Wei H

References (28)

Title : In vitro and in vivo stability of a highly efficient long-acting cocaine hydrolase - Shang_2024_Sci.Rep_14_10952
Author(s) : Shang L , Wei H , Deng J , Stewart MJ , LeSaint JE , Kyomuhangi A , Park S , Maul EC , Zhan CG , Zheng F
Ref : Sci Rep , 14 :10952 , 2024
Abstract : It is recognized as a promising therapeutic strategy for cocaine use disorder to develop an efficient enzyme which can rapidly convert cocaine to physiologically inactive metabolites. We have designed and discovered a series of highly efficient cocaine hydrolases, including CocH5-Fc(M6) which is the currently known as the most efficient cocaine hydrolase with both the highest catalytic activity against (-)-cocaine and the longest biological half-life in rats. In the present study, we characterized the time courses of protein appearance, pH, structural integrity, and catalytic activity against cocaine in vitro and in vivo of a CocH5-Fc(M6) bulk drug substance produced in a bioreactor for its in vitro and in vivo stability after long-time storage under various temperatures (-80, -20, 4, 25, or 37 degreesC). Specifically, all the tested properties of the CocH5-Fc(M6) protein did not significantly change after the protein was stored at any of four temperatures including -80, -20, 4, and 25 degreesC for~18 months. In comparison, at 37 degreesC, the protein was less stable, with a half-life of~82 days for cocaine hydrolysis activity. Additionally, the in vivo studies further confirmed the linear elimination PK profile of CocH5-Fc(M6) with an elimination half-life of~9 days. All the in vitro and in vivo data on the efficacy and stability of CocH5-Fc(M6) have consistently demonstrated that CocH5-Fc(M6) has the desired in vitro and in vivo stability as a promising therapeutic candidate for treatment of cocaine use disorder.
ESTHER : Shang_2024_Sci.Rep_14_10952
PubMedSearch : Shang_2024_Sci.Rep_14_10952
PubMedID: 38740850

Title : Long-lasting blocking of interoceptive effects of cocaine by a highly efficient cocaine hydrolase in rats - Wei_2024_Sci.Rep_14_927
Author(s) : Wei H , LeSaint JE , Jin Z , Zhan CG , Zheng F
Ref : Sci Rep , 14 :927 , 2024
Abstract : Cocaine dependence is a serious world-wide public health problem without an FDA-approved pharmacotherapy. We recently designed and discovered a highly efficient long-acting cocaine hydrolase CocH5-Fc(M6). The present study examined the effectiveness and duration of CocH5-Fc(M6) in blocking interoceptive effects of cocaine by performing cocaine discrimination tests in rats, demonstrating that the duration of CocH5-Fc(M6) in blocking cocaine discrimination was dependent on cocaine dose and CocH5-Fc(M6) plasma concentration. Particularly, a dose of 3 mg/kg CocH5-Fc(M6) effectively attenuated discriminative stimulus effects of 10 mg/kg cocaine, cumulative doses of 10 and 32 mg/kg cocaine, and cumulative doses of 10, 32 and 56 mg/kg cocaine by <= 20% for 41, 19, and 10 days, and completely blocked the discriminative stimulus effects for 30, 13, and 5 days with corresponding threshold plasma CocH5-Fc(M6) concentrations of 15.9, 72.2, and 221 nM, respectively, under which blood cocaine concentration was negligible. Additionally, based on the data obtained, cocaine discrimination model is more sensitive than the locomotor activity to reveal cocaine effects and that CocH5-Fc(M6) itself has no long-term toxicity regarding behavioral activities such as lever pressing and food consumption in rats, further demonstrating that CocH5-Fc(M6) has the desired properties as a promising therapeutic candidate for prevenance of cocaine dependence.
ESTHER : Wei_2024_Sci.Rep_14_927
PubMedSearch : Wei_2024_Sci.Rep_14_927
PubMedID: 38195724

Title : Structural Insights into (Tere)phthalate-Ester Hydrolysis by a Carboxylesterase and Its Role in Promoting PET Depolymerization - von Haugwitz_2022_ACS.Catal_12_15259
Author(s) : von Haugwitz G , Han X , Pfaff L , Li Q , Wei H , Gao J , Methling K , Ao Y , Brack Y , Jan Mican J , Feiler CG , Weiss MS , Bednar D , Palm GJ , Lalk M , Lammers M , Damborsky J , Weber G , Liu W , Bornscheuer UT , Wei R
Ref : ACS Catal , 12 :15259 , 2022
Abstract : TfCa, a promiscuous carboxylesterase from Thermobifida fusca, was found to hydrolyze polyethylene terephthalate (PET) degradation intermediates such as bis(2-hydroxyethyl) terephthalate (BHET) and mono-(2-hydroxyethyl)-terephthalate (MHET). In this study, we elucidated the structures of TfCa in its apo form, as well as in complex with a PET monomer analogue and with BHET. The structurefunction relationship of TfCa was investigated by comparing its hydrolytic activity on various ortho- and para-phthalate esters of different lengths. Structure-guided rational engineering of amino acid residues in the substrate-binding pocket resulted in the TfCa variant I69W/V376A (WA), which showed 2.6-fold and 3.3-fold higher hydrolytic activity on MHET and BHET, respectively, than the wild-type enzyme. TfCa or its WA variant was mixed with a mesophilic PET depolymerizing enzyme variant [Ideonella sakaiensis PETase (IsPETase) PM] to degrade PET substrates of various crystallinity. The dual enzyme system with the wild-type TfCa or its WA variant produced up to 11-fold and 14-fold more terephthalate (TPA) than the single IsPETase PM, respectively. In comparison to the recently published chimeric fusion protein of IsPETase and MHETase, our system requires 10% IsPETase and one-fourth of the reaction time to yield the same amount of TPA under similar PET degradation conditions. Our simple dual enzyme system reveals further advantages in terms of cost-effectiveness and catalytic efficiency since it does not require time-consuming and expensive cross-linking and immobilization approaches.
ESTHER : von Haugwitz_2022_ACS.Catal_12_15259
PubMedSearch : von Haugwitz_2022_ACS.Catal_12_15259
PubMedID: 36570084
Gene_locus related to this paper: thefu-1831

Title : Structural insight and engineering of a plastic degrading hydrolase Ple629 - Li_2022_Biochem.Biophys.Res.Commun_626_100
Author(s) : Li Z , Zhao Y , Wu P , Wang H , Li Q , nGao J , Qin HM , Wei H , Bornscheuer UT , Han X , Wei R , Liu W
Ref : Biochemical & Biophysical Research Communications , 626 :100 , 2022
Abstract : Polyethylene terephthalate (PET) is one of the most abundantly produced synthetic polyesters. The vast number of waste plastics including PET has challenged the waste management sector while also posing a serious threat to the environment due to improper littering. Recently, enzymatic PET degradation has been shown to be a viable option for a circular plastic economy, which can mitigate the plastic pollution. While protein engineering studies on specific PET degradation enzymes such as leaf-branch compost cutinase (LCC), Thermobifida sp. cutinases and Ideonella sakaiensis PETase (IsPETase) have been extensively published, other homologous PET degrading enzymes have received less attention. Ple629 is a polyester hydrolase identified from marine microbial consortium having activity on PET and the bioplastic polybutylene adipate terephthalate (PBAT). In order to explore its catalytic mechanism and improve its potential for PET hydrolysis, we solved its crystal structure in complex with a PET monomer analogue, and validated its structural and mechanistic similarity to known PET hydrolases. By structural comparisons, we identified some hot spot positions described in previous research on protein engineering of PET hydrolases. We substitute these amino acid residues in Ple629, and obtained variants with improved activity and thermo-stability. The most promising variant D226A/S279A exhibited a more than 5.5-fold improved activity on PET nanoparticles than the wild-type enzyme, suggesting its potential applicability in the biotechnological plastic recycling.
ESTHER : Li_2022_Biochem.Biophys.Res.Commun_626_100
PubMedSearch : Li_2022_Biochem.Biophys.Res.Commun_626_100
PubMedID: 35981419
Gene_locus related to this paper: 9zzzz-Ple629

Title : LIPG is a novel prognostic biomarker and correlated with immune infiltrates in lung adenocarcinoma - Wang_2022_J.Clin.Lab.Anal__e24824
Author(s) : Wang S , Chen Z , Lv H , Wang C , Wei H , Yu J
Ref : J Clin Lab Anal , :e24824 , 2022
Abstract : BACKGROUND: Although many biomarkers for lung adenocarcinoma (LUAD) have been identified, their specificity and sensitivity remain unsatisfactory. Endothelial lipase gene (LIPG) plays an important role in a variety of cancers, but its role in lung adenocarcinoma remains unclear. METHODS: TCGA, GEO, K-M plotter, CIBERSORT, GSEA, HPA, and GDSC were used to analyze LIPG in LUAD. Data analysis was mainly achieved by R 4.0.3. RESULTS: The expression of LIPG in LUAD tissues was higher than that in adjacent normal tissues, especially in women, patients aged >65 years, and those with lymph node metastasis. High expression predicted a poor prognosis. The results of enrichment analysis suggest that LIPG may exert profound effects on the development of LUAD through multiple stages of lipid metabolism and immune system regulation. In addition, LIPG expression was significantly correlated with the expression levels of multiple immune checkpoint genes and the abundance of multiple immune infiltrates, including the activated memory CD4 T cell, M1 macrophage, neutrophil, plasma cells, and T follicular helper (Tfh) cells in the LUAD microenvironment content. At the same time, patients with high LIPG expression respond well to a variety of antitumor drugs and have a low rate of drug resistance. CONCLUSIONS: LIPG is a prognostic marker and is associated with lipid metabolism and immune infiltration in LUAD.
ESTHER : Wang_2022_J.Clin.Lab.Anal__e24824
PubMedSearch : Wang_2022_J.Clin.Lab.Anal__e24824
PubMedID: 36572999
Gene_locus related to this paper: human-LIPG

Title : Odorant degrading carboxylesterases modulate foraging and mating behaviors of Grapholita molesta - Wei_2021_Chemosphere_270_128647
Author(s) : Wei H , Tan S , Li Z , Li J , Moural TW , Zhu F , Liu X
Ref : Chemosphere , 270 :128647 , 2021
Abstract : Odorant degrading carboxylesterases (CXEs) play key roles in the process of odor signal reception via degrading ester odorants. But the functional mechanisms of CXEs in modulating insect behaviors are unclear. Herein, we studied the roles that CXEs played in mating, foraging, and signal receptions of sex pheromones and host volatiles in Grapholita molesta. As a result, 23 candidate CXEs were identified by transcriptome analysis of G. molesta. The GmolCXE1 and 5 highly expressed in the antennae of male moths and GmolCXE14 and 21 abundantly expressed in larval heads, were significantly upregulated after exposure with odors from female adults or fresh ripe fruits respectively. After knockdown of GmolCXE1 and 5, or GmolCXE14 and 21 by RNA interference, the behavioral responses of G. molesta to ester sex pheromones or host volatiles were decreased, by exhibiting an inhibited searching behavior of G. molesta for females or fruits, respectively. Then evidence form GC-MS analysis, showed that the protein GmolCXE1 and GmolCXE5 could metabolize the sex pheromone components (Z/E)-8-dodecenyl acetate to their metabolites products (Z/E)-8-dodecenol, and that GmolCXE14 and GmolCXE21 could metabolize ethyl butanoate and ethyl hexanoate of ripe pears. In addition, fluorescent binding assays verified that GmolCXEs could degrade the free ester odor molecules, but not degrade the odor molecules protected by odorant-binding proteins. Our study not only demonstrated CXEs modulated the mating and foraging behaviors of G. molesta through inactivation of ester sex pheromone and host volatiles, but also discovered great potential molecular targets to develop behavioral inhibitors for pest management.
ESTHER : Wei_2021_Chemosphere_270_128647
PubMedSearch : Wei_2021_Chemosphere_270_128647
PubMedID: 33757271

Title : Novel Reversible-Binding PET Ligands for Imaging Monoacylglycerol Lipase Based on the Piperazinyl Azetidine Scaffold - Rong_2021_J.Med.Chem__
Author(s) : Rong J , Mori W , Xia X , Schafroth MA , Zhao C , Van RS , Yamasaki T , Chen J , Xiao Z , Haider A , Ogasawara D , Hiraishi A , Shao T , Zhang Y , Chen Z , Pang F , Hu K , Xie L , Fujinaga M , Kumata K , Gou Y , Fang Y , Gu S , Wei H , Bao L , Xu H , Collier TL , Shao Y , Carson RE , Cravatt BF , Wang L , Zhang MR , Liang SH
Ref : Journal of Medicinal Chemistry , : , 2021
Abstract : Monoacylglycerol lipase (MAGL) is a 33 kDa serine protease primarily responsible for hydrolyzing 2-arachidonoylglycerol into the proinflammatory eicosanoid precursor arachidonic acid in the central nervous system. Inhibition of MAGL constitutes an attractive therapeutic concept for treating psychiatric disorders and neurodegenerative diseases. Herein, we present the design and synthesis of multiple reversible MAGL inhibitor candidates based on a piperazinyl azetidine scaffold. Compounds 10 and 15 were identified as the best-performing reversible MAGL inhibitors by pharmacological evaluations, thus channeling their radiolabeling with fluorine-18 in high radiochemical yields and favorable molar activity. Furthermore, evaluation of [(18)F]10 and [(18)F]15 ([(18)F]MAGL-2102) by autoradiography and positron emission tomography (PET) imaging in rodents and nonhuman primates demonstrated favorable brain uptakes, heterogeneous radioactivity distribution, good specific binding, and adequate brain kinetics, and [(18)F]15 demonstrated a better performance. In conclusion, [(18)F]15 was found to be a suitable PET radioligand for the visualization of MAGL, harboring potential for the successful translation into humans.
ESTHER : Rong_2021_J.Med.Chem__
PubMedSearch : Rong_2021_J.Med.Chem__
PubMedID: 34569803
Gene_locus related to this paper: human-MGLL

Title : Physiological and transcriptomic changes of zebrafish (Danio rerio) embryos-larvae in response to 2-MIB exposure - Zhou_2021_J.Hazard.Mater_416_126142
Author(s) : Zhou W , Li X , Wang Y , Wang J , Zhang J , Wei H , Peng C , Wang Z , Li G , Li D
Ref : J Hazard Mater , 416 :126142 , 2021
Abstract : 2-Methylisoborneol (2-MIB), a natural odorous substance, is widely distributed in water environment, but there is a paucity of information concerning its systemic toxicity. Herein, we investigated the effects of 2-MIB exposure on developmental parameters, locomotive behavior, oxidative stress, apoptosis and transcriptome of zebrafish. Zebrafish embryos exposed to different concentrations (0, 0.5, 5 and 42.8 microg/L) of 2-MIB showed no changes in mortality, hatchability, and malformation rate, but the body length of zebrafish larvae was significantly increased in a dose-dependent manner, and accompanied by the changes of growth hormone/insulin-like growth factor (GH/IGF) axis and the hypothalamic-pituitary-thyroid (HPT) axis genes. Moreover, the swimming activity of zebrafish larvae increased, which may be due to the increase of acetylcholinesterase (AChE) activity. Meanwhile, 2-MIB caused oxidative stress and apoptosis in zebrafish larvae by altering the NF-E2-related factor 2 (Nrf2) and mitochondrial signaling pathways, respectively. Transcriptome sequencing assay showed that the phototransduction signaling pathway was significantly enriched, and most of the genes in this pathway exhibited enhanced expression after exposure to 2-MIB. These findings provide an important reference for risk assessment and early warning to 2-MIB exposure.
ESTHER : Zhou_2021_J.Hazard.Mater_416_126142
PubMedSearch : Zhou_2021_J.Hazard.Mater_416_126142
PubMedID: 34492931

Title : Genomics-Driven Discovery of Phytotoxic Cytochalasans Involved in the Virulence of the Wheat Pathogen Parastagonospora nodorum - Li_2020_ACS.Chem.Biol_15_226
Author(s) : Li H , Wei H , Hu J , Lacey E , Sobolev AN , Stubbs KA , Solomon PS , Chooi YH
Ref : ACS Chemical Biology , 15 :226 , 2020
Abstract : The etiology of fungal pathogenesis of grains is critical to global food security. The large number of orphan biosynthetic gene clusters uncovered in fungal plant pathogen genome sequencing projects suggests that we have a significant knowledge gap about the secondary metabolite repertoires of these pathogens and their roles in plant pathogenesis. Cytochalasans are a family of natural products of significant interest due to their ability to bind to actin and interfere with cellular processes that involved actin polymerization; however, our understanding of their biosynthesis and biological roles remains incomplete. Here, we identified a putative polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) gene cluster (phm) that was upregulated in the pathogen Parastagonospora nodorum during its infection on wheat. Overexpression of the transcription factor gene phmR encoded in the phm gene cluster resulted in the production of two leucine-derived cytochalasans, phomacins D and E (1 and 2, respectively), and an acetonyl adduct phomacin F. Heterologous expression of the PKS-NRPS gene phmA and the trans-enoyl reductase (ER) gene phmE in Aspergillus nidulans resulted in the production of a novel 2-pyrrolidone precursor prephomacin. Reverse genetics and wheat seedling infection assays showed that deltaphmA mutants exhibited significantly reduced virulence compared to the wild type. We further demonstrated that both 1 and 2 showed potent actin polymerization-inhibitory activities and exhibited potentially monocot-specific antigerminative activities. The findings from this study have advanced our knowledge based on the biosynthesis and biological roles of cytochalasans, the latter of which could have significant implications for our understanding of the molecular mechanisms of fungus-plant interactions.
ESTHER : Li_2020_ACS.Chem.Biol_15_226
PubMedSearch : Li_2020_ACS.Chem.Biol_15_226
PubMedID: 31815421
Gene_locus related to this paper: phano-phmG

Title : The Effect of Protein FAM172A on Proliferation in HepG2 Cells and Investigation of the Possible Molecular Mechanism - Zhao_2019_Anal.Cell.Pathol.(Amst)_2019_5901083
Author(s) : Zhao H , Wang Y , Liu Y , Hao X , Wei H , Xie W
Ref : Anal Cell Pathol (Amst) , 2019 :5901083 , 2019
Abstract : BACKGROUND: In our previous study, we found that the FAM172A recombinant protein could promote proliferation of L02 cells. However, the underlying mechanisms are still unknown. The present study was aimed at investigating the effect of FAM172A on proliferation of HepG2 cells and exploring the possible molecular mechanisms and its role in hepatocellular carcinoma (HCC). METHODS: Cell proliferation was measured by MTT assay. Western blot test was carried out to investigate the mechanism. Rabbit antibodies against FAM172A and membrane proteins isolated from lysate of HepG2 cell were coprecipitated and the resultant precipitates were analyzed by mass spectrum. RESULTS: The MTT assay showed that recombinant protein FAM172A isoform 1 (FAM172A-1) could induce HepG2 cell proliferation at the concentration of 10-100 ng/mL, while protein FAM172A isoform 3 (FAM172A-3) was at the concentration of 80-100 ng/mL. Western blot demonstrated that both FAM172A-1 and FAM172A-3 could activate the mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) pathway and the phosphatidylinositol 3-kinase/threonine-protein kinase (PI3K/Akt) pathway. Mass spectrum analysis suggested that there were some membrane proteins interacting with FAM172A. Several candidate interacting proteins might mediate proliferation signals induced by FAM172A recombinant protein, including seven membrane proteins. CONCLUSION: In conclusion, FAM172A recombinant protein could induce proliferation of HepG2 cells, in which the MAPK/ERK and PI3K/Akt signaling pathways might be involved. The role of FAM172A in HepG2 cell proliferation also indicated its possible involvement in HCC. The receptor of FAM172A on cells still needs to be exploited.
ESTHER : Zhao_2019_Anal.Cell.Pathol.(Amst)_2019_5901083
PubMedSearch : Zhao_2019_Anal.Cell.Pathol.(Amst)_2019_5901083
PubMedID: 31915594
Gene_locus related to this paper: human-f172a

Title : Reengineering of Albumin-Fused Cocaine Hydrolase CocH1 (TV-1380) to Prolong Its Biological Half-Life - Cai_2019_AAPS.J_22_5
Author(s) : Cai Y , Zhou S , Jin Z , Wei H , Shang L , Deng J , Zhan CG , Zheng F
Ref : AAPS J , 22 :5 , 2019
Abstract : Therapeutic treatment of cocaine toxicity or addiction is a grand medical challenge. As a promising therapeutic strategy for treatment of cocaine toxicity and addiction to develop a highly efficient cocaine hydrolase (CocH) capable of accelerating cocaine metabolism to produce physiologically/biologically inactive metabolites, our previously designed A199S/S287G/A328W/Y332G mutant of human butyrylcholinesterase (BChE), known as cocaine hydrolase-1 (CocH1), possesses the desirably high catalytic activity against cocaine. The C-terminus of CocH1, truncated after amino acid #529, was fused to human serum albumin (HSA) to extend the biological half-life. The C-terminal HSA-fused CocH1 (CocH1-HSA), known as Albu-CocH1, Albu-CocH, AlbuBChE, Albu-BChE, or TV-1380 in literature, has shown favorable preclinical and clinical profiles. However, the actual therapeutic value of TV-1380 for cocaine addiction treatment is still limited by the short half-life. In this study, we designed and tested a new type of HSA-fused CocH1 proteins, i.e., N-terminal HSA-fused CocH1, with or without a linker between the HSA and CocH1 domains. It has been demonstrated that the catalytic activity of these new fusion proteins against cocaine is similar to that of TV-1380. However, HSA-CocH1 (without a linker) has a significantly longer biological half-life (t1/2 = 14 +/- 2 h) compared to the corresponding C-terminal HSA-fused CocH1, i.e., CocH1-HSA (TV-1380 with t1/2 = 5-8 h), in rats. Further, the N-terminal HSA-fused CocH1 proteins with a linker have further prolonged biological half-lives: t1/2 = 17 +/- 2 h for both HSA-EAAAK-CocH1 and HSA-PAPAP-CocH1, and t1/2 = 18 +/- 3 h for HSA-(PAPAP)2-CocH1. These N-terminal HSA-fused CocH1 proteins may serve as more promising protein drug candidates for cocaine addiction treatment.
ESTHER : Cai_2019_AAPS.J_22_5
PubMedSearch : Cai_2019_AAPS.J_22_5
PubMedID: 31754920

Title : Development of a long-acting Fc-fused cocaine hydrolase with improved yield of protein expression - Chen_2019_Chem.Biol.Interact_13ChEPon_306_89
Author(s) : Chen X , Deng J , Zheng X , Zhang J , Zhou Z , Wei H , Zhan CG , Zheng F
Ref : Chemico-Biological Interactions , 306 :89 , 2019
Abstract : Human butyrylcholinesterase (BChE) is known as a safe and effective protein for detoxification of organophosphorus (OP) nerve agents. Its rationally designed mutants with considerably improved catalytic activity against cocaine, known as cocaine hydrolases (CocHs), are recognized as the most promising drug candidates for the treatment of cocaine abuse. However, it is a grand challenge to efficiently produce active recombinant BChE and CocHs with a sufficiently long biological half-life. In the present study, starting from a promising CocH, known as CocH3 (i.e. A199S/F227A/S287G/A328W/Y332G mutant of human BChE), which has a approximately 2000-fold improved catalytic activity against cocaine compared to wild-type BChE, we designed an N-terminal fusion protein, Fc(M3)-(PAPAP)2-CocH3, which was constructed by fusing Fc of human IgG1 to the N-terminal of CocH3 and further optimized by inserting a linker between the two protein domains. Without lowering the enzyme activity, Fc(M3)-(PAPAP)2-CocH3 expressed in Chinese hamster ovary (CHO) cells has not only a long biological half-life of 105+/-7h in rats, but also a high yield of protein expression. Particularly, Fc(M3)-(PAPAP)2-CocH3 has a approximately 21-fold increased protein expression yield in CHO cells compared to CocH3 under the same experimental conditions. Given the observations that Fc(M3)-(PAPAP)2-CocH3 has not only a high catalytic activity against cocaine and a long biological half-life, but also a high yield of protein expression, this new protein entity reported in this study would be a more promising candidate for therapeutic treatment of cocaine overdose and addiction.
ESTHER : Chen_2019_Chem.Biol.Interact_13ChEPon_306_89
PubMedSearch : Chen_2019_Chem.Biol.Interact_13ChEPon_306_89
PubMedID: 30986387

Title : Maternal obesity aggravates the abnormality of porcine placenta by increasing N(6)-methyladenosine - Song_2018_Int.J.Obes.(Lond)_42_1812
Author(s) : Song T , Lu J , Deng Z , Xu T , Yang Y , Wei H , Li S , Jiang S , Peng J
Ref : Int J Obes (Lond) , 42 :1812 , 2018
Abstract : BACKGROUND: The growing prevalence of overweight or obese pregnancies shows an increasing risk for aberrant fetal growth and postnatal complications. Maternal obesity is associated with low birth weight (LBW) of piglets. However, the development of LBW from maternal obesity is not well understood. OBJECTIVE: This study attempts to investigate the novel RNA modification N6-methyladenosine (m(6)A) in the placenta tissues by using sows with high backfat thickness as a model for obese pregnancy. SUBJECTS/METHODS: Forty four placentas from eight sows (backfat thickness >/=21 mm) were divided into four groups by piglet weight, with group1 being LBW group (<1.0 kg), group2 (1.0-1.4 kg), group3 (1.4-1.6 kg), and group4 (>1.6 kg) as the comparative groups of normal birth weight. QPCR was used to measure the mRNA levels of the genes and western blot was used to test the content of proteins. At the same time, LC-MS/MS method was built to test the content of m(6)A modification in the placental RNA, and finally MeRIP-QPCR technology was employed to check the specific m(6)A modification in the key genes. RESULTS: Compared with the comparative groups, the expression levels of PPARgamma, VEGFA, ABHD5, and GPR120 in both mRNA and protein decreased noticeably in the LBW group. It was also observed that the density of the H&E stained vessels became attenuated in LBW group. Importantly, for the first time, the increased m(6)A levels were found in LBW placentas. Lower protein level of FTO (the key demethylase of m(6)A) was observed in LBW placentas, whereas no difference was found among the four groups in the expression levels of METTL3, the main methyltransferase of m(6)A. By using MeRIP-QPCR technology, the m(6)A modification in PPARgamma, VEGFA, ABHD5, and GPR120, as well as FTO, was considerably enhanced in the placentas from LBW group. CONCLUSION: We infer that in maternity obesity, the higher m(6)A modification displayed in the genes related to placental development, lipid metabolism and angiogenesis may result in the down regulation of these genes, which could be associated with m(6)A demethylase FTO.
ESTHER : Song_2018_Int.J.Obes.(Lond)_42_1812
PubMedSearch : Song_2018_Int.J.Obes.(Lond)_42_1812
PubMedID: 29795472

Title : Tacrine(10)-Hupyridone Prevents Post-operative Cognitive Dysfunction via the Activation of BDNF Pathway and the Inhibition of AChE in Aged Mice - Chen_2018_Front.Cell.Neurosci_12_396
Author(s) : Chen H , Wu X , Gu X , Zhou Y , Ye L , Zhang K , Pan H , Wang J , Wei H , Zhu B , Naman CB , Mak SH , Carlier PR , Cui W , Han YF
Ref : Front Cell Neurosci , 12 :396 , 2018
Abstract : Post-operative cognitive dysfunction (POCD) could cause short-term or long-term cognitive disruption lasting weeks or months after anesthesia and surgery in elderly. However, no effective treatment of POCD is currently available. Previous studies indicated that the enhancement of brain-derived neurotrophic factor (BDNF) expression, and the elevation the cholinergic system, might be effective to prevent POCD. In this study, we have discovered that tacrine(10)-hupyridone (A10E), a novel acetylcholinesterase (AChE) inhibitor derived from tacrine and huperzine A, could prevent surgery-induced short-term and long-term impairments of recognition and spatial cognition, as evidenced by the novel object recognition test and Morris water maze (MWM) tests, in aged mice. Moreover, A10E significantly increased the expression of BDNF and activated the downstream Akt and extracellular regulated kinase (ERK) signaling in the surgery-treated mice. Furthermore, A10E substantially enhanced choline acetyltransferase (ChAT)-positive area and decreased AChE activity, in the hippocampus regions of surgery-treated mice, indicating that A10E could prevent surgery-induced dysfunction of cholinergic system, possibly via increasing the synthesis of acetylcholine and the inhibition of AChE. In conclusion, our results suggested that A10E might prevent POCD via the activation of BDNF pathway and the inhibition of AChE, concurrently, in aged mice. These findings also provided a support that A10E might be developed as a potential drug lead for POCD.
ESTHER : Chen_2018_Front.Cell.Neurosci_12_396
PubMedSearch : Chen_2018_Front.Cell.Neurosci_12_396
PubMedID: 30483056

Title : A pH responsive AIE probe for enzyme assays - Shi_2018_Analyst_143_741
Author(s) : Shi L , Liu Y , Wang Q , Wang T , Ding Y , Cao Y , Li Z , Wei H
Ref : Analyst , 143 :741 , 2018
Abstract : By combining leucine (Leu) and tetraphenylethene (TPE), a pH-sensitive aggregation induced emission (AIE) probe TPE-Leu was developed. The aliphatic amine in TPE-Leu was more easily protonated under acidic conditions, which made TPE-Leu more water soluble. Therefore, the protonated AIE probe showed weak fluorescence under acidic conditions. When the pH was changed to basic conditions, it showed strong fluorescence due to the hydrophobic nature of TPE-Leu. We demonstrated that the probe showed high selectivity toward pH changes with the coexistence of other potential species such as metal ions, redox agents, and biomolecules. In contrast, TPE-NH2 did not exhibit obvious pH-sensitive properties. Moreover, TPE-Leu was further utilized to develop a sensitive and selective sensing platform for urease and acetylcholinesterase (AChE) detection. The current study not only provides a new strategy for designing pH-sensitive fluorescent probes for bioassays but also broadens the applications of AIE probes.
ESTHER : Shi_2018_Analyst_143_741
PubMedSearch : Shi_2018_Analyst_143_741
PubMedID: 29323362

Title : A new method to characterize the kinetics of cholinesterases inhibited by carbamates - Xiao_2017_J.Pharm.Biomed.Anal_144_175
Author(s) : Xiao Q , Zhou H , Wei H , Du H , Tan W , Zhan Y , Pistolozzi M
Ref : J Pharm Biomed Anal , 144 :175 , 2017
Abstract : The inhibition of cholinesterases (ChEs) by carbamates includes a carbamylation (inhibition) step, in which the drug transfers its carbamate moiety to the active site of the enzyme and a decarbamylation (activity recovery) step, in which the carbamyl group is hydrolyzed from the enzyme. The carbamylation and decarbamylation kinetics decide the extent and the duration of the inhibition, thus the full characterization of candidate carbamate inhibitors requires the measurement of the kinetic constants describing both steps. Carbamylation and decarbamylation rate constants are traditionally measured by two separate set of experiments, thus making the full characterization of candidate inhibitors time-consuming. In this communication we show that by the analysis of the area under the inhibition-time curve of cholinesterases inhibited by carbamates it is possible to calculate the decarbamylation rate constant from the same data traditionally used to characterize only the carbamylation kinetics, therefore it is possible to obtain a full characterization of the inhibition with a single set of experiments. The characterization of the inhibition kinetics of human and dog plasma butyrylcholinesterase and of human acetylcholinesterase by bambuterol and bambuterol monocarbamate enantiomers was used to demonstrate the validity of the approach. The results showed that the proposed method provides reliable estimations of carbamylation and decarbamylation rate constants thus representing a simple and useful approach to reduce the time required for the characterization of carbamate inhibitors.
ESTHER : Xiao_2017_J.Pharm.Biomed.Anal_144_175
PubMedSearch : Xiao_2017_J.Pharm.Biomed.Anal_144_175
PubMedID: 28483282

Title : Design, synthesis, and evaluation of multitarget-directed ligands against Alzheimer's disease based on the fusion of donepezil and curcumin - Yan_2017_Bioorg.Med.Chem_25_2946
Author(s) : Yan J , Hu J , Liu A , He L , Li X , Wei H
Ref : Bioorganic & Medicinal Chemistry , 25 :2946 , 2017
Abstract : By fusing donepezil and curcumin, a novel series of compounds were obtained as multitarget-directed ligands against Alzheimer's disease. Among them, compound 11b displayed potent acetylcholinesterase (AChE) inhibition (IC50=187nM) and the highest BuChE/AChE selectivity (66.3). Compound 11b also inhibited 45.3% Abeta1-42 self-aggregation at 20muM and displayed remarkable antioxidant effects. The metal-chelating property of compound 11b was elucidated by determining the 1:1 stoichiometry for the 11b-Cu(II) complex. The excellent blood-brain barrier permeability of 11b also indicated the potential for the compound to penetrate the central nervous system.
ESTHER : Yan_2017_Bioorg.Med.Chem_25_2946
PubMedSearch : Yan_2017_Bioorg.Med.Chem_25_2946
PubMedID: 28454848

Title : Stereoselective inhibition of human butyrylcholinesterase by the enantiomers of bambuterol and their intermediates - Pistolozzi_2015_Drug.Metab.Dispos_43_344
Author(s) : Pistolozzi M , Du H , Wei H , Tan W
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 43 :344 , 2015
Abstract : This work describes the sequential hydrolysis of bambuterol enantiomers and their monocarbamate metabolites (MONO) catalyzed by human butyrylcholinesterase (BChE) as well as the enzyme inhibition resulting from this process. Particular emphasis is given to the contribution given by MONO to the enzyme inhibition because it was not fully characterized in previous works. Bambuterol and MONO enantiomers displayed the same time- and concentration-dependent mechanism of interaction with the enzyme. The hydrolysis kinetics of both bambuterol and MONO was enantioselective, and the (R)-enantiomer of each compound was hydrolyzed fourfold faster than the respective (S)-enantiomer. Even though the enzyme inhibition rates of (R)- and (S)-MONO were much slower than those of their respective bambuterol enantiomers ( approximately 15-fold), both MONO enantiomers showed a significant BChE inhibition when physiologically relevant concentrations of enzyme and inhibitors were used ( approximately 50% of their respective bambuterol enantiomers). The kinetic constants obtained by testing each single compound were used to model the contribution given by MONO to the enzyme inhibition observed for bambuterol. The hydrolysis of MONO enantiomers enhanced the inhibitory power of bambuterol enantiomers of about 27.5% (R) and 12.5% (S) and extended more than 1 hour the duration of inhibition. The data indicate that MONO contribute significantly to the inhibition of BChE occurring in humans upon administration of normal doses of bambuterol. In addition, the hydrolysis of MONO resulted in the rate-limiting step in the conversion of bambuterol in its pharmacologically active metabolite terbutaline; therefore, MONO concentrations should always be monitored during pharmacokinetic studies of bambuterol.
ESTHER : Pistolozzi_2015_Drug.Metab.Dispos_43_344
PubMedSearch : Pistolozzi_2015_Drug.Metab.Dispos_43_344
PubMedID: 25504505

Title : Genome sequence of cultivated Upland cotton (Gossypium hirsutum TM-1) provides insights into genome evolution - Li_2015_Nat.Biotechnol_33_524
Author(s) : Li F , Fan G , Lu C , Xiao G , Zou C , Kohel RJ , Ma Z , Shang H , Ma X , Wu J , Liang X , Huang G , Percy RG , Liu K , Yang W , Chen W , Du X , Shi C , Yuan Y , Ye W , Liu X , Zhang X , Liu W , Wei H , Wei S , Zhu S , Zhang H , Sun F , Wang X , Liang J , Wang J , He Q , Huang L , Cui J , Song G , Wang K , Xu X , Yu JZ , Zhu Y , Yu S
Ref : Nat Biotechnol , 33 :524 , 2015
Abstract : Gossypium hirsutum has proven difficult to sequence owing to its complex allotetraploid (AtDt) genome. Here we produce a draft genome using 181-fold paired-end sequences assisted by fivefold BAC-to-BAC sequences and a high-resolution genetic map. In our assembly 88.5% of the 2,173-Mb scaffolds, which cover 89.6% approximately 96.7% of the AtDt genome, are anchored and oriented to 26 pseudochromosomes. Comparison of this G. hirsutum AtDt genome with the already sequenced diploid Gossypium arboreum (AA) and Gossypium raimondii (DD) genomes revealed conserved gene order. Repeated sequences account for 67.2% of the AtDt genome, and transposable elements (TEs) originating from Dt seem more active than from At. Reduction in the AtDt genome size occurred after allopolyploidization. The A or At genome may have undergone positive selection for fiber traits. Concerted evolution of different regulatory mechanisms for Cellulose synthase (CesA) and 1-Aminocyclopropane-1-carboxylic acid oxidase1 and 3 (ACO1,3) may be important for enhanced fiber production in G. hirsutum.
ESTHER : Li_2015_Nat.Biotechnol_33_524
PubMedSearch : Li_2015_Nat.Biotechnol_33_524
PubMedID: 25893780
Gene_locus related to this paper: gosra-a0a0d2rxs2 , gosra-a0a0d2tng2 , gosra-a0a0d2twz7 , goshi-a0a1u8hr03 , gosra-a0a0d2vdc5 , goshi-a0a1u8ljh5 , gosra-a0a0d2vj24 , goshi-a0a1u8pxd3 , gosra-a0a0d2sr31 , goshi-a0a1u8knd1 , goshi-a0a1u8nhw9 , goshi-a0a1u8mt09 , goshi-a0a1u8kis4 , goshi-a0a1u8ibk3 , goshi-a0a1u8ieg2 , goshi-a0a1u8iki6 , goshi-a0a1u8jvp4 , goshi-a0a1u8jw35 , gosra-a0a0d2pzd7 , goshi-a0a1u8ied7

Title : Tacrine-propargylamine derivatives with improved acetylcholinesterase inhibitory activity and lower hepatotoxicity as a potential lead compound for the treatment of Alzheimer's disease - Mao_2015_J.Enzyme.Inhib.Med.Chem_30_995
Author(s) : Mao F , Li J , Wei H , Huang L , Li X
Ref : J Enzyme Inhib Med Chem , 30 :995 , 2015
Abstract : A series of tacrine-propargylamine derivatives were synthesised and evaluated as possible anti-Alzheimer's disease (AD) agents. Among these derivatives, compounds 3a and 3b exhibited superior activities and a favourable balance of AChE and BuChE activities (3a: IC50 values of 51.3 and 77.6 nM; 3b: IC50 values of 11.2 and 83.5 nM). Compounds 3a and 3b also exhibited increased hAChE inhibitory activity compared with tacrine by approximately 5- and 28-fold, respectively, and low neurotoxicity. Importantly, these compounds also had lower hepatotoxicity than tacrine. Based on these results, compounds 3a and 3b could be considered as potential lead compounds for the treatment of AD and other AChE related diseases, such as schizophrenia, glaucoma and myasthenia gravis.
ESTHER : Mao_2015_J.Enzyme.Inhib.Med.Chem_30_995
PubMedSearch : Mao_2015_J.Enzyme.Inhib.Med.Chem_30_995
PubMedID: 25792506

Title : Validation of a high-throughput, automated electrophysiology platform for the screening of nicotinic agonists and antagonists - Graef_2013_J.Biomol.Screen_18_116
Author(s) : Graef JD , Benson LC , Sidach SS , Wei H , Lippiello PM , Bencherif M , Fedorov NB
Ref : J Biomol Screen , 18 :116 , 2013
Abstract : High-throughput compound screening using electrophysiology-based assays represents an important tool for biomedical research and drug discovery programs. The recent development and availability of devices capable of performing high-throughput electrophysiology-based screening have brought the need to validate these tools by producing data that are consistent with results obtained with conventional electrophysiological methods. In this study, we compared the response properties of halpha3beta4 and halpha4beta2 nicotinic receptors to their endogenous ligand acetylcholine (ACh) using three separate electrophysiology platforms: Dynaflow (low-throughput, manual system), PatchXpress 7000A (medium-throughput automated platform), and IonWorks Barracuda (high-throughput automated platform). We found that despite the differences in methodological approaches between these technologies, the EC(50) values from the ACh dose-response curves were consistent between all three platforms. In addition, we have validated the IonWorks Barracuda for both competitive and uncompetitive inhibition assays by using the competitive nicotinic antagonist dihydro-beta-erythroidin (DHbetaE) and uncompetitive nicotinic antagonist mecamylamine. Furthermore, we have demonstrated the utility of a custom-written algorithm for generating dose-response curves from multiple extrapolated current metrics that allows for discriminating between competitive and uncompetitive inhibition while maintaining high-throughput capacity. This study provides validation of the consistency of results using low-, medium-, and high-throughput electrophysiology platforms and supports their use for screening nicotinic compounds.
ESTHER : Graef_2013_J.Biomol.Screen_18_116
PubMedSearch : Graef_2013_J.Biomol.Screen_18_116
PubMedID: 22960782

Title : Construction of an ZEN-jjm expressing vector and its expression in Pichia pastoris. - Tan_2010_Zhongguo.Wei.Sheng.Tai.Xue.Za.Zhi_22_1061
Author(s) : Tan QL , Xu F , Li P , Cheng BC , Luo J , Wei H
Ref : Zhongguo Wei Sheng Tai Xue Za Zhi , 22 :1061 , 2010
Abstract : Objective: To construct an Pichia pastoris expressing vector pPIC9-ZEN-jjm and screen the strains which could express high-level active proteins. Method: ZEN-jjm gene was spliced into pPIC9 after digested with EcoR I and Not I, then transformed into Pichia pastoris GS115 by electroporation. The recombinant yeast strains were screened with RDB medium and methanol inducible expression. The ZEN degradation capabilities of expressed supernatant was verified by HPLC test. Result: DNA sequencing demonstrated that ZEN-jjm was inserted into pPIC9. SDS-PAGE demonstrated that one yeast strain with high-level expression was obtained, and the molecular weight of the expressed protein was about 29 kDa. The HPLC result showed that the expressed protein could effectively degrade ZEN. Conclusion: ZEN-degrading enzyme is highly expressed in Pichia pastoris.
ESTHER : Tan_2010_Zhongguo.Wei.Sheng.Tai.Xue.Za.Zhi_22_1061
PubMedSearch : Tan_2010_Zhongguo.Wei.Sheng.Tai.Xue.Za.Zhi_22_1061
PubMedID:
Gene_locus related to this paper: biooc-ZHD101

Title : ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones - Wei_2008_Hum.Mol.Genet_17_469
Author(s) : Wei H , Kim SJ , Zhang Z , Tsai PC , Wisniewski KE , Mukherjee AB
Ref : Hum Mol Genet , 17 :469 , 2008
Abstract : It is estimated that more than 40 different lysosomal storage disorders (LSDs) cumulatively affect one in 5000 live births, and in the majority of the LSDs, neurodegeneration is a prominent feature. Neuronal ceroid lipofuscinoses (NCLs), as a group, represent one of the most common (one in 12,500 births) neurodegenerative LSDs. The infantile NCL (INCL) is the most devastating neurodegenerative LSD, which is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. We previously reported that neuronal death by apoptosis in INCL, and in the PPT1-knockout (PPT1-KO) mice that mimic INCL, is at least in part caused by endoplasmic reticulum (ER) and oxidative stresses. In the present study, we sought to determine whether ER and oxidative stresses are unique manifestations of INCL or they are common to both neurodegenerative and non-neurodegenerative LSDs. Unexpectedly, we found that ER and oxidative stresses are common manifestations in cells from both neurodegenerative and non-neurodegenerative LSDs. Moreover, all LSD cells studied show extraordinary sensitivity to brefeldin-A-induced apoptosis, which suggests pre-existing ER stress conditions. Further, we uncovered that chemical disruption of lysosomal homeostasis in normal cells causes ER stress, suggesting a cross-talk between the lysosomes and the ER. Most importantly, we found that chemical chaperones that alleviate ER and oxidative stresses are also cytoprotective in all forms of LSDs studied. We propose that ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative LSDs and suggest that the beneficial effects of chemical/pharmacological chaperones are exerted, at least in part, by alleviating these stress conditions.
ESTHER : Wei_2008_Hum.Mol.Genet_17_469
PubMedSearch : Wei_2008_Hum.Mol.Genet_17_469
PubMedID: 17989065

Title : Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration - Zhang_2007_Hum.Mol.Genet_16_837
Author(s) : Zhang Z , Lee YC , Kim SJ , Choi MS , Tsai PC , Saha A , Wei H , Xu Y , Xiao YJ , Zhang P , Heffer A , Mukherjee AB
Ref : Hum Mol Genet , 16 :837 , 2007
Abstract : In the majority of neurodegenerative storage disorders, neuronal death in the brain is followed by infiltration of phagocytic cells (e.g. activated microglia, astroglia and macrophages) for the efficient removal of cell corpses. However, it is increasingly evident that these phagocytes may also cause death of adjoining viable neurons contributing to rapid progression of neurodegeneration. Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating, neurodegenerative, lysosomal storage disorder caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 catalyzes the cleavage of thioester linkages in S-acylated (palmitoylated) proteins and its deficiency leads to abnormal accumulation of thioesterified polypeptides (ceroid) in lysosomes causing INCL pathogenesis. PPT1-knockout (PPT1-KO) mice mimic the clinical and pathological features of human INCL including rapid neuronal death by apoptosis and phagocyte infiltration. We previously reported that in PPT1-KO mice, the neurons undergo endoplasmic reticulum stress activating unfolded protein response, which mediates caspase-12 activation and apoptosis. However, the molecular mechanism(s) by which the phagocytic cells are recruited in the PPT1-KO mouse brain remains poorly understood. We report here that increased production of lysophosphatidylcholine (LPC), catalyzed by the activation of cytosolic phospholipase A(2) (cPLA(2)) in the PPT1-KO mouse brain, is a 'lipid signal' for phagocyte recruitment. We also report that an age-dependent increase in LPC levels in the PPT1-KO mouse brain positively correlates with elevated expression of the genes characteristically associated with phagocytes. We propose that increased cPLA(2)-catalyzed LPC production in the brain is at least one of the mechanisms that mediate phagocyte infiltration contributing to INCL neuropathology.
ESTHER : Zhang_2007_Hum.Mol.Genet_16_837
PubMedSearch : Zhang_2007_Hum.Mol.Genet_16_837
PubMedID: 17341491
Gene_locus related to this paper: mouse-ppt

Title : The Genomes of Oryza sativa: a history of duplications - Yu_2005_PLoS.Biol_3_e38
Author(s) : Yu J , Wang J , Lin W , Li S , Li H , Zhou J , Ni P , Dong W , Hu S , Zeng C , Zhang J , Zhang Y , Li R , Xu Z , Li X , Zheng H , Cong L , Lin L , Yin J , Geng J , Li G , Shi J , Liu J , Lv H , Li J , Deng Y , Ran L , Shi X , Wang X , Wu Q , Li C , Ren X , Li D , Liu D , Zhang X , Ji Z , Zhao W , Sun Y , Zhang Z , Bao J , Han Y , Dong L , Ji J , Chen P , Wu S , Xiao Y , Bu D , Tan J , Yang L , Ye C , Xu J , Zhou Y , Yu Y , Zhang B , Zhuang S , Wei H , Liu B , Lei M , Yu H , Li Y , Xu H , Wei S , He X , Fang L , Huang X , Su Z , Tong W , Tong Z , Ye J , Wang L , Lei T , Chen C , Chen H , Huang H , Zhang F , Li N , Zhao C , Huang Y , Li L , Xi Y , Qi Q , Li W , Hu W , Tian X , Jiao Y , Liang X , Jin J , Gao L , Zheng W , Hao B , Liu S , Wang W , Yuan L , Cao M , McDermott J , Samudrala R , Wong GK , Yang H
Ref : PLoS Biol , 3 :e38 , 2005
Abstract : We report improved whole-genome shotgun sequences for the genomes of indica and japonica rice, both with multimegabase contiguity, or almost 1,000-fold improvement over the drafts of 2002. Tested against a nonredundant collection of 19,079 full-length cDNAs, 97.7% of the genes are aligned, without fragmentation, to the mapped super-scaffolds of one or the other genome. We introduce a gene identification procedure for plants that does not rely on similarity to known genes to remove erroneous predictions resulting from transposable elements. Using the available EST data to adjust for residual errors in the predictions, the estimated gene count is at least 38,000-40,000. Only 2%-3% of the genes are unique to any one subspecies, comparable to the amount of sequence that might still be missing. Despite this lack of variation in gene content, there is enormous variation in the intergenic regions. At least a quarter of the two sequences could not be aligned, and where they could be aligned, single nucleotide polymorphism (SNP) rates varied from as little as 3.0 SNP/kb in the coding regions to 27.6 SNP/kb in the transposable elements. A more inclusive new approach for analyzing duplication history is introduced here. It reveals an ancient whole-genome duplication, a recent segmental duplication on Chromosomes 11 and 12, and massive ongoing individual gene duplications. We find 18 distinct pairs of duplicated segments that cover 65.7% of the genome; 17 of these pairs date back to a common time before the divergence of the grasses. More important, ongoing individual gene duplications provide a never-ending source of raw material for gene genesis and are major contributors to the differences between members of the grass family.
ESTHER : Yu_2005_PLoS.Biol_3_e38
PubMedSearch : Yu_2005_PLoS.Biol_3_e38
PubMedID: 15685292
Gene_locus related to this paper: orysa-Q7XTC5 , orysa-Q852M6 , orysa-Q8GSE8 , orysa-Q9S7P1 , orysa-Q9FYP7 , orysa-Q5ZBH3 , orysa-Q5ZA26 , orysa-Q5JLP6 , orysa-Q8H5P9 , orysa-Q8H5P5 , orysa-Q7F1Y5 , orysa-Q949C9 , orysa-cbp1 , orysa-cbp3 , orysa-cbpx , orysa-Q33B71 , orysa-Q8GSJ3 , orysa-LPL1 , orysa-Q6YSZ8 , orysa-Q8S5X5 , orysa-Q8LIG3 , orysa-Q6K7F5 , orysa-Q7F1B1 , orysa-Q8H4S9 , orysa-Q69UB1 , orysa-Q9FW17 , orysa-Q337C3 , orysa-Q7F959 , orysa-Q84QZ6 , orysa-Q84QY7 , orysa-Q851E3 , orysa-Q6YTH5 , orysa-Q0JK71 , orysa-Q8S1D9 , orysa-Q5N8V4 , orysa-Q0JCY4 , orysa-Q8GTK2 , orysa-B9EWJ8 , orysa-Q8H3K6 , orysa-Q6ZDG8 , orysa-Q6ZDG6 , orysa-Q6ZDG5 , orysa-Q6ZDG4 , orysa-Q5NAI4 , orysa-Q658B2 , orysa-Q5JMQ8 , orysa-Q5QMD9 , orysa-Q5N7L1 , orysa-Q8RYV9 , orysa-Q8H3R3 , orysa-Q5SNH3 , orysa-Q8W0F0 , orysa-pir7a , orysa-pir7b , orysa-q2qlm4 , orysa-q2qm78 , orysa-q2qm82 , orysa-q2qn31 , orysa-q2qnj4 , orysa-q2qnt9 , orysa-q2qur1 , orysa-q2qx94 , orysa-q2qyi1 , orysa-q2qyj1 , orysa-q2r051 , orysa-q2r077 , orysa-q2ram0 , orysa-q2rat1 , orysa-q2rbb3 , orysa-Q4VWY7 , orysa-q5na00 , orysa-q5nbu1 , orysa-Q5QLC0 , orysa-q5smv5 , orysa-Q5VP27 , orysa-q5vrt2 , orysa-q5w6c5 , orysa-q5z5a3 , orysa-q5z9i2 , orysa-q5z417 , orysa-q5z901 , orysa-Q5ZAM8 , orysa-Q5ZBI5 , orysa-Q5ZCR3 , orysa-q6atz0 , orysa-q6ave2 , orysa-q6f358 , orysa-q6h6s1 , orysa-q6h7i6 , orysa-q6i5q3 , orysa-q6i5u7 , orysa-q6j657 , orysa-q6k3d9 , orysa-q6k4q2 , orysa-q6k880 , orysa-q6l5b6 , orysa-Q6L5F5 , orysa-q6l556 , orysj-q6yse8 , orysa-q6yy42 , orysa-q6yzk1 , orysa-q6z8b1 , orysa-q6z995 , orysa-q6zc62 , orysa-q6zia4 , orysa-q6zjq6 , orysa-q7x7y5 , orysa-Q7XC50 , orysa-q7xej4 , orysa-q7xem8 , orysa-q7xkj9 , orysa-q7xr62 , orysa-q7xr63 , orysa-q7xr64 , orysa-q7xsg1 , orysa-q7xsq2 , orysa-q7xts6 , orysa-q7xv53 , orysa-Q7XVB5 , orysa-Q8L562 , orysa-Q8LQS5 , orysa-Q8RZ40 , orysa-Q8RZ79 , orysa-Q8S0U8 , orysa-Q8S0V0 , orysa-Q8S125 , orysa-Q8SAY7 , orysa-Q8SAY9 , orysa-Q8W3C6 , orysa-Q8W3F2 , orysa-Q8W3F4 , orysa-Q8W3F6 , orysa-Q9LHX5 , orysa-q33aq0 , orysa-q53lh1 , orysa-q53m20 , orysa-q53nd8 , orysa-q60e79 , orysa-q60ew8 , orysa-q67iz2 , orysa-q67iz3 , orysa-q67iz7 , orysa-q67iz8 , orysa-q67j02 , orysa-q67j05 , orysa-q67j07 , orysa-q67j09 , orysa-q67j10 , orysa-q67tr6 , orysa-q67tv0 , orysa-q67uz1 , orysa-q67v34 , orysa-q67wz5 , orysa-q69j38 , orysa-q69k08 , orysa-q69md7 , orysa-q69me0 , orysa-q69pf3 , orysa-q69ti3 , orysa-q69xr2 , orysa-q69y12 , orysa-q69y21 , orysa-q75hy2 , orysa-q75i01 , orysa-Q94JD7 , orysa-Q0J0A4 , orysa-q651a8 , orysa-q651z3 , orysa-q652g4 , orysa-q688m0 , orysa-q688m8 , orysa-q688m9 , orysa-Q6H8G1 , orysi-a2wn01 , orysi-a2xc83 , orysi-a2yh83 , orysi-a2z179 , orysi-a2zef2 , orysi-b8a7e6 , orysi-b8a7e7 , orysi-b8bfe5 , orysi-b8bhp9 , orysj-a3b9l8 , orysj-b9eub8 , orysj-b9eya5 , orysj-b9fi05 , orysj-b9fkb0 , orysj-b9fn42 , orysj-b9gbb7 , orysj-cgep , orysj-PLA7 , orysj-q0d4u5 , orysj-q0djj0 , orysj-q0jaf0 , orysj-q5jl22 , orysj-q5jlw7 , orysj-q5z419 , orysj-q6h7q9 , orysj-q6yvk6 , orysj-q6z6i1 , orysj-q7f8x1 , orysj-q7xcx3 , orysj-q9fwm6 , orysj-q10j20 , orysj-q10ss2 , orysj-q69uw6 , orysj-q94d71 , orysj-q338c0 , orysi-b8bly4 , orysj-b9gbs4 , orysi-a2zb88 , orysj-b9gbs1 , orysi-b8b698 , orysj-pla4 , orysj-pla1

Title : Pyridoacridine Alkaloids Inducing Neuronal Differentiation in a Neuroblastoma Cell Line, from Marine Sponge Biemna fortis - Aoki_2003_Bioorg.Med.Chem_11_1969
Author(s) : Aoki S , Wei H , Matsui K , Rachmat R , Kobayashi M
Ref : Bioorganic & Medicinal Chemistry , 11 :1969 , 2003
Abstract : A new and three known pyridoacridine alkaloids were isolated from the Indonesian marine sponge Biemna fortis as neuronal differentiation inducers against a murine neuroblastoma cell line, Neuro 2A. The chemical structure of the new compound, labuanine A (1), was determined by spectroscopic study and chemical conversion. These pyridoacridine alkaloids induced multipolar neuritogenesis in more than 50% of cells at 0.03-3 micro M concentration. Compound 3, which showed the strongest neuritogenic activity among them, also induced increase of acetylcholinesterase, a neuronal marker in Neuro 2A and arrested cell cycle at the G2/M phase.
ESTHER : Aoki_2003_Bioorg.Med.Chem_11_1969
PubMedSearch : Aoki_2003_Bioorg.Med.Chem_11_1969
PubMedID: 12670647

Title : Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family - Qu_2002_Mol.Cell.Biochem_229_35
Author(s) : Qu X , Zhai Y , Wei H , Zhang C , Xing G , Yu Y , He F
Ref : Molecular & Cellular Biochemistry , 229 :35 , 2002
Abstract : NDRG1 (N-Myc downstream regulated) is upregulated during cell differentiation, repressed by N-myc and c-myc in embryonic cells, and suppressed in several tumor cells. A nonsense mutation in the NDRG1 gene has been reported to be causative for hereditary motor and sensory neuropathy-Lom (HMSNL), indicating that NDRG1 functions in the peripheral nervous system necessary for axonal survival. Here, we cloned three human cDNAs encoding NDRG2 (371aa), NDRG3 (375aa) and NDRG4 (339aa), which are homologous to NDRG1. These three genes, together with NDRG1, constitute the NDRG gene family. The phylogenetic analysis of the family demonstrated that human NDRG1 and NDRG3 belong to a subfamily, and NDRG2 and NDRG4 to another. At amino acid (aa) level, the four members share 53-65% identity. Each of the four proteins contains an alpha/beta hydrolase fold as in human lysosomal acid lipase. Expression of the fusion proteins NDRG2/GFP, NDRG3/GFP and NDRG4/GFP in COS-7 cells showed that all of them are cytosolic proteins. Based on UniGene cluster analysis, the genes NDRG2, NDRG3 and NDRG4 are located at chromosome 14q11.1-11.2, 20q12-11.23 and 16q21-22.1, respectively. Northern and dot blot analysis shows that all of the three genes are highly expressed in adult brain and almost not detected in the eight human cancer lines. In addition, in contrast to the relatively ubiquitous expression of NDRG1, NDRG2 is highly expressed in adult skeletal muscle and brain, NDRG3 highly expressed in brain and testis, and NDRG4 specifically expressed in brain and heart, suggesting that they might display different specific functions in distinct tissues.
ESTHER : Qu_2002_Mol.Cell.Biochem_229_35
PubMedSearch : Qu_2002_Mol.Cell.Biochem_229_35
PubMedID: 11936845
Gene_locus related to this paper: human-NDRG1 , human-NDRG2 , human-NDRG3 , human-NDRG4

Title : Carboxymethylation of the PP2A catalytic subunit in Saccharomyces cerevisiae is required for efficient interaction with the B-type subunits Cdc55p and Rts1p - Wei_2001_J.Biol.Chem_276_1570
Author(s) : Wei H , Ashby DG , Moreno CS , Ogris E , Yeong FM , Corbett AH , Pallas DC
Ref : Journal of Biological Chemistry , 276 :1570 , 2001
Abstract : Protein phosphatase 2A (PP2A) is an essential eukaryotic serine/threonine phosphatase known to play important roles in cell cycle regulation. Association of different B-type targeting subunits with the heterodimeric core (A/C) enzyme is known to be an important mechanism of regulating PP2A activity, substrate specificity, and localization. However, how the binding of these targeting subunits to the A/C heterodimer might be regulated is unknown. We have used the budding yeast Saccharomyces cerevisiae as a model system to investigate the hypothesis that covalent modification of the C subunit (Pph21p/Pph22p) carboxyl terminus modulates PP2A complex formation. Two approaches were taken. First, S. cerevisiae cells were generated whose survival depended on the expression of different carboxyl-terminal Pph21p mutants. Second, the major S. cerevisiae methyltransferase (Ppm1p) that catalyzes the methylation of the PP2A C subunit carboxyl-terminal leucine was identified, and cells deleted for this methyltransferase were utilized for our studies. Our results demonstrate that binding of the yeast B subunit, Cdc55p, to Pph21p was disrupted by either acidic substitution of potential carboxyl-terminal phosphorylation sites on Pph21p or by deletion of the gene for Ppm1p. Loss of Cdc55p association was accompanied in each case by a large reduction in binding of the yeast A subunit, Tpd3p, to Pph21p. Moreover, decreased Cdc55p and Tpd3p binding invariably resulted in nocodazole sensitivity, a known phenotype of CDC55 or TPD3 deletion. Furthermore, loss of methylation also greatly reduced the association of another yeast B-type subunit, Rts1p. Thus, methylation of Pph21p is important for formation of PP2A trimeric and dimeric complexes, and consequently, for PP2A function. Taken together, our results indicate that methylation and phosphorylation may be mechanisms by which the cell dynamically regulates PP2A complex formation and function.
ESTHER : Wei_2001_J.Biol.Chem_276_1570
PubMedSearch : Wei_2001_J.Biol.Chem_276_1570
PubMedID: 11038366