Han X

References (45)

Title : Adipose Triglyceride Lipase Deficiency Aggravates Angiotensin II-Induced Atrial Fibrillation by Reducing Peroxisome Proliferator-Activated Receptor alpha Activation in Mice - Han_2023_Lab.Invest_103_100004
Author(s) : Han X , Zhang YL , Zhao YX , Guo SB , Yin WP , Li HH
Ref : Lab Invest , 103 :100004 , 2023
Abstract : Atrial fibrillation (AF) is a main risk factor for cerebrovascular diseases but lacks precision therapy. Adipose triglyceride lipase (ATGL) is a key enzyme involved in the intracellular degradation of triacylglycerol and plays an important role in lipid and energy metabolism. However, the role of ATGL in the regulation of AF remains unclear. In this study, AF was induced by infusion of angiotensin II (Ang II, 2000 ng/kg/min) for 3 weeks in male ATGL knockout (KO) mice and age-matched C57BL/6 wild-type mice. The atrial volume was measured by echocardiography. Atrial fibrosis, inflammatory cells, and superoxide production were detected by histologic examinations. The results showed that ATGL expression was significantly downregulated in the atrial tissue of the Ang II-infused mice. Moreover, Ang II-induced increase in the inducibility and duration of AF, atrial dilation, fibrosis, inflammation, and oxidative stress in wild-type mice were markedly accelerated in ATGL KO mice; however, these effects were dramatically reversed in the ATGL KO mice administered with peroxisome proliferator-activated receptor (PPAR)-alpha agonist clofibric acid. Mechanistically, Ang II downregulated ATGL expression and inhibited PPAR-alpha activity, activated multiple signaling pathways (inhibiting kappa B kinase alpha/beta-nuclear factor-kappaB, nicotinamide adenine dinucleotide phosphate oxidase, and transforming growth factor-beta1/SMAD2/3) and reducing Kv1.5, Cx40, and Cx43 expression, thereby contributing to atrial structural and electrical remodeling and subsequent AF. In summary, our results indicate that ATGL KO enhances AF inducibility, possibly through inhibiting PPAR-alpha activation and suggest that activating ATGL might be a new therapeutic option for treating hypertensive AF.
ESTHER : Han_2023_Lab.Invest_103_100004
PubMedSearch : Han_2023_Lab.Invest_103_100004
PubMedID: 36748188

Title : Visual and Rapid Detection of Nerve Agent Mimics in Gas and Solution Phase by a Simple Fluorescent Probe - Chen_2023_Anal.Chem__
Author(s) : Chen Q , Liu J , Liu S , Zhang J , He L , Liu R , Jiang H , Han X , Zhang K
Ref : Analytical Chemistry , : , 2023
Abstract : Chemical nerve agents are highly toxic organophosphorus compounds that are easy to obtain and can be utilized by terrorists to threaten homeland security and human safety. Those organophosphorus nerve agents contain nucleophilic ability that can react with acetylcholinesterase leading to muscular paralysis and human death. Therefore, there is great importance to explore a reliable and simple method to detect chemical nerve agents. Herein, the o-phenylenediamine-linked dansyl chloride as a colorimetric and fluorescent probe has been prepared to detect specific chemical nerve agent stimulants in the solution and vapor phase. The o-phenylenediamine unit serves as a detection site that can react with diethyl chlorophosphate (DCP) in a rapid response within 2 min. A satisfied relationship line was obtained between fluorescent intensity and the concentration of DCP in the range of 0-90 microM. In the optimized conditions, we conducted the fluorescent titration to measure the limits of detection (0.082 microM) with the fluorescent enhancement up to 18-fold. Fluorescence titration and NMR studies were also conducted to explore the detection mechanism, indicating that the formation of phosphate ester causes the intensity of fluorescent change during the PET process. Finally, probe 1 coated with the paper test is utilized to detect DCP vapor and solution by the naked eye. We expect that this probe may give some admiration to design the small molecule organic probe and applied in the selectivity detection of chemical nerve agents.
ESTHER : Chen_2023_Anal.Chem__
PubMedSearch : Chen_2023_Anal.Chem__
PubMedID: 36802493

Title : Characterization of a PBAT Degradation Carboxylesterase from Thermobacillus composti KWC4 - Wu_2023_Catalysts_13_340
Author(s) : Wu P , Li Z , Gao J , Zhao Y , Wang H , Qin H , Gu Q , Wei R , Liu W , Han X
Ref : Catalysts , 13 :340 , 2023
Abstract : The large amount of waste synthetic polyester plastics has complicated waste management and also endangering the environment due to improper littering. In this study, a novel carboxylesterase from Thermobacillus composti KWC4 (Tcca) was identified, heterologously expressed in Escherichia coli, purified and characterized with various plastic substrates. Irregular grooves were detected on polybutylene adipate terephthalate (PBAT) film by scanning electron microscopy (SEM) after Tcca treatment, and Tcca can also hydrolyze short-chain diester bis(hydroxyethyl) terephthalate (BHET). The optimal pH and temperature for Tcca were 7.0 and 40 C, respectively. In order to explore its catalytic mechanism and improve its potential for plastic hydrolysis, we modeled the protein structure of Tcca and compared it with its homologous structures, and we identified positions that might be crucial for the binding of substrates. We generated a variety of Tcca variants by mutating these key positions; the variant F325A exhibited a more than 1.4-fold improvement in PBAT hydrolytic activity, and E80A exhibited a more than 4.1-fold increase in BHET activity when compared to the wild type. Tcca and its variants demonstrated future applicability for the recycling of bioplastic waste containing a PBAT fraction.
ESTHER : Wu_2023_Catalysts_13_340
PubMedSearch : Wu_2023_Catalysts_13_340
PubMedID:
Gene_locus related to this paper: theck-l0ef70

Title : Clinical and genetic characteristics of CEL-MODY (MODY8): a literature review and screening in Chinese individuals diagnosed with early-onset type 2 diabetes - Sun_2023_Endocrine__
Author(s) : Sun S , Gong S , Li M , Wang X , Wang F , Cai X , Liu W , Luo Y , Zhang S , Zhang R , Zhou L , Zhu Y , Ma Y , Ren Q , Zhang X , Chen J , Chen L , Wu J , Gao L , Zhou X , Li Y , Zhong L , Han X , Ji L
Ref : Endocrine , : , 2023
Abstract : OBJECTIVE: CEL-related maturity-onset diabetes of the young (CEL-MODY, MODY8) is a special type of monogenetic diabetes caused by mutations in the carboxyl-ester lipase (CEL) gene. This study aimed to summarize the genetic and clinical characteristics of CEL-MODY patients and to determine the prevalence of the disease among Chinese patients with early-onset type 2 diabetes (EOD). METHODS: We systematically reviewed the literature associated with CEL-MODY in PubMed, Embase, Web of Science, China National Knowledge Infrastructure and Wanfang Data to analyze the features of patients with CEL-MODY. We screened and evaluated rare variants of the CEL gene in a cohort of 679 Chinese patients with EOD to estimate the prevalence of CEL-MODY in China. RESULTS: In total, 21 individuals reported in previous studies were diagnosed with CEL-MODY based on the combination of diabetes and pancreatic exocrine dysfunction as well as frameshift mutations in exon 11 of the CEL gene. CEL-MODY patients were nonobese and presented with exocrine pancreatic affection (e.g., chronic pancreatitis, low fecal elastase levels, pancreas atrophy and lipomatosis) followed by insulin-dependent diabetes. No carriers of CEL missense mutations were reported with exocrine pancreatic dysfunction. Sequencing of CEL in Chinese EOD patients led to the identification of the variant p.Val736Cysfs*22 in two patients. However, these patients could not be diagnosed with CEL-MODY because there were no signs that the exocrine pancreas was afflicted. CONCLUSION: CEL-MODY is a very rare disease caused by frameshift mutations affecting the proximal VNTR segments of the CEL gene. Signs of exocrine pancreatic dysfunction provide diagnostic clues for CEL-MODY, and genetic testing is vital for proper diagnosis. Further research in larger cohorts is needed to investigate the characteristics and prevalence of CEL-MODY in the Chinese population.
ESTHER : Sun_2023_Endocrine__
PubMedSearch : Sun_2023_Endocrine__
PubMedID: 37726640

Title : Identifying Sex-Specific Serum Patterns of Alzheimer's Mice through Deep TMT Profiling and a Concentration-Dependent Concatenation Strategy - Dey_2023_J.Proteome.Res__
Author(s) : Dey KK , Yarbro JM , Liu D , Han X , Wang Z , Jiao Y , Wu Z , Yang S , Lee D , Dasgupta A , Yuan ZF , Wang X , Zhu L , Peng J
Ref : J Proteome Res , : , 2023
Abstract : Alzheimer's disease (AD) is the most prevalent form of dementia, disproportionately affecting women in disease prevalence and progression. Comprehensive analysis of the serum proteome in a common AD mouse model offers potential in identifying possible AD pathology- and gender-associated biomarkers. Here, we introduce a multiplexed, nondepleted mouse serum proteome profiling via tandem mass-tag (TMTpro) labeling. The labeled sample was separated into 475 fractions using basic reversed-phase liquid chromatography (RPLC), which were categorized into low-, medium-, and high-concentration fractions for concatenation. This concentration-dependent concatenation strategy resulted in 128 fractions for acidic RPLC-tandem mass spectrometry (MS/MS) analysis, collecting -5 million MS/MS scans and identifying 3972 unique proteins (3413 genes) that cover a dynamic range spanning at least 6 orders of magnitude. The differential expression analysis between wild type and the commonly used AD model (5xFAD) mice exhibited minimal significant protein alterations. However, we detected 60 statistically significant (FDR < 0.05), sex-specific proteins, including complement components, serpins, carboxylesterases, major urinary proteins, cysteine-rich secretory protein 1, pregnancy-associated murine protein 1, prolactin, amyloid P component, epidermal growth factor receptor, fibrinogen-like protein 1, and hepcidin. The results suggest that our platform possesses the sensitivity and reproducibility required to detect sex-specific differentially expressed proteins in mouse serum samples.
ESTHER : Dey_2023_J.Proteome.Res__
PubMedSearch : Dey_2023_J.Proteome.Res__
PubMedID: 37910662

Title : Rosmarinic acid potentiates and detoxifies tacrine in combination for Alzheimer's disease - Yang_2023_Phytomedicine_109_154600
Author(s) : Yang M , Zhang X , Qiao O , Ji H , Zhang Y , Han X , Wang W , Li X , Wang J , Guo L , Huang L , Gao W
Ref : Phytomedicine , 109 :154600 , 2023
Abstract : BACKGROUND: There is no doubt that Alzheimer's disease (AD) is one of the greatest threats facing mankind today. Within the next few decades, Acetylcholinesterase inhibitors (AChEIs) will be the most widely used treatment for Alzheimer's disease. The withdrawal of the first generation AChEIs drug Tacrine (TAC)/ Cognex from the market as a result of hepatotoxicity has always been an interesting case study. Rosmarinic acid (RA) is a natural compound of phenolic acids that has pharmacological activity for inhibiting Alzheimer's disease, as well as liver protection. PURPOSE AND STUDY DESIGN: In this study, we determined that RA can reduce the hepatotoxicity of TAC, and both of them act synergistically to inhibit the progression of AD in mice. METHODS: In addition to the wild type mice (WT) group, the 6-month-old APP/PS1 (APPswe/PSEN1dE9) double-transgenic (Tg) mice were randomly divided into 6 groups: Tg group, TAC group, RA group, TAC+Silymarin (SIL) group, TAC+RA-L (Rosmarinic Acid Low Dose) goup and TAC+RA-H (Rosmarinic Acid High Dose) group. A series of experiments were carried out, including open field test, Morris water maze test, Hematoxylin - Eosin (HE) staining, Nissl staining, biochemical analysis, immunofluorescence analysis, western blotting analysis and so on. RESULTS: RA combined with TAC could enter the brain tissue of AD mice, and the combination of drugs could better improve the cognitive behavior and brain pathological damage of AD mice, reduce the expression of A beta oligomer, inhibit the deposition of A beta, inhibit the activity of AChE and enhance the level of Ach in hippocampus. Both in vivo and in vitro experiments showed that RA could alleviate the hepatotoxicity or liver injury induced by TAC. The Western blot analysis of the liver of AD mice showed that RA combined with TAC might inhibit the apoptosis of Bcl-2/Bax, reduce the programmed apoptosis mediated by caspase-3 and reduce the burden of liver induced by TAC, could inhibit the development of liver apoptosis by alleviating the hepatotoxicity of TAC and inhibiting the phosphorylation of JNK. CONCLUSION: The potential drug combination that combines rosmarinic acid with tacrine could reduce tacrine's hepatotoxicity as well as enhance its therapeutic effect on Alzheimer's disease.
ESTHER : Yang_2023_Phytomedicine_109_154600
PubMedSearch : Yang_2023_Phytomedicine_109_154600
PubMedID: 36610144

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 : Multiple Substrate Binding Mode-Guided Engineering of a Thermophilic PET Hydrolase - Pfaff_2022_ACS.Catalysis_12_9790
Author(s) : Pfaff L , Gao J , Li Z , Jackering A , Weber G , Mican J , Chen Y , Dong W , Han X , Feiler CG , Ao YF , Badenhorst CPS , Bednar D , Palm GJ , Lammers M , Damborsky J , Strodel B , Liu W , Bornscheuer UT , Wei R
Ref : ACS Catal , 12 :9790 , 2022
Abstract : Thermophilic polyester hydrolases (PES-H) have recently enabled biocatalytic recycling of the mass-produced synthetic polyester polyethylene terephthalate (PET), which has found widespread use in the packaging and textile industries. The growing demand for efficient PET hydrolases prompted us to solve high-resolution crystal structures of two metagenome-derived enzymes (PES-H1 and PES-H2) and notably also in complex with various PET substrate analogues. Structural analyses and computational modeling using molecular dynamics simulations provided an understanding of how product inhibition and multiple substrate binding modes influence key mechanistic steps of enzymatic PET hydrolysis. Key residues involved in substratebinding and those identified previously as mutational hotspots in homologous enzymes were subjected to mutagenesis. At 72 C, the L92F/Q94Y variant of PES-H1 exhibited 2.3-fold and 3.4-fold improved hydrolytic activity against amorphous PET films and pretreated real-world PET waste, respectively. The R204C/S250C variant of PES-H1 had a 6.4 C higher melting temperature than the wild-type enzyme but retained similar hydrolytic activity. Under optimal reaction conditions, the L92F/Q94Y variant of PES-H1 hydrolyzed low-crystallinity PET materials 2.2-fold more efficiently than LCC ICCG, which was previously the most active PET hydrolase reported in the literature. This property makes the L92F/ Q94Y variant of PES-H1 a good candidate for future applications in industrial plastic r"cycling processes.
ESTHER : Pfaff_2022_ACS.Catalysis_12_9790
PubMedSearch : Pfaff_2022_ACS.Catalysis_12_9790
PubMedID: 35966606
Gene_locus related to this paper: 9firm-PHL7

Title : Isoprocarb causes neurotoxicity of zebrafish embryos through oxidative stress-induced apoptosis - Wang_2022_Ecotoxicol.Environ.Saf_242_113870
Author(s) : Wang S , Han X , Yu T , Liu Y , Zhang H , Mao H , Hu C , Xu X
Ref : Ecotoxicology & Environmental Safety , 242 :113870 , 2022
Abstract : Isoprocarb is a widely used carbamate insecticide in agriculture and aquaculture. Overuse of isoprocarb always leaves toxic residues in soil and water, however, the potential ecotoxicity of isoprocarb to organisms is still confusing. In this study, zebrafish embryo was used as a model to evaluate the toxicity of isoprocarb. Zebrafish embryos (96 hpf) were separately exposed at different concentrations of isoprocarb. The mortality rate, hatchability rate, average heart beat of the zebrafish embryo were separately calculated. Our results suggested that exposure to isoprocarb induced developmental toxicity in zebrafish embryos. HE staining showed that exposure to isoprocarb caused developmental defect in the hindbrain of zebrafish embryos. As expected, the behavioral analysis also showed that the motor ability of zebrafish embryos were significantly inhibited following exposure to isoprocarb. In terms of mechanism, The expressions of genes involved in neurodevelopment signaling pathways, such as foxo3a, gfap, syn2a, elavl3 and sox19b, were inhibited in zebrafish embryos after exposure to isoprocarb. The acetylcholinesterase (AChE) activity was also reduced in isoprocarb-treated zebrafish embryos. Moreover, oxidative stress was induced by increasing the reactive oxygen species (ROS) level and decreasing the activity of antioxidant enzyme (SOD) after exposure to isoprocarb. Expectedly, acridine orange (AO) staining and the detection of some apoptosis-related genes revealed that oxidative stress resulted in apoptosis. In short, the expressions of genes associated with the neurodevelopmental signaling pathway are inhibited, and oxidative stress is also induced in zebrafish embryos after exposure to isoprocarb, which may be the molecular basics of isoprocarb-induced neurotoxicity in zebrafish embryos.
ESTHER : Wang_2022_Ecotoxicol.Environ.Saf_242_113870
PubMedSearch : Wang_2022_Ecotoxicol.Environ.Saf_242_113870
PubMedID: 35816841

Title : Characterization of a new chlorimuron-ethyl-degrading strain Cedecea sp. LAM2020 and biodegradation pathway revealed by multiomics analysis - Ma_2022_J.Hazard.Mater_443_130197
Author(s) : Ma Q , Han X , Song J , Wang J , Li Q , Parales RE , Li L , Ruan Z
Ref : J Hazard Mater , 443 :130197 , 2022
Abstract : The widespread use of the herbicide chlorimuron-methyl is hazard to rotational crops and causes soil degradation problems. Biodegradation is considered a promising way for removing herbicide residues from the environment. Here, a new isolated strain, Cedecea sp. LAM2020, enabled complete degradation of 100 mg/L chlorimuron-methyl within five days. Transcriptome analysis revealed that ABC transporters, atrazine degradation and purine metabolism were enriched in the KEGG pathway. Integrating GO and KEGG classification with related reports, we predict that carboxylesterases are involved in the biodegradation of chlorimuron-methyl by LAM2020. Heterologous expression of the carboxylesterase gene carH showed 26.67% degradation of 50 mg/L chlorimuron-methyl within 6 h. The intracellular potential biological response and extracellular degradation process of chlorimuron-ethyl were analyzed by the nontarget metabolomic and mass spectrometry respectively, and the biodegradation characteristics and complete mineralization pathway was revealed. The cleavage of the sulfonylurea bridge and the ester bond achieved the first step in the degradation of chlorimuron-methyl. Together, these results reveal the presence of acidolysis and enzymatic degradation of chlorimuron-methyl by strain LAM2020. Hydroponic corn experiment showed that the addition of strain LAM2020 alleviated the toxic effects of chlorimuron-ethyl on the plants. Collectively, strain LAM2020 may be a promising microbial agent for plants chlorimuron-ethyl detoxification and soil biofertilizer.
ESTHER : Ma_2022_J.Hazard.Mater_443_130197
PubMedSearch : Ma_2022_J.Hazard.Mater_443_130197
PubMedID: 36272371
Gene_locus related to this paper: 9entr-CarHBioH

Title : Molecular and Biochemical Differences of the Tandem and Cold-Adapted PET Hydrolases Ple628 and Ple629, Isolated From a Marine Microbial Consortium - Meyer-Cifuentes_2022_Front.Bioeng.Biotechnol_10_930140
Author(s) : Meyer-Cifuentes IE , Wu P , Zhao Y , Liu W , Neumann-Schaal M , Pfaff L , Barys J , Li Z , Gao J , Han X , Bornscheuer UT , Wei R , Ozturk B
Ref : Front Bioeng Biotechnol , 10 :930140 , 2022
Abstract : Polybutylene adipate terephthalate (PBAT) is a biodegradable alternative to polyethylene and can be broadly used in various applications. These polymers can be degraded by hydrolases of terrestrial and aquatic origin. In a previous study, we identified tandem PETase-like hydrolases (Ples) from the marine microbial consortium I1 that were highly expressed when a PBAT blend was supplied as the only carbon source. In this study, the tandem Ples, Ple628 and Ple629, were recombinantly expressed and characterized. Both enzymes are mesophilic and active on a wide range of oligomers. The activities of the Ples differed greatly when model substrates, PBAT-modified polymers or PET nanoparticles were supplied. Ple629 was always more active than Ple628. Crystal structures of Ple628 and Ple629 revealed a structural similarity to other PETases and can be classified as member of the PETases IIa subclass, alpha/beta hydrolase superfamily. Our results show that the predicted functions of Ple628 and Ple629 agree with the bioinformatic predictions, and these enzymes play a significant role in the plastic degradation by the consortium.
ESTHER : Meyer-Cifuentes_2022_Front.Bioeng.Biotechnol_10_930140
PubMedSearch : Meyer-Cifuentes_2022_Front.Bioeng.Biotechnol_10_930140
PubMedID: 35935485
Gene_locus related to this paper: 9zzzz-Ple628 , 9zzzz-Ple629

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 : Fenpropathrin exposure induces neurotoxicity in zebrafish embryos - Yu_2022_Fish.Physiol.Biochem__
Author(s) : Yu T , Xu X , Mao H , Han X , Liu Y , Zhang H , Lai J , Gu J , Xia M , Hu C , Li D
Ref : Fish Physiol Biochem , : , 2022
Abstract : Fenpropathrin has been a commonly used insecticide to control agricultural and household insects over a few decades. Up to now, fenpropathrin residue in soil and water has been often determined due to its widespread use, which poses serious threat to environment and aquatic organisms. The potential of fenpropathrin to affect aquatic lives is still poorly understood. In this study, we used zebrafish (Danio rerio) embryo as an experimental model system to evaluate the toxicity of fenpropathrin to the development of zebrafish nervous system. Zebrafish embryos were separately exposed to fenpropathrin at the dose of 0.016 mg/L, 0.032 mg/L, 0.064 mg/L, starting at 6 h post-fertilizationhpf (hpf) up to 96 hpf. The results showed that fenpropathrin exposure gives rise to physiological, behavioral, and neurodevelopmental impairments in zebrafish embryos, including enhanced acetylcholinesterase (AChE) activity, abnormal swimming behavior, karyopyknosis in brain cells, increased intercellular space, and uneven migration of neuron in brain area. In addition, the expressions of genes concerning neurodevelopment and neurotransmitter system were inhibited following fenpropathrin exposure. We also found that fenpropathrin exposure distinctly induced oxidative stress by increasing reactive oxygen species (ROS) generation and inhibiting the production of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). Expectedly, some apoptosis-associated genes were induced and the apoptosis appeared in the brain and heart cells of zebrafish embryos. Moreover, fenpropathrin exposure also inhibited the expressions of genes in Nrf2 signaling pathway, such as heme oxygenase-1 (HO-1) and SOD. In summary, the results of this study indicate that oxidative stress-triggered apoptosis may be an underlying fundamental of fenpropathrin-induced neurotoxicity in zebrafish embryos.
ESTHER : Yu_2022_Fish.Physiol.Biochem__
PubMedSearch : Yu_2022_Fish.Physiol.Biochem__
PubMedID: 36266516

Title : Substrate-Binding Mode of a Thermophilic PET Hydrolase and Engineering the Enzyme to Enhance the Hydrolytic Efficacy - Zeng_2022_ACS.Catal_12_3033
Author(s) : Zeng W , Li X , Yang Y , Min J , Huang JW , Liu W , Niu D , Yang X , Han X , Zhang L , Dai L , Chen CC , Guo RT
Ref : ACS Catal , 12 :3033 , 2022
Abstract : Polyethylene terephthalate (PET) is among the most extensively produced plastics, but huge amounts of PET wastes that have accumulated in the environment have become a serious threat to the ecosystem. Applying PET hydrolytic enzymes to depolymerize PET is an attractive measure to manage PET pollution, and searching for more effective enzymes is a prerequisite to achieve this goal. A thermostable cutinase that originates from the leaf-branch compost termed ICCG is the most effective PET hydrolase reported so far. Here, we illustrated the crystal structure of ICCG in complex with the PET analogue, mono(2-hydroxyethyl)terephthalic acid, to reveal the enzyme-substrate interaction network. Furthermore, we applied structure-based engineering to modify ICCG and screened for variants that exhibit higher efficacy than the parental enzyme. As a result, several variants with the measured melting temperature approaching 99 C and elevated PET hydrolytic activity were obtained. Finally, crystallographic analyses were performed to reveal the structural stabilization effects mediated by the introduced mutations. These results are of importance in the context of understanding the mechanism of action of the thermostable PET hydrolytic enzyme and shall be beneficial to the development of PET biodegradation platforms.
ESTHER : Zeng_2022_ACS.Catal_12_3033
PubMedSearch : Zeng_2022_ACS.Catal_12_3033
PubMedID:
Gene_locus related to this paper: 9bact-g9by57

Title : Identification and Characterization of Two Novel Compounds: Heterozygous Variants of Lipoprotein Lipase in Two Pedigrees With Type I Hyperlipoproteinemia - Wang_2022_Front.Endocrinol.(Lausanne)_13_874608
Author(s) : Wang S , Cheng Y , Shi Y , Zhao W , Gao L , Fang L , Jin X , Han X , Sun Q , Li G , Zhao J , Xu C
Ref : Front Endocrinol (Lausanne) , 13 :874608 , 2022
Abstract : BACKGROUND: Type I hyperlipoproteinemia, characterized by severe hypertriglyceridemia, is caused mainly by loss-of-function mutation of the lipoprotein lipase (LPL) gene. To date, more than 200 mutations in the LPL gene have been reported, while only a limited number of mutations have been evaluated for pathogenesis. OBJECTIVE: This study aims to explore the molecular mechanisms underlying lipoprotein lipase deficiency in two pedigrees with type 1 hyperlipoproteinemia. METHODS: We conducted a systematic clinical and genetic analysis of two pedigrees with type 1 hyperlipoproteinemia. Postheparin plasma of all the members was used for the LPL activity analysis. In vitro studies were performed in HEK-293T cells that were transiently transfected with wild-type or variant LPL plasmids. Furthermore, the production and activity of LPL were analyzed in cell lysates or culture medium. RESULTS: Proband 1 developed acute pancreatitis in youth, and her serum triglycerides (TGs) continued to be at an ultrahigh level, despite the application of various lipid-lowering drugs. Proband 2 was diagnosed with type 1 hyperlipoproteinemia at 9 months of age, and his serum TG levels were mildly elevated with treatment. Two novel compound heterozygous variants of LPL (c.3G>C, p. M1? and c.835_836delCT, p. L279Vfs*3, c.188C>T, p. Ser63Phe and c.662T>C, p. Ile221Thr) were identified in the two probands. The postheparin LPL activity of probands 1 and 2 showed decreases of 72.22 +/- 9.46% (p<0.01) and 54.60 +/- 9.03% (p<0.01), respectively, compared with the control. In vitro studies showed a substantial reduction in the expression or enzyme activity of LPL in the LPL variants. CONCLUSIONS: Two novel compound heterozygous variants of LPL induced defects in the expression and function of LPL and caused type I hyperlipoproteinemia. The functional characterization of these variants was in keeping with the postulated LPL mutant activity.
ESTHER : Wang_2022_Front.Endocrinol.(Lausanne)_13_874608
PubMedSearch : Wang_2022_Front.Endocrinol.(Lausanne)_13_874608
PubMedID: 35923617
Gene_locus related to this paper: human-LPL

Title : Single-Nucleotide Polymorphisms Promote Dysregulation Activation by Essential Gene Mediated Bio-Molecular Interaction in Breast Cancer - Wang_2021_Front.Oncol_11_791943
Author(s) : Wang X , Zhao Z , Han X , Zhang Y , Li F , Li H
Ref : Front Oncol , 11 :791943 , 2021
Abstract : BACKGROUND: Breast cancer (BRCA) is a malignant tumor with a high mortality rate and poor prognosis in patients. However, understanding the molecular mechanism of breast cancer is still a challenge. MATERIALS AND METHODS: In this study, we constructed co-expression networks by weighted gene co-expression network analysis (WGCNA). Gene-expression profiles and clinical data were integrated to detect breast cancer survival modules and the leading genes related to prognostic risk. Finally, we introduced machine learning algorithms to build a predictive model aiming to discover potential key biomarkers. RESULTS: A total of 42 prognostic modules for breast cancer were identified. The nomogram analysis showed that 42 modules had good risk assessment performance. Compared to clinical characteristics, the risk values carried by genes in these modules could be used to classify the high-risk and low-risk groups of patients. Further, we found that 16 genes with significant differential expressions and obvious bridging effects might be considered biological markers related to breast cancer. Single-nucleotide polymorphisms on the CYP24A1 transcript induced RNA structural heterogeneity, which affects the molecular regulation of BRCA. In addition, we found for the first time that ABHD11-AS1 was significantly highly expressed in breast cancer. CONCLUSION: We integrated clinical prognosis information, RNA sequencing data, and drug targets to construct a breast cancer-related risk module. Through bridging effect measurement and machine learning modeling, we evaluated the risk values of the genes in the modules and identified potential biomarkers for breast cancer. The protocol provides new insight into deciphering the molecular mechanism and theoretical basis of BRCA.
ESTHER : Wang_2021_Front.Oncol_11_791943
PubMedSearch : Wang_2021_Front.Oncol_11_791943
PubMedID: 34926308
Gene_locus related to this paper: human-ABHD11

Title : Computational redesign of a PETase for plastic biodegradation under ambient condition by the GRAPE strategy - Cui_2021_ACS.Catal_11_1340
Author(s) : Cui Y , Chen Y , Liu X , Dong S , Tian Y , Qiao Y , Mitra R , Han J , Li C , Han X
Ref : ACS Catal , 11 :1340 , 2021
Abstract : Nature has provided a fantastic array of enzymes that are responsible for essential biochemical functions but not usually suitable for technological applications. Not content with the natural repertoire, protein engineering holds promise to extend the applications of improved enzymes with tailored properties. However, engineering of robust proteins remains a difficult task since the positive mutation library may not cooperate to reach the target function in most cases owing to the ubiquity of epistatic effects. The main demand lies in identifying an efficient path of accumulated mutations. Herein, we devised a computational strategy (greedy accumulated strategy for protein engineering, GRAPE) to improve the robustness of a PETase from Ideonella sakaiensis. A systematic clustering analysis combined with greedy accumulation of beneficial mutations in a computationally derived library enabled the redesign of a variant, DuraPETase, which exhibits an apparent melting temperature that is drastically elevated by 31 C and a strikingly enhanced degradation toward semicrystalline poly(ethylene terephthalate) (PET) films (30%) at mild temperatures (over 300-fold). Complete biodegradation of 2 g/L microplastics to water-soluble products under mild conditions is also achieved, opening up opportunities to steer the biological degradation of uncollectable PET waste and further conversion of the resulting monomers to high-value molecules. The crystal structure revealed the individual mutation match with the design model. Concurrently, synergistic effects are captured, while epistatic interactions are alleviated during the accumulation process. We anticipate that our design strategy will provide a broadly applicable strategy for global optimization of enzyme performance.
ESTHER : Cui_2021_ACS.Catal_11_1340
PubMedSearch : Cui_2021_ACS.Catal_11_1340
PubMedID:
Gene_locus related to this paper: idesa-peth

Title : Background-free sensing platform for on-site detection of carbamate pesticide through upconversion nanoparticles-based hydrogel suit - Su_2021_Biosens.Bioelectron_194_113598
Author(s) : Su D , Zhao X , Yan X , Han X , Zhu Z , Wang C , Jia X , Liu F , Sun P , Liu X , Lu G
Ref : Biosensors & Bioelectronics , 194 :113598 , 2021
Abstract : On-site monitoring of carbamate pesticide in complex matrix remians as a challenge in terms of the real-time control of food safety and supervision of environmental quality. Herein, we fabricated robust upconversion nanoparticles (UCNPS)/polydopamine (PDA)-based hydrogel portable suit that precisely quantified carbaryl in complex tea samples with smartphone detector. UCNPS/PDA nanoprobe was developed by polymerization of dopamine monomers on the surface of NaErF(4): 0.5% Tm(3+)@NaYF(4) through electrostatic interaction, leading to efficient red luminescence quenching of UCNPS under near-infrared excitation, which circumvented autofluorescence and background interference in complicated environment. Such a luminescence quenching could be suppressed by thiocholine that was produced by acetylcholinesterase-mediated catalytic reaction, thus enabling carbaryl bioassay by inhibiting the activity of enzyme. Bestowed with the feasibility analysis of fluorescent output, portable platform was designed by integrating UCNPS-embedded sodium alginate hydrogel with 3D-printed smartphone device for quantitatively on-site monitoring of carbaryl in the range of 0.5-200 ng mL(-1) in tea sample, accompanied by a detection limit of 0.5 ng mL(-1). Owing to specific UCNPS signatures and hydrogel immobilization, this modular platform displayed sensitive response, portability and anti-interference capability in complex matrix analysis, thus holding great potential in point-of-care application.
ESTHER : Su_2021_Biosens.Bioelectron_194_113598
PubMedSearch : Su_2021_Biosens.Bioelectron_194_113598
PubMedID: 34507097

Title : Rational Design for Broadened Substrate Specificity and Enhanced Activity of a Novel Acetyl Xylan Esterase from Bacteroides thetaiotaomicron - Wang_2021_J.Agric.Food.Chem_69_6665
Author(s) : Wang L , Han X , Wang Y , Wei X , Liu S , Shao S , Yang S , Sun L , Xin F
Ref : Journal of Agricultural and Food Chemistry , 69 :6665 , 2021
Abstract : Gut bacteria-derived enzymes play important roles in the metabolism of dietary fiber through enabling the hydrolysis of polysaccharides. In this study, we identified and characterized a 29 kDa novel acetyl xylan esterase, BTAxe1, from Bacteroides thetaiotaomicron VPI5482. Then, we solved the structure of BTAxe1 and performed the rational design. Mutants N65S and N65A increased the activities toward short-chain (pNPA, pNPB) to near four-fold, and gained the activities toward longer-chain substrate (pNPO). Molecular docking analysis showed that the mutant N65S had a larger substrate binding pocket than the wild type. Hydrolysis studies using natural substrates showed that either N65S or N65A showed higher activity of that of wild-type, yielding 131.31 and 136.09 mM of acetic acid from xylan. This is the first study on the rational design of gut bacteria-derived Axes with broadened substrate specificity and enhanced activity, which can be referenced by other acetyl esterases or gut-derived enzymes.
ESTHER : Wang_2021_J.Agric.Food.Chem_69_6665
PubMedSearch : Wang_2021_J.Agric.Food.Chem_69_6665
PubMedID: 34074097
Gene_locus related to this paper: bacth-BT1008

Title : General features to enhance enzymatic activity of poly(ethylene terephthalate) hydrolysis - Chen_2021_Nat.Catal_4_425
Author(s) : Chen CC , Han X , Li X , Jiang P , Niu D , Ma L , Liu W , Li S , Qu Y , Hu H , Min J , Yang Y , Zhang L , Zeng W , Huang JW , Dai L , Guo RT , Chen, CC
Ref : Nature Catalysis , 4 :425 , 2021
Abstract : Poly(ethylene terephthalate) (PET) is the most abundant polyester plastic and a major contributor to plastic pollution. IsPETase, from the PET-assimilating bacterium Ideonella sakaiensis, is a unique PET-hydrolytic enzyme that shares high sequence identity to canonical cutinases, but shows substrate preference towards PET and exhibits higher PET-hydrolytic activity at ambient temperature. Structural analyses suggest that IsPETase harbours a substrate-binding residue, W185, with a wobbling conformation and a highly flexible W185-locating beta6-beta7 loop. Here, we show that these features result from the presence of S214 and I218 in IsPETase, whose equivalents are strictly His and Phe, respectively, in all other homologous enzymes. We found that mutating His/Phe residues to Ser/Ile could enhance the PET-hydrolytic activity of several IsPETase-like enzymes. In conclusion, the Ser/Ile mutations should provide an important strategy to improve the activity of potential PET-hydrolytic enzymes with properties that may be useful for various applications.
ESTHER : Chen_2021_Nat.Catal_4_425
PubMedSearch : Chen_2021_Nat.Catal_4_425
PubMedID:
Gene_locus related to this paper: 9burk-a0a1f4jxw8 , idesa-peth

Title : BCL6B hypermethylation predicts metastasis and poor prognosis in early-stage hepatocellular carcinoma after thermal ablation - Li_2021_J.Cancer.Res.Ther_17_644
Author(s) : Li X , Guo M , Yang L , Cheng Z , Yu X , Han Z , Liu F , Sun Q , Han X , Yu J , Liang P
Ref : J Cancer Research Ther , 17 :644 , 2021
Abstract : AIMS: The aim of this study was to evaluate the role of BCL6B methylation in the progression of early-stage hepatocellular carcinoma (HCC) after thermal ablation. SETTINGS AND DESIGN: This is a retrospective study and written informed consent was obtained from all patients or their legal guardians. SUBJECTS AND METHODS: Between October 2008 and December 2013, 73 patients with early-stage HCC within the Milan criteria, who received thermal ablation, were recruited. STATISTICAL ANALYSIS USED: Based on methylation-specific polymerase chain reaction, the relationship between BCL6B methylation and patient characteristics and prognosis was analyzed using univariate, multivariate, and Kaplan-Meier analysis. RESULTS: The median follow-up period was 56 (8-110) months. For the BCL6B unmethylated group, the 1-, 3- and 5-year metastasis and overall survival (OS) rates after thermal ablation were 10.0%, 10.0%, and 40.0% and 100%, 100% and 90.0%, respectively. The 1-, 3-, and 5-year metastasis and OS rates of the methylated group were 23.8%, 66.7% and 88.9% and 66.2%, 71.4% and 41.3%, respectively. Levels of absolute count lymphocyte, serum cholinesterase and albumin in the BCL6B unmethylated group were higher than those in the methylated group (P = 0.020, 0.000, and 0.009, respectively). Kaplan-Meier analysis revealed that BCL6B methylation was related to metastasis and poor prognosis (P = 0.001 and 0.018, respectively). Univariate analysis revealed that BCL6B methylation was a risk factor for metastasis and poor prognosis (odds ratio [OR]: 5.663; 95% confidence interval [CI], 1.745-18.375, P = 0.004 and OR: 3.734; 95% CI, 1.151-12.110, P = 0.028, respectively). Multivariate analysis revealed that BCL6B methylation was an independent risk factor for metastasis (OR: 3.736; 95% CI, 1.000-13.963,P = 0.05) and not for prognosis (OR: 2.780; 95% CI, 0.835-9.250,P = 0.096). CONCLUSIONS: BCL6B methylation could be a valuable prognostic factor for metastasis and poor prognosis in early-stage HCC after thermal ablation, which is an independent risk factor for metastasis. Our findings provide insights for combining ablation and epigenetic therapy for patients with HCC.
ESTHER : Li_2021_J.Cancer.Res.Ther_17_644
PubMedSearch : Li_2021_J.Cancer.Res.Ther_17_644
PubMedID: 34269294

Title : Runx2 Regulates Mouse Tooth Root Development Via Activation of WNT Inhibitor NOTUM - Wen_2020_J.Bone.Miner.Res_35_2252
Author(s) : Wen Q , Jing J , Han X , Feng J , Yuan Y , Ma Y , Chen S , Ho TV , Chai Y
Ref : J Bone Miner Res , 35 :2252 , 2020
Abstract : Progenitor cells are crucial in controlling organ morphogenesis. Tooth development is a well-established model for investigating the molecular and cellular mechanisms that regulate organogenesis. Despite advances in our understanding of how tooth crown formation is regulated, we have limited understanding of tooth root development. Runt-related transcription factor 2 (RUNX2) is a well-known transcription factor in osteogenic differentiation and early tooth development. However, the function of RUNX2 during tooth root formation remains unknown. We revealed in this study that RUNX2 is expressed in a subpopulation of GLI1+ root progenitor cells, and that loss of Runx2 in these GLI1+ progenitor cells and their progeny results in root developmental defects. Our results provide in vivo evidence that Runx2 plays a crucial role in tooth root development and in regulating the differentiation of root progenitor cells. Furthermore, we identified that Gli1, Pcp4, NOTUM, and Sfrp2 are downstream targets of Runx2 by integrating bulk and single-cell RNA sequencing analyses. Specifically, ablation of Runx2 results in downregulation of WNT inhibitor NOTUM and upregulation of canonical WNT signaling in the odontoblastic site, which disturbs normal odontoblastic differentiation. Significantly, exogenous NOTUM partially rescues the impaired root development in Runx2 mutant molars. Collectively, our studies elucidate how Runx2 achieves functional specificity in regulating the development of diverse organs and yields new insights into the network that regulates tooth root development. 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
ESTHER : Wen_2020_J.Bone.Miner.Res_35_2252
PubMedSearch : Wen_2020_J.Bone.Miner.Res_35_2252
PubMedID: 32569388

Title : Computational redesign of a PETase for plastic biodegradation by the GRAPE strategy - Cui_2020_Biorxiv__
Author(s) : Cui YL , Chen YC , Liu XY , Dong SJ , Han J , Xiang H , Chen Q , Liu HY , Han X , Liu WD , Tang SY , Wu B
Ref : Biorxiv , : , 2020
Abstract : The excessive use of plastics has been accompanied by severe ecologically damaging effects. The recent discovery of a PETase from Ideonella sakaiensis that decomposes poly(ethylene terephthalate) (PET) under mild conditions provides an attractive avenue for the biodegradation of plastics. However, the inherent instability of the enzyme limits its practical utilization. Here, we devised a novel computational strategy (greedy accumulated strategy for protein engineering, GRAPE). A systematic clustering analysis combined with greedy accumulation of beneficial mutations in a computationally derived library enabled the design of a variant, DuraPETase, which exhibits an apparent melting temperature that is drastically elevated by 31C and strikingly enhanced degradation performance toward semicrystalline PET films (23%) at mild temperatures (over two orders of magnitude improvement). The mechanism underlying the robust promotion of enzyme performance has been demonstrated via a crystal structure and molecular dynamics simulations. This work shows the capabilities of computational enzyme design to circumvent antagonistic epistatic effects and provides a valuable tool for further understanding and advancing polyester hydrolysis in the natural environment
ESTHER : Cui_2020_Biorxiv__
PubMedSearch : Cui_2020_Biorxiv__
PubMedID:
Gene_locus related to this paper: idesa-peth

Title : Neuroprotective Effect of Resveratrol via Activation of Sirt1 Signaling in a Rat Model of Combined Diabetes and Alzheimer's Disease - Ma_2019_Front.Neurosci_13_1400
Author(s) : Ma X , Sun Z , Han X , Li S , Jiang X , Chen S , Zhang J , Lu H
Ref : Front Neurosci , 13 :1400 , 2019
Abstract : Background: Alzheimer's disease (AD) and diabetes mellitus (DM) often coexist in patients because having one of these conditions increases risk for the other. These two diseases share several pathophysiological mechanisms, such as specific inflammatory signaling pathways, oxidative stress, and cell apoptosis. It is still unclear exactly which mechanisms associated with DM are responsible for increased AD risk. Studies have found that even transient elevation of brain Abeta levels can allow T2DM to slightly disrupt the neural milieu in a way that encourages pathologies associated with the onset of memory deficits and AD. A recent study argues that a potential common pathogenetic mechanism underlying both DM and AD is evidenced by the cooccurrence of amyloid brain legions and deposits containing both tau and Abeta in pancreatic beta cells. Given these links, an investigation detailing disease mechanisms as well as treatment options for patients with cooccurring DM and AD is urgently needed. The biological effects of resveratrol relevant to DM and AD treatment include its abilities to modulate oxidative stress and reduce inflammation. A rat model of DM and concomitant AD was created for this study using intraperitoneal injection of streptozotocin and hippocampal injection of Abeta1-40 to characterize resveratrol's potential protective action. Results: Resveratrol significantly increased the Sirt1 expression, inhibited the memory impairment, the increased acetylcholinesterase, malondialdehyde, interleukin-1beta and interleukin 6 levels, and the decreased levels of choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione in this rat model of diabetes and concomitant AD. The Sirt 1 inhibitor EX527 partially reversed the effects of resveratrol. Conclusion: This study suggests that resveratrol may have a neuroprotective action through activation of Sirt1 signaling in diabetes and AD with concurrent onset.
ESTHER : Ma_2019_Front.Neurosci_13_1400
PubMedSearch : Ma_2019_Front.Neurosci_13_1400
PubMedID: 32038127

Title : Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors - Gao_2019_J.Enzyme.Inhib.Med.Chem_34_150
Author(s) : Gao CZ , Dong W , Cui ZW , Yuan Q , Hu XM , Wu QM , Han X , Xu Y , Min ZL
Ref : J Enzyme Inhib Med Chem , 34 :150 , 2019
Abstract : A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 +/- 1.25 nM) and MDA-MB-436 cancer cell (11.62 +/- 2.15 muM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer's disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 +/- 0.91 muM) which was stronger than neostigmine (12.01 +/- 0.45 muM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer's disease.
ESTHER : Gao_2019_J.Enzyme.Inhib.Med.Chem_34_150
PubMedSearch : Gao_2019_J.Enzyme.Inhib.Med.Chem_34_150
PubMedID: 30427217

Title : Design, Synthesis, and Evaluation of Novel Ferulic Acid Derivatives as Multi-Target-Directed Ligands for the Treatment of Alzheimer's Disease - Sang_2019_ACS.Chem.Neurosci_10_1008
Author(s) : Sang Z , Wang K , Han X , Cao M , Tan Z , Liu W
Ref : ACS Chem Neurosci , 10 :1008 , 2019
Abstract : A novel series of ferulic acid derivatives was designed and synthesized on the basis of the multi-target-directed ligands strategy for the treatment of Alzheimer's disease (AD). In vitro results revealed that all the target compounds were highly effective and selective butyrylcholinesterase (BuChE) inhibitors. In particular, compound TM-10 showed the best BuChE inhibitory activity, with IC(50) = 8.9 nM, and remarkable monoamine oxidase A and B inhibitory potency, with IC(50) = 6.3 and 8.6 microM, respectively. TM-10 could inhibit (53.9%) and disaggregate (43.8%) self-induced amyloid-beta peptide (Abeta) aggregation. In addition, TM-10 exhibited potent antioxidant activity (ORAC = 0.52 equiv) and neuroprotective effect against Abeta(1-42)-mediated SH-SY5Y neurotoxicity, and it acted as an autophagic activator. TM-10 also showed good blood-brain barrier penetration. Furthermore, TM-10 exhibited a favorable dyskinesia recovery rate and response efficiency on an AlCl(3)-induced zebrafish AD model and a potent neuroprotective effect on Abeta(1-40)-induced zebrafish vascular injury. Further, in vivo assays demonstrated that TM-10 showed low acute toxicity, and the step-down passive avoidance test indicated that this compound could improve scopolamine-induced memory deficit in mice. Therefore, the present study displays evidence that TM-10 is a potent, multi-functional agent against AD and could be a promising lead candidate for anti-Alzheimer's disease drug development.
ESTHER : Sang_2019_ACS.Chem.Neurosci_10_1008
PubMedSearch : Sang_2019_ACS.Chem.Neurosci_10_1008
PubMedID: 30537804

Title : Structural studies reveal the molecular mechanism of PETase - Chen_2018_FEBS.J_285_3717
Author(s) : Chen CC , Han X , Ko TP , Liu W , Guo RT
Ref : Febs J , 285 :3717 , 2018
Abstract : Poly(ethylene terephthalate) (PET) is a class of plastic material widely used in modern society, but large amounts of PET waste cause severe environmental problems. Obtained from a PET-consuming bacterium Ideonella sakaiensis, the enzyme PETase exhibits superb hydrolytic activity and substrate preference toward PET. Here, we summarize some recent advances in the crystallographic analysis of PETase. These reports uncover structural features of PETase that are involved in its catalytic activity. In comparison to homologous enzymes, PETase contains an additional disulfide bond as well as an extended beta8-alpha6 loop. More importantly, the crystal structures of PETase in complex with substrate and product analogs provide critical information for understanding the mechanism of action of PETase. In particular, the wobbling conformation of W156 is closely related to the binding of substrate and product. These new findings are of great importance for further in-depth research and engineering development of PETase, and should advance the implementation of plastic biodegradation strategy.
ESTHER : Chen_2018_FEBS.J_285_3717
PubMedSearch : Chen_2018_FEBS.J_285_3717
PubMedID: 30048043

Title : Structural insight into catalytic mechanism of PET hydrolase - Han_2017_Nat.Commun_8_2106
Author(s) : Han X , Liu W , Huang JW , Ma J , Zheng Y , Ko TP , Xu L , Cheng YS , Chen CC , Guo RT
Ref : Nat Commun , 8 :2106 , 2017
Abstract : PET hydrolase (PETase), which hydrolyzes polyethylene terephthalate (PET) into soluble building blocks, provides an attractive avenue for the bioconversion of plastics. Here we present the structures of a novel PETase from the PET-consuming microbe Ideonella sakaiensis in complex with substrate and product analogs. Through structural analyses, mutagenesis, and activity measurements, a substrate-binding mode is proposed, and several features critical for catalysis are elucidated.
ESTHER : Han_2017_Nat.Commun_8_2106
PubMedSearch : Han_2017_Nat.Commun_8_2106
PubMedID: 29235460
Gene_locus related to this paper: idesa-peth

Title : Design, synthesis and biological evaluation of phthalimide-alkylamine derivatives as balanced multifunctional cholinesterase and monoamine oxidase-B inhibitors for the treatment of Alzheimer's disease - Sang_2017_Bioorg.Med.Chem.Lett_27_5053
Author(s) : Sang Z , Wang K , Wang H , Yu L , Ma Q , Ye M , Han X , Liu W
Ref : Bioorganic & Medicinal Chemistry Lett , 27 :5053 , 2017
Abstract : A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer's disease (AD). The results showed that compound TM-9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B (huAChE, huBuChE, and huMAO-B with IC50 values of 1.2muM, 3.8muM and 2.6muM, respectively) with low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-9 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Interestingly, compound TM-9 abided by Lipinski's rule of five. Furthermore, our investigation proved that TM-9 indicated weak cytotoxicity, and it could cross the blood-brain barrier (BBB) in vitro. The results suggest that compound TM-9, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease.
ESTHER : Sang_2017_Bioorg.Med.Chem.Lett_27_5053
PubMedSearch : Sang_2017_Bioorg.Med.Chem.Lett_27_5053
PubMedID: 29033232

Title : Structure of the S1 subunit C-terminal domain from bat-derived coronavirus HKU5 spike protein - Han_2017_Virology_507_101
Author(s) : Han X , Qi J , Song H , Wang Q , Zhang Y , Wu Y , Lu G , Yuen KY , Shi Y , Gao GF
Ref : Virology , 507 :101 , 2017
Abstract : Accumulating evidence indicates that MERS-CoV originated from bat coronaviruses (BatCoVs). Previously, we demonstrated that both MERS-CoV and BatCoV HKU4 use CD26 as a receptor, but how the BatCoVs evolved to bind CD26 is an intriguing question. Here, we solved the crystal structure of the S1 subunit C-terminal domain of HKU5 (HKU5-CTD), another BatCoV that is phylogenetically related to MERS-CoV but cannot bind to CD26. We observed that the conserved core subdomain and those of other betacoronaviruses (betaCoVs) have a similar topology of the external subdomain, indicating the same ancestor of lineage C betaCoVs. However, two deletions in two respective loops located in HKU5-CTD result in conformational variations in CD26-binding interface and are responsible for the non-binding of HKU5-CTD to CD26. Combined with sequence variation in the HKU5-CTD receptor binding interface, we propose the necessity for surveilling the mutation in BatCoV HKU5 spike protein in case of bat-to-human interspecies transmission.
ESTHER : Han_2017_Virology_507_101
PubMedSearch : Han_2017_Virology_507_101
PubMedID: 28432925

Title : Effects and mechanism of cerebroprotein hydrolysate on learning and memory ability in mice - An_2016_Genet.Mol.Res_15_
Author(s) : An L , Han X , Li H , Ma Y , Shi L , Xu G , Yuan G , Sun J , Zhao N , Sheng Y , Wang M , Du P
Ref : Genet Mol Res , 15 : , 2016
Abstract : Cerebroprotein hydrolysate is an extract from porcine brain tissue that acts on the central nervous system in various ways to protect neurons and improve memory, attention, and vigilance. This study examined the effect and mechanism of cerebroprotein hydrolysate on learning and memory in mice with scopolamine-induced impairment. Mice were given an intraperitoneal injection of scopolamine hydrobromide to establish a murine model of learning and memory impairment. After 35 successive days of cerebroprotein hydrolysate treatment, their behaviors were observed in the Morris water maze and step-down test. Superoxide dismutase (SOD), Na+-K+-ATPase, and acetylcholinesterase (AChE) activity, and malondialdehyde (MDA), gamma-aminobutyric acid (GABA), and glutamic acid (Glu) levels in the brain tissue of the mice were determined, and pathological changes in the hippocampus were examined. The results of the water-maze test showed that cerebroprotein hydrolysate shortened the escape latency and increased the number of platform crossings. In the step-down test, cerebroprotein hydrolysate treatment prolonged the step-down latency and reduced the number of errors; cerebroprotein hydrolysate increased the activity of SOD, Na+-K+-ATPase, and AChE, reduced the levels of MDA, decreased the Glu/GABA ratio in brain tissue, and reduced pathological changes in the hippocampus. The results indicate that cerebroprotein hydrolysate can improve learning and memory in mice with scopolamine-induced impairment. This effect may be associated with its ability to reduce injury caused by free radicals, improve acetylcholine function, and modulate the Glu/GABA learning and memory regulation system, reducing excitotoxicity caused by Glu.
ESTHER : An_2016_Genet.Mol.Res_15_
PubMedSearch : An_2016_Genet.Mol.Res_15_
PubMedID: 27525868

Title : Lipoprotein lipase deficiency leads to alpha-synuclein aggregation and ubiquitin C-terminal hydrolase L1 reduction - Yang_2015_Neurosci_290_1
Author(s) : Yang H , Zhou T , Wang H , Liu T , Ueda K , Zhan R , Zhao L , Tong Y , Tian X , Zhang T , Jin Y , Han X , Li Z , Zhao Y , Guo X , Xiao W , Fan D , Liu G , Chui D
Ref : Neuroscience , 290 :1 , 2015
Abstract : We have previously reported that presynaptic dysfunction and cognitive decline have been found in lipoprotein lipase (LPL) deficient mice, but the mechanism remains to be elucidated. Accumulating evidence supported that alpha-synuclein (alpha-syn) and ubiquitin C-terminal hydrolase L1 (UCHL1) are required for normal synaptic and cognitive function. In this study, we found that alpha-syn aggregated and the expression of UCHL1 decreased in the brain of LPL deficient mice. Reduction of UCHL1 was resulted from nuclear retention of DNA cytosine-5-methyltransferase 1 in LPL knockout mice. Reverse changes were found in cultured cells overexpressing LPL. Furthermore, deficiency of LPL increased ubiquitination of alpha-syn. These results indicated that aggregation of alpha-syn and reduction of UCHL1 expression in LPL-deficient mice may affect synaptic function.
ESTHER : Yang_2015_Neurosci_290_1
PubMedSearch : Yang_2015_Neurosci_290_1
PubMedID: 25595992

Title : Muscle-specific deletion of comparative gene identification-58 (CGI-58) causes muscle steatosis but improves insulin sensitivity in male mice - Xie_2015_Endocrinology_156_1648
Author(s) : Xie P , Kadegowda AK , Ma Y , Guo F , Han X , Wang M , Groban L , Xue B , Shi H , Li H , Yu L
Ref : Endocrinology , 156 :1648 , 2015
Abstract : Intramyocellular accumulation of lipids is often associated with insulin resistance. Deficiency of comparative gene identification-58 (CGI-58) causes cytosolic deposition of triglyceride (TG)-rich lipid droplets in most cell types, including muscle due to defective TG hydrolysis. It was unclear, however, whether CGI-58 deficiency-induced lipid accumulation in muscle influences insulin sensitivity. Here we show that muscle-specific CGI-58 knockout mice relative to their controls have increased glucose tolerance and insulin sensitivity on a Western-type high-fat diet, despite TG accumulation in both heart and oxidative skeletal muscle and cholesterol deposition in heart. Although the intracardiomyocellular lipid deposition results in cardiac ventricular fibrosis and systolic dysfunction, muscle-specific CGI-58 knockout mice show increased glucose uptake in heart and soleus muscle, improved insulin signaling in insulin-sensitive tissues, and reduced plasma concentrations of glucose, insulin, and cholesterol. Hepatic contents of TG and cholesterol are also decreased in these animals. Cardiac steatosis is attributable, at least in part, to decreases in cardiac TG hydrolase activity and peroxisome proliferator-activated receptor-alpha/peroxisome proliferator-activated receptor-gamma coactivator-1-dependent mitochondrial fatty acid oxidation. In conclusion, muscle CGI-58 deficiency causes cardiac dysfunction and fat deposition in oxidative muscles but induces a series of favorable metabolic changes in mice fed a high-fat diet.
ESTHER : Xie_2015_Endocrinology_156_1648
PubMedSearch : Xie_2015_Endocrinology_156_1648
PubMedID: 25751639

Title : Quantitative-profiling of neurotransmitter abnormalities in the disease progression of experimental diabetic encephalopathy rat - Zhou_2015_Can.J.Physiol.Pharmacol_93_1007
Author(s) : Zhou X , Zhu Q , Han X , Chen R , Liu Y , Fan H , Yin X
Ref : Canadian Journal of Physiology & Pharmacology , 93 :1007 , 2015
Abstract : Diabetic encephalopathy (DE) is one of the most prevalent chronic complications of diabetes mellitus (DM), with neither effective prevention nor proven therapeutic regimen. This study aims to uncover the potential dysregulation pattern of the neurotransmitters in a rat model of streptozotocin (STZ)-induced experimental DE. For that purpose, male Sprague-Dawley (SD) rats were treated with a single intraperitoneal injection of STZ. Cognitive performance was detected with the Morris water maze (MWM) test. Serum, cerebrospinal fluid (CSF), and brain tissues were collected to measure the levels of neurotransmitters. Compared with the control rats, the acetylcholine (ACh) levels in serum, CSF, hippocampus, and cortex were all significantly down-regulated as early as 6 weeks in the STZ treatment group. In contrast, the glutamate (Glu) levels were decreased in CSF and the hippocampus, but unaffected in the serum and cortex of STZ-treated rats. As for gamma-aminobutyric acid (GABA), it was down-regulated in serum, but up-regulated in CSF, hippocampus, and the cortex in the STZ-treated group. The mRNA expressions of neurotransmitter-related rate limiting enzymes (including AChE, GAD1, and GAD2) and pro-inflammatory cytokines (including IL-1beta and TNF-alpha) were all increased in the DE rats. Our data suggest that DM induces isoform-dependent and tissue-specific neurotransmitter abnormalities, and that neuroinflammation may underlay the nervous system dysfunction observed in the progression of DE.
ESTHER : Zhou_2015_Can.J.Physiol.Pharmacol_93_1007
PubMedSearch : Zhou_2015_Can.J.Physiol.Pharmacol_93_1007
PubMedID: 26426748

Title : Genome sequencing of the high oil crop sesame provides insight into oil biosynthesis - Wang_2014_Genome.Biol_15_R39
Author(s) : Wang L , Yu S , Tong C , Zhao Y , Liu Y , Song C , Zhang Y , Zhang X , Wang Y , Hua W , Li D , Li F , Yu J , Xu C , Han X , Huang S , Tai S , Wang J , Xu X , Li Y , Liu S , Varshney RK
Ref : Genome Biol , 15 :R39 , 2014
Abstract : BACKGROUND: Sesame, Sesamum indicum L., is considered the queen of oilseeds for its high oil content and quality, and is grown widely in tropical and subtropical areas as an important source of oil and protein. However, the molecular biology of sesame is largely unexplored. RESULTS: Here, we report a high-quality genome sequence of sesame assembled de novo with a contig N50 of 52.2 kb and a scaffold N50 of 2.1 Mb, containing an estimated 27,148 genes. The results reveal novel, independent whole genome duplication and the absence of the Toll/interleukin-1 receptor domain in resistance genes. Candidate genes and oil biosynthetic pathways contributing to high oil content were discovered by comparative genomic and transcriptomic analyses. These revealed the expansion of type 1 lipid transfer genes by tandem duplication, the contraction of lipid degradation genes, and the differential expression of essential genes in the triacylglycerol biosynthesis pathway, particularly in the early stage of seed development. Resequencing data in 29 sesame accessions from 12 countries suggested that the high genetic diversity of lipid-related genes might be associated with the wide variation in oil content. Additionally, the results shed light on the pivotal stage of seed development, oil accumulation and potential key genes for sesamin production, an important pharmacological constituent of sesame. CONCLUSIONS: As an important species from the order Lamiales and a high oil crop, the sesame genome will facilitate future research on the evolution of eudicots, as well as the study of lipid biosynthesis and potential genetic improvement of sesame.
ESTHER : Wang_2014_Genome.Biol_15_R39
PubMedSearch : Wang_2014_Genome.Biol_15_R39
PubMedID: 24576357
Gene_locus related to this paper: sesin-a0a6i9snr9

Title : Macrophage CGI-58 deficiency activates ROS-inflammasome pathway to promote insulin resistance in mice - Miao_2014_Cell.Rep_7_223
Author(s) : Miao H , Ou J , Ma Y , Guo F , Yang Z , Wiggins M , Liu C , Song W , Han X , Wang M , Cao Q , Chung BH , Yang D , Liang H , Xue B , Shi H , Gan L , Yu L
Ref : Cell Rep , 7 :223 , 2014
Abstract : Overnutrition activates a proinflammatory program in macrophages to induce insulin resistance (IR), but its molecular mechanisms remain incompletely understood. Here, we show that saturated fatty acid and lipopolysaccharide, two factors implicated in high-fat diet (HFD)-induced IR, suppress macrophage CGI-58 expression. Macrophage-specific CGI-58 knockout (MaKO) in mice aggravates HFD-induced glucose intolerance and IR, which is associated with augmented systemic/tissue inflammation and proinflammatory activation of adipose tissue macrophages. CGI-58-deficient macrophages exhibit mitochondrial dysfunction due to defective peroxisome proliferator-activated receptor (PPAR)gamma signaling. Consequently, they overproduce reactive oxygen species (ROS) to potentiate secretion of proinflammatory cytokines by activating NLRP3 inflammasome. Anti-ROS treatment or NLRP3 silencing prevents CGI-58-deficient macrophages from oversecreting proinflammatory cytokines and from inducing proinflammatory signaling and IR in the cocultured fat slices. Anti-ROS treatment also prevents exacerbation of inflammation and IR in HFD-fed MaKO mice. Our data thus establish CGI-58 as a suppressor of overnutrition-induced NLRP3 inflammasome activation in macrophages.
ESTHER : Miao_2014_Cell.Rep_7_223
PubMedSearch : Miao_2014_Cell.Rep_7_223
PubMedID: 24703845

Title : Genetic variants in epoxide hydrolases modify the risk of oligozoospermia and asthenospermia in Han-Chinese population - Qin_2012_Gene_510_171
Author(s) : Qin Y , Han X , Peng Y , Shen R , Guo X , Cao L , Song L , Sha J , Xia Y , Wang X
Ref : Gene , 510 :171 , 2012
Abstract : OBJECTIVES Epoxide hydrolases are involved in detoxifying and excreting the environmental chemicals which are associated with decreased semen quality and male infertility We hypothesized that polymorphisms in epoxide hydrolases may be associated with risk of oligozoospermia and asthenospermia DESIGN AND METHODS In this study 468 fertile controls and 672 idiopathic male infertile patients were recruited SNPstream and TaqMan assay were used to genotype four single nucleotide polymorphisms in EPHX1 and EPHX2 The semen analysis was performed by computer-assisted semen analysis system RESULTS Our results demonstrated that rs1042064 of EPHX2 was significantly associated with decreased risk of oligozoospermia OR=0.65 95 CI 0.44-0.98 and asthenospermia OR=0.66 95 CI 0.46-0.94 CONCLUSIONS Our results provided evidence that genetic variants in epoxide hydrolases may modify the risk of oligozoospermia and asthenospermia in Han-Chinese population.
ESTHER : Qin_2012_Gene_510_171
PubMedSearch : Qin_2012_Gene_510_171
PubMedID: 22986331

Title : In vitro synthesis of polyhydroxyalkanoate (PHA) incorporating lactate (LA) with a block sequence by using a newly engineered thermostable PHA synthase from Pseudomonas sp. SG4502 with acquired LA-polymerizing activity - Tajima_2012_Appl.Microbiol.Biotechnol_94_365
Author(s) : Tajima K , Han X , Satoh Y , Ishii A , Araki Y , Munekata M , Taguchi S
Ref : Applied Microbiology & Biotechnology , 94 :365 , 2012
Abstract : Recently, we succeeded in isolating a thermotolerant bacterium, Pseudomonas sp. SG4502, which is capable of accumulating polyhydroxyalkanoate (PHA) even at 55 degrees C, as a source of thermostable enzymes. In this study, we cloned a pha locus from the bacterium and identified two genes encoding PHA synthases (PhaC1(SG) and PhaC2(SG)). Two mutations, Ser324Thr and Gln480Lys, corresponding to those of a lactate (LA)-polymerizing enzyme (LPE) from mesophilic Pseudomonas sp. 61-3 were introduced into PhaC1(SG) to evaluate the potential of the resulting protein as a "thermostable LPE". The mutated PhaC1(SG) [PhaC1(SG)(STQK)] showed high thermal stability in synthesizing P(LA-co-3HB) in an in vitro reaction system under a range of high temperatures. Requirement of 3HBCoA as a priming unit for LA polymerization by the LPE has been suggested in both of the in vitro and in vivo experiments. Based on the finding, the PhaC1(SG)(STQK)-mediated synthesis of a LA-based copolymer with a block sequence was achieved in the in vitro system by sequential feeding of the corresponding two substrates. This in vitro reaction system using the thermostable LPE provides us with a versatile way to synthesize the various types of LA-based copolymers with desired sequence patterns, random or block, depending on the way of supplying hydroxyalkanoates (mixed or sequential feeding).
ESTHER : Tajima_2012_Appl.Microbiol.Biotechnol_94_365
PubMedSearch : Tajima_2012_Appl.Microbiol.Biotechnol_94_365
PubMedID: 22249718

Title : Genome sequence of Streptomyces auratus strain AGR0001, a phoslactomycin-producing actinomycete - Han_2012_J.Bacteriol_194_5472
Author(s) : Han X , Li M , Ding Z , Zhao J , Ji K , Wen M , Lu T
Ref : Journal of Bacteriology , 194 :5472 , 2012
Abstract : Streptomyces auratus strain AGR0001 produces neophoslactomycin A, a novel analog of phoslactomycin that possesses potent activity against some phytopathogenic fungi. Here, the draft genome sequence of S. auratus strain AGR0001 is presented, which would provide insight into the biosynthetic mechanism of neophoslactomycin A.
ESTHER : Han_2012_J.Bacteriol_194_5472
PubMedSearch : Han_2012_J.Bacteriol_194_5472
PubMedID: 22965094
Gene_locus related to this paper: 9acto-j2ju40 , 9acto-j1zwn4 , 9acto-j2a066 , 9acto-j2jvz9 , 9actn-j1zqi7

Title : CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance - Brown_2010_J.Lipid.Res_51_3306
Author(s) : Brown JM , Betters JL , Lord C , Ma Y , Han X , Yang K , Alger HM , Melchior J , Sawyer J , Shah R , Wilson MD , Liu X , Graham MJ , Lee R , Crooke R , Shulman GI , Xue B , Shi H , Yu L
Ref : J Lipid Res , 51 :3306 , 2010
Abstract : Mutations of Comparative Gene Identification-58 (CGI-58) in humans cause triglyceride (TG) accumulation in multiple tissues. Mice genetically lacking CGI-58 die shortly after birth due to a skin barrier defect. To study the role of CGI-58 in integrated lipid and energy metabolism, we utilized antisense oligonucleotides (ASOs) to inhibit CGI-58 expression in adult mice. Treatment with two distinct CGI-58-targeting ASOs resulted in approximately 80-95% knockdown of CGI-58 protein expression in both liver and white adipose tissue. In chow-fed mice, ASO-mediated depletion of CGI-58 did not alter weight gain, plasma TG, or plasma glucose, yet raised hepatic TG levels approximately 4-fold. When challenged with a high-fat diet (HFD), CGI-58 ASO-treated mice were protected against diet-induced obesity, but their hepatic contents of TG, diacylglycerols, and ceramides were all elevated, and intriguingly, their hepatic phosphatidylglycerol content was increased by 10-fold. These hepatic lipid alterations were associated with significant decreases in hepatic TG hydrolase activity, hepatic lipoprotein-TG secretion, and plasma concentrations of ketones, nonesterified fatty acids, and insulin. Additionally, HFD-fed CGI-58 ASO-treated mice were more glucose tolerant and insulin sensitive. Collectively, this work demonstrates that CGI-58 plays a critical role in limiting hepatic steatosis and maintaining hepatic glycerophospholipid homeostasis and has unmasked an unexpected role for CGI-58 in promoting HFD-induced obesity and insulin resistance.
ESTHER : Brown_2010_J.Lipid.Res_51_3306
PubMedSearch : Brown_2010_J.Lipid.Res_51_3306
PubMedID: 20802159
Gene_locus related to this paper: human-ABHD5 , mouse-abhd5

Title : Complete genome sequence of the rifamycin SV-producing Amycolatopsis mediterranei U32 revealed its genetic characteristics in phylogeny and metabolism - Zhao_2010_Cell.Res_20_1096
Author(s) : Zhao W , Zhong Y , Yuan H , Wang J , Zheng H , Wang Y , Cen X , Xu F , Bai J , Han X , Lu G , Zhu Y , Shao Z , Yan H , Li C , Peng N , Zhang Z , Zhang Y , Lin W , Fan Y , Qin Z , Hu Y , Zhu B , Wang S , Ding X , Zhao GP
Ref : Cell Res , 20 :1096 , 2010
Abstract : Amycolatopsis mediterranei is used for industry-scale production of rifamycin, which plays a vital role in antimycobacterial therapy. As the first sequenced genome of the genus Amycolatopsis, the chromosome of strain U32 comprising 10,236,715 base pairs, is one of the largest prokaryotic genomes ever sequenced so far. Unlike the linear topology found in streptomycetes, this chromosome is circular, particularly similar to that of Saccharopolyspora erythraea and Nocardia farcinica, representing their close relationship in phylogeny and taxonomy. Although the predicted 9,228 protein-coding genes in the A. mediterranei genome shared the greatest number of orthologs with those of S. erythraea, it was unexpectedly followed by Streptomyces coelicolor rather than N. farcinica, indicating the distinct metabolic characteristics evolved via adaptation to diverse ecological niches. Besides a core region analogous to that common in streptomycetes, a novel 'quasi-core' with typical core characteristics is defined within the non-core region, where 21 out of the total 26 gene clusters for secondary metabolite production are located. The rifamycin biosynthesis gene cluster located in the core encodes a cytochrome P450 enzyme essential for the conversion of rifamycin SV to B, revealed by comparing to the highly homologous cluster of the rifamycin B-producing strain S699 and further confirmed by genetic complementation. The genomic information of A. mediterranei demonstrates a metabolic network orchestrated not only for extensive utilization of various carbon sources and inorganic nitrogen compounds but also for effective funneling of metabolic intermediates into the secondary antibiotic synthesis process under the control of a seemingly complex regulatory mechanism.
ESTHER : Zhao_2010_Cell.Res_20_1096
PubMedSearch : Zhao_2010_Cell.Res_20_1096
PubMedID: 20567260
Gene_locus related to this paper: amyme-ester , amymu-d8hj63 , amymu-d8hka5 , amymu-d8hl19 , amymu-d8hp99 , amymu-d8hpp2 , amymu-d8htc9 , amymu-d8hu68 , amymu-d8hu87 , amymu-d8hy40 , amymu-d8hy73 , amymu-d8i2j5 , amymu-d8i4g6 , amymu-d8i8i8 , amymu-d8hri1 , amymu-d8hsx7 , amymu-d8hzu8 , amymu-d8i5g7 , amyms-g0g7f0 , amymu-a0a0h3cwx4 , amymu-a0a0h3d2a5 , amymu-a0a0h3d6r8

Title : Genome sequence and identification of candidate vaccine antigens from the animal pathogen Dichelobacter nodosus - Myers_2007_Nat.Biotechnol_25_569
Author(s) : Myers GS , Parker D , Al-Hasani K , Kennan RM , Seemann T , Ren Q , Badger JH , Selengut JD , DeBoy RT , Tettelin H , Boyce JD , McCarl VP , Han X , Nelson WC , Madupu R , Mohamoud Y , Holley T , Fedorova N , Khouri H , Bottomley SP , Whittington RJ , Adler B , Songer JG , Rood JI , Paulsen IT
Ref : Nat Biotechnol , 25 :569 , 2007
Abstract : Dichelobacter nodosus causes ovine footrot, a disease that leads to severe economic losses in the wool and meat industries. We sequenced its 1.4-Mb genome, the smallest known genome of an anaerobe. It differs markedly from small genomes of intracellular bacteria, retaining greater biosynthetic capabilities and lacking any evidence of extensive ongoing genome reduction. Comparative genomic microarray studies and bioinformatic analysis suggested that, despite its small size, almost 20% of the genome is derived from lateral gene transfer. Most of these regions seem to be associated with virulence. Metabolic reconstruction indicated unsuspected capabilities, including carbohydrate utilization, electron transfer and several aerobic pathways. Global transcriptional profiling and bioinformatic analysis enabled the prediction of virulence factors and cell surface proteins. Screening of these proteins against ovine antisera identified eight immunogenic proteins that are candidate antigens for a cross-protective vaccine.
ESTHER : Myers_2007_Nat.Biotechnol_25_569
PubMedSearch : Myers_2007_Nat.Biotechnol_25_569
PubMedID: 17468768
Gene_locus related to this paper: dicnv-a5evg0 , dicnv-a5ewn0 , dicnv-a5ewp3

Title : Lysosomal phospholipase A2 and phospholipidosis - Hiraoka_2006_Mol.Cell.Biol_26_6139
Author(s) : Hiraoka M , Abe A , Lu Y , Yang K , Han X , Gross RW , Shayman JA
Ref : Molecular & Cellular Biology , 26 :6139 , 2006
Abstract : A lysosomal phospholipase A2, LPLA2, was recently characterized and shown to have substrate specificity for phosphatidylcholine and phosphatidylethanolamine. LPLA2 is ubiquitously expressed but is most highly expressed in alveolar macrophages. Double conditional gene targeting was employed to elucidate the function of LPLA2. LPLA2-deficient mice (Lpla2-/-) were generated by the systemic deletion of exon 5 of the Lpla2 gene, which encodes the lipase motif essential for the phospholipase A2 activity. The survival of the Lpla2-/- mice was normal. Lpla2-/- mouse mating pairs yielded normal litter sizes, indicating that the gene deficiency did not impair fertility or fecundity. Alveolar macrophages from wild-type but not Lpla2-/- mice readily degraded radiolabeled phosphatidylcholine. A marked accumulation of phospholipids, in particular phosphatidylethanolamine and phosphatidylcholine, was found in the alveolar macrophages, the peritoneal macrophages, and the spleens of Lpla2-/- mice. By 1 year of age, Lpla2-/- mice demonstrated marked splenomegaly and increased lung surfactant phospholipid levels. Ultrastructural examination of Lpla2-/- mouse alveolar and peritoneal macrophages revealed the appearance of foam cells with lamellar inclusion bodies, a hallmark of cellular phospholipidosis. Thus, a deficiency of lysosomal phospholipase A2 results in foam cell formation, surfactant lipid accumulation, splenomegaly, and phospholipidosis in mice.
ESTHER : Hiraoka_2006_Mol.Cell.Biol_26_6139
PubMedSearch : Hiraoka_2006_Mol.Cell.Biol_26_6139
PubMedID: 16880524

Title : Structural transitions in the synaptic SNARE complex during Ca2+-triggered exocytosis - Han_2006_J.Cell.Biol_172_281
Author(s) : Han X , Jackson MB
Ref : Journal of Cell Biology , 172 :281 , 2006
Abstract : The synaptic SNARE complex is a highly stable four-helix bundle that links the vesicle and plasma membranes and plays an essential role in the Ca(2+)-triggered release of neurotransmitters and hormones. An understanding has yet to be achieved of how this complex assembles and undergoes structural transitions during exocytosis. To investigate this question, we have mutated residues within the hydrophobic core of the SNARE complex along the entire length of all four chains and examined the consequences using amperometry to measure fusion pore opening and dilation. Mutations throughout the SNARE complex reduced two distinct rate processes before fusion pore opening to different degrees. These results suggest that two distinct, fully assembled conformations of the SNARE complex drive transitions leading to open fusion pores. In contrast, a smaller number of mutations that were scattered through the SNARE complex but were somewhat concentrated in the membrane-distal half stabilized open fusion pores. These results suggest that a structural transition within a partially disassembled complex drives the dilation of open fusion pores. The dependence of these three rate processes on position within the SNARE complex does not support vectorial SNARE complex zipping during exocytosis.
ESTHER : Han_2006_J.Cell.Biol_172_281
PubMedSearch : Han_2006_J.Cell.Biol_172_281
PubMedID: 16418536

Title : Muscarinic cholinergic signaling in cardiac myocytes: dynamic targeting of M2AChR to sarcolemmal caveolae and eNOS activation - Feron_1999_Life.Sci_64(6-7)_471
Author(s) : Feron O , Han X , Kelly RA
Ref : Life Sciences , 64 :471 , 1999
Abstract : The isoform of nitric oxide synthase (eNOS or NOS3) originally described in endothelial cells is also expressed in a number of other cell types, including cardiac myocytes. eNOS is activated in both atrial and ventricular myocytes, including specialized pacemaker cells, by M2AChR agonists, among other stimuli. In cardiac myocytes, as in endothelial cells, eNOS is targeted to sarcolemmal caveolae, due to both co-translational myristoylation and later palmitoylation, and by the presence of a caveolin binding domain in eNOS which interacts with the caveolin scaffolding domain. In the absence of ligand, the M2AChR is not associated with caveolar microdomains, but translates into caveolae upon agonist (but not antagonist) binding. Finally, the role of M2AChR-induced eNOS activation in regulating I(Ca-L) via activation of guanylyl cyclase has been confirmed in ventricular myocytes of mice that lack functional eNOS (i.e., eNOS(null)).
ESTHER : Feron_1999_Life.Sci_64(6-7)_471
PubMedSearch : Feron_1999_Life.Sci_64(6-7)_471
PubMedID: 10069512