against this potential threat. Of the ChEs evaluated so far, human serum butyrylcholinesterase (HuBChE) is most suitable for human use. A dose of 200 mg (3 mg/kg) of HuBChE is envisioned as a prophylactic treatment in humans that can protect from an exposure of up to 2 x LD50 of soman. In addition to its use as a prophylactic for a variety of wartime scenarios, including covert actions, it also has potential use for first responders (civilians) reacting to terrorist nerve gas release. We recently, developed a procedure for the large-scale purification of HuBChE, which yielded approximately 6 g of highly purified enzyme from 120 kg of Cohn fraction IV-4. The enzyme had a specific activity of 700-750 U/mg and migrated as a single band on SDS-PAGE. To provide data for initiating an investigational new drug (IND) application for the use of this enzyme as a bioscavenger in humans, we established its pharmacokinetic properties, examined its safety in mice, and evaluated its shelf life at various temperatures. In mice administered various doses up to 90 mg/kg, enzyme activity reached peak levels in circulation at 10 and 24 h following i.p. and i.m. injections, respectively. The enzyme displayed a mean residence time (MRT) of 40-50 h, regardless of the route of administration or dose of injected enzyme. Mice were euthanized 2 weeks following enzyme administration and tissues were examined grossly or microscopically for possible toxic effects. Results suggest that HuBChE does not exhibit any toxicity in mice as measured by general observation, serum chemistry, hematology, gross or histologic tissue changes. The shelf life of this enzyme stored at 4, 25, 37, and 45 degrees C was determined in lyophilized form. The enzyme was found to be stable when stored in lyophilized form at -20, 4, 25, or 37 degrees C to date (2 years), as measured by specific activity and SDS polyacrylamide gel electrophoresis. The effect of storage on circulatory stability was determined by measuring MRT in mice; there was no change in the MRT of lyophilized enzyme stored at -20 degrees C to date (2 years). These results provide convincing data that HuBChE is a safe bioscavenger that can provide protection against all OP nerve agents. Efforts are now underway to prepare the required documentation for submission of an IND application to the United States Food and Drug Administration (USFDA).
ESTHER : Saxena_2005_Chem.Biol.Interact_157-158_199
PubMedSearch : Saxena_2005_Chem.Biol.Interact_157-158_199
PubMedID: 16263104

Title : Polyethylene glycosylation prolongs the circulatory stability of recombinant human butyrylcholinesterase - Chilukuri_2005_Chem.Biol.Interact_157-158_115
Author(s) : Chilukuri N , Parikh K , Sun W , Naik R , Tipparaju P , Doctor BP , Saxena A
Ref : Chemico-Biological Interactions , 157-158 :115 , 2005
Abstract : Previous studies in rodents and non-human primates have demonstrated that pretreatment of animals with cholinesterases could provide significant protection against organophosphate (OP) nerve agent toxicity. Gene delivery/therapy is emerging as an approach to achieve high-level expression of proteins in vivo that are very similar to their native counterparts. Recently, adenoviral (Ad) vectors have proven to be excellent vehicles for delivering genes to cells in vitro and in vivo. In this study, we explored the use of the newly designed AdenoVATOR system for the expression of recombinant human butyrylcholinesterase (rHu BChE) in human embryonic kidney 293A (HEK-293A) cells. In these cells, rHu BChE was expressed as mostly tetrameric form by the simultaneous expression of proline-rich attachment domain. By optimizing the culture conditions, 1.5-2.0 U/ml of rHu BChE could be expressed in HEK-293A cells. Recombinant Hu BChE was purified to homogeneity by ammonium sulfate fractionation followed by affinity column chromatography using procainamide Sepharose and cobalt Sepharose gels. The enzymatic and physico-chemical properties of purified rHu BChE were similar to those of native serum-derived Hu BChE. To determine the suitability of this preparation for use as an antidote against highly toxic nerve agents, its pharmacokinetics were evaluated in mice. Recombinant Hu BChE exhibited a mean residence time of 18.3 h which was 2.5-fold shorter than that observed for native Hu BChE in mice. However, rHu BChE chemically modified with polyethyleneglycol (PEG) displayed a mean residence time of 36.2 h suggesting that PEG-modification can prolong the circulatory stability of rHu BChE. The efficacy of Ad-Hu BChE to induce the production of therapeutic levels of bioscavenger in vivo is under evaluation.
ESTHER : Chilukuri_2005_Chem.Biol.Interact_157-158_115
PubMedSearch : Chilukuri_2005_Chem.Biol.Interact_157-158_115
PubMedID: 16253215

Title : Safety and pharmacokinetics of human serum butyrylcholinesterase in guinea pigs - Sun_2005_Chem.Biol.Interact_157-158_428
Author(s) : Sun W , Doctor BP , Saxena A
Ref : Chemico-Biological Interactions , 157-158 :428 , 2005
Abstract : Human serum butyrylcholinesterase (Hu BChE) has been demonstrated to be a highly effective detoxifying enzyme for counteracting the acute toxicity of organophosphorus (OP) nerve agents. In order to initiate an investigational new drug (IND) application for human use, the safety and pharmacokinetic properties of the enzyme were assessed in guinea pigs. Sixty milligrams per kilogram of Hu BChE was administered to guinea pigs by either i.p. or i.m. injection. Blood was drawn at various time points for up to 2 weeks following enzyme injection for the measurement of blood BChE activity. Hu BChE displayed a mean residence time of 110 h, regardless of the route of administration and the enzyme activity remained almost 10-fold above baseline level even after 2 weeks post enzyme injection. Fourteen days post Hu BChE administration, all animals were subjected to 20 panel serum chemistry, hematology, and complete gross/histopathology examination. Results showed no toxic effects as measured by general observation, serum chemistry, hematology, and gross and histological tissue changes. In conclusion, Hu BChE displays a long-lasting stability in the circulation of guinea pigs, and is devoid of any toxic side effects. These results provide convincing data for the safe and effective use of Hu BChE as a bioscavenger to protect humans against all OP nerve agents.
ESTHER : Sun_2005_Chem.Biol.Interact_157-158_428
PubMedSearch : Sun_2005_Chem.Biol.Interact_157-158_428
PubMedID: 16429577

Title : Effects of physostigmine and human butyrylcholinesterase on acoustic startle reflex and prepulse inhibition in C57BL\/6J mice - Clark_2005_Pharmacol.Biochem.Behav_81_497
Author(s) : Clark MG , Sun W , Myers TM , Bansal R , Doctor BP , Saxena A
Ref : Pharmacol Biochem Behav , 81 :497 , 2005
Abstract : The use of exogenously administered cholinesterases as bioscavengers of highly toxic organophosphorus nerve agents is a viable prophylactic against this threat. To use this strategy, cholinesterases must provide protection without disrupting behavior when administered alone. To assess behavioral safety, the acoustic startle reflex and prepulse inhibition (PPI) of C57BL/6J mice were investigated following administration of human plasma-derived butyrylcholinesterase (HuBChE). Two hours before testing, four groups of mice (n=10 per group) were pretreated with saline or HuBChE (2000 U, ip). Fifteen minutes before testing, subjects received either saline or the carbamate physostigmine (0.4 mg/kg, sc). Mice exposed to physostigmine exhibited a significant attenuation of the startle reflex, an increased time to peak startle amplitude, and significantly increased PPI. This effect was partially mitigated in mice pretreated with HuBChE. HuBChE alone did not change startle behavior or PPI significantly compared to saline controls. The circulatory time-course of butyrylcholinesterase was assessed in a separate group of mice and revealed levels approximately 600 times the physiological norm 2-4 h post administration. Thus, HuBChE does not appear to significantly alter startle or PPI behavior at a dose 30-fold higher than that estimated to be necessary for protection against 2LD50 of soman in humans.
ESTHER : Clark_2005_Pharmacol.Biochem.Behav_81_497
PubMedSearch : Clark_2005_Pharmacol.Biochem.Behav_81_497
PubMedID: 15913750

Title : Voltage-sensitive and ligand-gated channels in differentiating neural stem-like cells derived from the nonhematopoietic fraction of human umbilical cord blood - Sun_2005_Stem.Cells_23_931
Author(s) : Sun W , Buzanska L , Domanska-Janik K , Salvi RJ , Stachowiak MK
Ref : Stem Cells , 23 :931 , 2005
Abstract : Fetal cells with the characteristics of neural stem cells (NSCs) can be derived from the nonhematopoietic fraction of human umbilical cord blood (HUCB), expanded as a nonimmortalized cell line (HUCB-NSC), and further differentiated into neuron-like cells (HUCB-NSCD); however, the functional and neuronal properties of these cells are poorly understood. To address this issue, we used whole-cell patch-clamp recordings, gene microarrays, and immunocytochemistry to identify voltage-gated channels and ligand-gated receptors on HUCB-NSCs and HUCB-NSCDs. Gene microarray analysis identified genes for voltage-dependent potassium and sodium channels and the neurotransmitter receptors acetylcholine (ACh), gamma-aminobutyric acid (GABA), glutamate, glycine, 5-hydroxytryptamine (5-HT), and dopamine (DA). Several of these genes (GABA-A, glycine and glutamate receptors, voltage-gated potassium channels, and voltage-gated sodium type XII alpha channels) were not expressed in the HUCB mono-nuclear fraction (HUCB-MC), which served as a starting cell population for HUCB-NSC. HUCB-NSCD acquired neuronal phenotypes and displayed an inward rectifying potassium current (Kir) and an outward rectifying potassium current (I(K+)). Kir was present on most HUCB-NSCs and HUCB-NSCDs, whereas I(K+) was present only on HUCB-NSCDs. Many HUCB-NSCDs were immunopositive for glutamate, glycine, nicotinic ACh, DA, 5-HT, and GABA receptors. Kainic acid (KA), a non-N-methyl-D-asparate (NMDA) glutamate-receptor agonist, induced an inward current in some HUCB-NSCDs. KA, glycine, DA, ACh, GABA, and 5-HT partially blocked Kir through their respective receptors. These results suggest that HUCB-NSCs differentiate toward neuron-like cells, with functional voltage- and ligand-gated channels identified in other neuronal systems.
ESTHER : Sun_2005_Stem.Cells_23_931
PubMedSearch : Sun_2005_Stem.Cells_23_931
PubMedID: 16043459

Title : Low-dose cholinesterase inhibitors do not induce delayed effects on cerebral blood flow and metabolism - Scremin_2005_Pharmacol.Biochem.Behav_80_529
Author(s) : Scremin OU , Shih TM , Huynh L , Roch M , Sun W , Chialvo DR , Jenden DJ
Ref : Pharmacol Biochem Behav , 80 :529 , 2005
Abstract : The acetylcholinesterase (AChE) inhibitors sarin and pyridostigmine bromide (PB) have been proposed as causes of neurobehavioral dysfunction in Persian Gulf War veterans. To test possible delayed effects of these agents, we exposed rats to low (subsymptomatic) levels of sarin (0.5 LD50 s.c. 3 times weekly) and/or PB (80 mg/L in drinking water) for 3 weeks. Controls received saline s.c. and tap water. At 2, 4 and 16 weeks after exposure, regional cerebral blood flow (rCBF) and glucose utilization (rCGU) were measured in conscious animals with the Iodo-14C-antipyrine and 14C-2 deoxyglucose methods, respectively. Two weeks after exposure, PB+sarin caused significant rCBF elevations, but no changes in rCGU, in neocortex, with lesser effects on allocortex. Four weeks after exposure, the same general pattern was found with sarin. Only a few changes were found at 16 weeks post-treatment. The predominant effects of sarin or PB+sarin on rCBF at earlier times after treatment are consistent with the well known direct cerebral vascular effect of cholinergic agonists. The lack of changes in rCBF and rCGU observed at 16 weeks after treatment does not support the hypothesis that repeat exposure to low-dose cholinesterase inhibitors can generate permanent alterations in cerebral activity.
ESTHER : Scremin_2005_Pharmacol.Biochem.Behav_80_529
PubMedSearch : Scremin_2005_Pharmacol.Biochem.Behav_80_529
PubMedID: 15820522

Title : Poster (36) Human serum butyrylcholinesterase: a future generation antidote for organophosphate chemical warfare agent toxicity -
Author(s) : Saxena A , Luo C , Bansal R , Sun W , Clark M , Ashani Y , Ross M , Doctor BP
Ref : In: Cholinesterases in the Second Millennium: Biomolecular and Pathological Aspects , (Inestrosa NC, Campos EO) P. Universidad Catolica de Chile-FONDAP Biomedicina :339 , 2004

Title : Human serum butyrylcholinesterase: A future generation antidote for organophosphate chemical warfare agent toxicity . -
Author(s) : Saxena A , Luo C , Bansal R , Sun W , Clark M , Ashani Y , Ross M , Doctor BP
Ref : In: Cholinesterases in the Second Millennium: Biomolecular and Pathological Aspects , (Inestrosa NC, Campos EO) P. Universidad Catolica de Chile-FONDAP Biomedicina :269 , 2004

Title : A single residual replacement improves the folding and stability of recombinant cassava hydroxynitrile lyase in E. coil - Yan_2003_Biotechnol.Lett_25_1041
Author(s) : Yan G , Cheng S , Zhao G , Wu S , Liu Y , Sun W
Ref : Biotechnol Lett , 25 :1041 , 2003
Abstract : Substitution of Ser113 for Gly113 in the cap domain of hydroxynitrile lyase from Manihot esculenta (MeHNL) was performed by site-directed mutagenesis to improve its self-generated folding and stability under denaturation conditions. The yield of the recombinant mutant HNL1 (mut-HNL1), which had higher specific activity than the wild type HNL0 (wt-HNL0), was increased by 2 to 3-fold. Thermostability of MeHNL was also enhanced, probably due to an increase in content of the beta-strand secondary structure according to CD analysis. Our data in this report suggest that Ser113 significantly contributes to the in vivo folding and stability of MeHNL and demonstrates an economic advantage of mut-HNL1 over the wt-HNL0.
ESTHER : Yan_2003_Biotechnol.Lett_25_1041
PubMedSearch : Yan_2003_Biotechnol.Lett_25_1041
PubMedID: 12889812
Gene_locus related to this paper: manes-hnl

Title : [The changes in the summating potential and morphology in the cochlea of guinea pigs with anoxia]. [Chinese] - Li_1994_Chung.Hua.Erh.Pi.Yen.Hou.Ko.Tsa.Chih_29_74
Author(s) : Li X , Sun J , Sun W
Ref : Chinese Journal of Otorhinolaryngology , 29 :74 , 1994
Abstract : The dynamic changes in the CAP, SP and EP in the scale media were examined with single micropipet during anoxia and reventilation with oxygen. Also, the morphologic changes in the IHC, OHC and synapse were observed in this experiment. It was found that the amplitude of the SP and EP values declined with alteration in polarity of these value. The changes in polarity and amplitude of the SP followed the changes of CAP threshold induced by anoxia. The histologic examinations revealed no evidence of acetylcholinesterase (AChE) alteration in the synapse and no succinic dehydrogenase (SDH) changes in IHC appeared. However, the activity of SDH in the OHC decreased. The results suggest that the polarity and amplitude of SP were influenced passively by the changes of EP value. In addition, the changes of SP polarity from positive to negative during anoxia is due to the loss of modulation process of OHC to IHC, while the SP polarity from negative to positive during the supply of oxygen is caused by regain of the modulation process of OHC.
ESTHER : Li_1994_Chung.Hua.Erh.Pi.Yen.Hou.Ko.Tsa.Chih_29_74
PubMedSearch : Li_1994_Chung.Hua.Erh.Pi.Yen.Hou.Ko.Tsa.Chih_29_74
PubMedID: 7803093