Zheng X

References (55)

Title : Comparative analysis of organophosphorus versus carbamate pesticide poisoning: a case study - Xia_2024_Arh.Hig.Rada.Toksikol_75_81
Author(s) : Xia JD , Wang H , Hua LW , Xu M , Zheng X , Zhang K
Ref : Arh Hig Rada Toksikol , 75 :81 , 2024
Abstract : Organophosphorus poisoning is a critical condition that can cause central nervous system depression, respiratory failure, and death early on. As its clinical manifestations closely resemble those of carbamate pesticide poisoning, the aim of this case study is to present a case of misdiagnosis, initially identifying carbofuran poisoning as organophosphate in a patient suspect of a heatstroke. We also present a case of intentional self-poisoning with organophosphate dichlorvos to underline the likelihood of pesticide poisoning in patients exhibiting acute cholinergic symptoms when the ingested substance is not known. In such cases, empirical treatment with atropine and oxime can be started pending timely differential diagnosis to adjust treatment as necessary.
ESTHER : Xia_2024_Arh.Hig.Rada.Toksikol_75_81
PubMedSearch : Xia_2024_Arh.Hig.Rada.Toksikol_75_81
PubMedID: 38548379

Title : Sublethal effects of chlorantraniliprole on growth, biochemical and molecular parameters in two chironomids, Chironomus kiiensis and Chironomus javanus - Lu_2023_Ecotoxicol.Environ.Saf_253_114658
Author(s) : Lu Y , Zheng X , He X , Guo J , Fu Q , Xu H , Lu Z
Ref : Ecotoxicology & Environmental Safety , 253 :114658 , 2023
Abstract : Pesticide residues have serious environmental impacts on rice-based ecosystems. In rice fields, Chironomus kiiensis and Chironomus javanus provide alternative food sources to predatory natural enemies of rice insect pests, especially when pests are low. Chlorantraniliprole is a substitute for older classes of insecticides and has been used extensively to control rice pests. To determine the ecological risks of chlorantraniliprole in rice fields, we evaluated its toxic effects on certain growth, biochemical and molecular parameters in these two chironomids. The toxicity tests were performed by exposing third-instar larvae to a range of concentrations of chlorantraniliprole. LC(50) values at 24 h, 48 h, and 10 days showed that chlorantraniliprole was more toxic to C. javanus than to C. kiiensis. Chlorantraniliprole significantly prolonged the larval growth duration, inhibited pupation and emergence, and decreased egg numbers of C. kiiensis and C. javanus at sublethal dosages (LC(10) = 1.50 mg/L and LC(25) = 3.00 mg/L for C. kiiensis; LC(10) = 0.25 mg/L and LC(25) = 0.50 mg/L for C. javanus). Sublethal exposure to chlorantraniliprole significantly decreased the activity of the detoxification enzymes carboxylesterase (CarE) and glutathione S-transferases (GSTs) in both C. kiiensis and C. javanus. Sublethal exposure to chlorantraniliprole also markedly inhibited the activity of the antioxidant enzyme peroxidase (POD) in C. kiiensis and POD and catalase (CAT) in C. javanus. Expression levels of 12 genes revealed that detoxification and antioxidant abilities were affected by sublethal exposures to chlorantraniliprole. There were significant changes in the expression levels of seven genes (CarE6, CYP9AU1, CYP6FV2, GSTo1, GSTs1, GSTd2, and POD) in C. kiiensis and ten genes (CarE6, CYP9AU1, CYP6FV2, GSTo1, GSTs1, GSTd2, GSTu1, GSTu2, CAT, and POD) in C. javanus. These results provide a comprehensive overview of the differences in chlorantraniliprole toxicity to chironomids, indicating that C. javanus is more susceptible and suitable as an indicator for ecological risk assessment in rice ecosystems.
ESTHER : Lu_2023_Ecotoxicol.Environ.Saf_253_114658
PubMedSearch : Lu_2023_Ecotoxicol.Environ.Saf_253_114658
PubMedID: 36796207

Title : Efficacy and safety of cetagliptin as monotherapy in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled phase 3 trial - Ji_2023_Diabetes.Obes.Metab_25_3671
Author(s) : Ji L , Lu J , Gao L , Ying C , Sun J , Han J , Zhao W , Gao Y , Wang K , Zheng X , Xie D , Ding J , Zhao J , Yu Q , Wang T
Ref : Diabetes Obes Metab , 25 :3671 , 2023
Abstract : AIM: To assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor, cetagliptin, as monotherapy in Chinese patients with type 2 diabetes (T2D) and inadequate glycaemic control. MATERIALS AND METHODS: In total, 504 eligible patients with T2D were enrolled and randomized to cetagliptin 50 mg once daily, cetagliptin 100 mg once daily or placebo at a ratio of 2:2:1 for 24 weeks of double-blind treatment, then all patients received cetagliptin 100 mg once daily for 28 weeks of open-label treatment. The primary efficacy endpoint was the change in HbA1c level from baseline at week 24. RESULTS: After 24 weeks, HbA1c from baseline was significantly reduced with cetagliptin 50 mg (-1.08%) and cetagliptin 100 mg (-1.07%) compared with placebo (-0.35%). The placebo-subtracted HbA1c reduction was -0.72% with cetagliptin 50 mg and 100 mg. Patients with a baseline HbA1c of 8.5% or higher had a greater HbA1c reduction with cetagliptin than those patients with a baseline HbA1c of less than 8.5%. Both doses studied led to a significantly higher proportion of patients (42.3% with 100 mg and 45.0% with 50 mg) achieving an HbA1c of less than 7.0% compared with placebo (12.9%). Cetagliptin also significantly lowered fasting plasma glucose and 2-hour postmeal plasma glucose relative to placebo. The incidence of adverse experiences was similar between cetagliptin and placebo. No drug-related hypoglycaemia was reported. CONCLUSIONS: Cetagliptin monotherapy was effective and well tolerated in Chinese patients with T2D who had inadequate glycaemic control on exercise and diet.
ESTHER : Ji_2023_Diabetes.Obes.Metab_25_3671
PubMedSearch : Ji_2023_Diabetes.Obes.Metab_25_3671
PubMedID: 37661308

Title : Triacylglycerol lipase, OsSG34, plays an important role in grain shape and appearance quality in rice - Jin_2023_Plant.J__
Author(s) : Jin X , Chen J , Khan A , Chen Z , Gao R , Lu Y , Zheng X
Ref : Plant J , : , 2023
Abstract : Optimal grain-appearance quality is largely determined by grain size. To date, dozens of grain size-related genes have been identified. However, the regulatory mechanism of slender grain formation is not fully clear. We identified the OsSG34 gene by map-based cloning. A 9-bp deletion on 5'-untranslated region of OsSG34, which resulted in the expression difference between the wild-type and sg34 mutant, led to the slender grains and good transparency in sg34 mutant. OsSG34 as an alpha/beta fold triacylglycerol lipase affected the triglyceride content directly, and the components of cell wall indirectly, especially the lignin between the inner and outer lemmas in rice grains, which could affect the change in grain size by altering cell proliferation and expansion, while the change in starch content and starch granule arrangement in endosperm could affect the grain-appearance quality. Moreover, the OsERF71 was identified to directly bind to cis-element on the mutant site, thereby regulating the OsSG34 expression. Knockout of three OsSG34 homologous genes resulted in slender grains as well. The study demonstrated OsSG34, involved in lipid metabolism, affected grain size and quality. Our findings suggest that the OsSG34 gene could be used in rice breeding for high yield and good grain-appearance quality via marker-assisted selection and gene-editing approaches.
ESTHER : Jin_2023_Plant.J__
PubMedSearch : Jin_2023_Plant.J__
PubMedID: 37938788
Gene_locus related to this paper: orysa-Q8H025 , orysa-Q8H024 , orysa-Q8RUY8 , orysa-Q7XI46 , orysa-q75lp9

Title : Fotagliptin monotherapy with alogliptin as an active comparator in patients with uncontrolled type 2 diabetes mellitus: a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial - Xu_2023_BMC.Med_21_388
Author(s) : Xu M , Sun K , Xu W , Wang C , Yan D , Li S , Cong L , Pi Y , Song W , Sun Q , Xiao R , Peng W , Wang J , Peng H , Zhang Y , Duan P , Zhang M , Liu J , Huang Q , Li X , Bao Y , Zeng T , Wang K , Qin L , Wu C , Deng C , Huang C , Yan S , Zhang W , Li M , Sun L , Wang Y , Li H , Wang G , Pang S , Zheng X , Wang H , Wang F , Su X , Ma Y , Li Z , Xie Z , Xu N , Ni L , Zhang L , Deng X , Pan T , Dong Q , Wu X , Shen X , Zhang X , Zou Q , Jiang C , Xi J , Ma J , Sun J , Yan L
Ref : BMC Med , 21 :388 , 2023
Abstract : BACKGROUND: Dipeptidyl peptidase-4 inhibitors (DPP-4i) have become firmly established in treatment algorithms and national guidelines for improving glycemic control in type 2 diabetes mellitus (T2DM).To report the findings from a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, which was designed to assess the efficacy and safety of a novel DPP-4 inhibitor fotagliptin in treatment-naive patients with T2DM. METHODS: Patients with T2DM were randomized to receive fotagliptin (n = 230), alogliptin (n = 113) or placebo (n = 115) at a 2:1:1 ratio for 24 weeks of double-blind treatment period, followed by an open-label treatment period, making up a total of 52 weeks. The primary efficacy endpoint was to determine the superiority of fotagliptin over placebo in the change of HbA1c from baseline to Week 24. All serious or significant adverse events were recorded. RESULTS: After 24 weeks, mean decreases in HbA1c from baseline were -0.70% for fotagliptin, -0.72% for alogliptin and -0.26% for placebo. Estimated mean treatment differences in HbA1c were -0.44% (95% confidence interval [CI]: -0.62% to -0.27%) for fotagliptin versus placebo, and -0.46% (95% CI: -0.67% to -0.26%) for alogliptin versus placebo, and 0.02% (95%CI: -0.16% to 0.19%; upper limit of 95%CI < margin of 0.4%) for fotagliptin versus alogliptin. So fotagliptin was non-inferior to alogliptin. Compared with subjects with placebo (15.5%), significantly more patients with fotagliptin (37.0%) and alogliptin (35.5%) achieved HbA1c < 7.0% after 24 weeks of treatment. During the whole 52 weeks of treatment, the overall incidence of hypoglycemia was low for both of the fotagliptin and alogliptin groups (1.0% each). No drug-related serious adverse events were observed in any treatment group. CONCLUSIONS: In summary, the study demonstrated improvement in glycemic control and a favorable safety profile for fotagliptin in treatment-naive patients with T2DM. TRIAL REGISTRATION: ClinicalTrail.gov NCT05782192.
ESTHER : Xu_2023_BMC.Med_21_388
PubMedSearch : Xu_2023_BMC.Med_21_388
PubMedID: 37814306

Title : Transesterification of phosphatidylcholine with DHA-rich algal oil using immobilized Candida antarctica lipase B to produce DHA-phosphatidylcholine - Shu_2023_Enzyme.Microb.Technol_169_110266
Author(s) : Shu L , Zheng X , Qi S , Lin S , Lu Y , Yao C , Ling X
Ref : Enzyme Microb Technol , 169 :110266 , 2023
Abstract : Docosahexaenoic acid (DHA) enriched with phospholipids (PLs) (DHA-PLs) is a type of structured PL with good physicochemical and nutritional properties. Compared to PLs and DHA, DHA-PLs has higher bioavailability and structural stability and many nutritional benefits. To improve the enzymatic synthesis of DHA-PLs, this study investigated the preparation of phosphatidylcholine (PC) enriched with DHA (DHA-PC) via enzymatic transesterification of algal oil, which is rich in DHA-triglycerides, using immobilized Candida antarctica lipase B (CALB). The optimized reaction system incorporated 31.2% DHA into the acyl chain of PC and converted 43.6% PC to DHA-PC within 72 h at 50 degreesC, 1:8 PC: algal oil mass ratio, 25% enzyme load (based on total substrate mass), and 0.02 g/mL molecular sieve concentration. Consequently, the side reactions of PC hydrolysis were effectively suppressed and products with high PC content (74.8%) were produced. Molecular structure analysis showed that exogenous DHA was specifically incorporated into the sn-1 site of the PC by immobilized CALB. Furthermore, the evaluation of reusability with eight cycles showed that the immobilized CALB had good operational stability in the present reaction system. Collectively, this study demonstrated the applicability of immobilized CALB as a biocatalyst for synthesizing DHA-PC and provided an improved enzyme-catalyzed method for future DHA-PL synthesis.
ESTHER : Shu_2023_Enzyme.Microb.Technol_169_110266
PubMedSearch : Shu_2023_Enzyme.Microb.Technol_169_110266
PubMedID: 37311283

Title : The MAX2-KAI2 module promotes salicylic acid-mediated immune responses in Arabidopsis - Zheng_2023_J.Integr.Plant.Biol__
Author(s) : Zheng X , Liu F , Yang X , Li W , Chen S , Yue X , Jia Q , Sun X
Ref : J Integr Plant Biol , : , 2023
Abstract : Arabidopsis MORE AXILLARY GROWTH2 (MAX2) is a key component in the strigolactone (SL) and karrikin (KAR) signaling pathways and regulates the degradation of SUPPRESSOR OF MAX2 1/SMAX1-like (SMAX1/SMXL) proteins, which are transcriptional co-repressors that regulate plant architecture, as well as abiotic and biotic stress responses. The max2 mutation reduces resistance against Pseudomonas syringae pv. tomato (Pst). To uncover the mechanism of MAX2-mediated resistance, we evaluated the resistance of various SL and KAR signaling pathway mutants. The resistance of SL-deficient mutants and of dwarf 14 (d14) was similar to that of the wild type, whereas the resistance of the karrikin insensitive 2 (kai2) mutant was compromised, demonstrating that the KAR signaling pathway, not the SL signaling pathway, positively regulates the immune response. We measured the resistance of smax1 and smxl mutants, as well as the double, triple, and quadruple mutants with max2, which revealed that both the smax1 mutant and smxl6/7/8 triple mutant rescue the low resistance phenotype of max2 and that SMAX1 accumulation diminishes resistance. The susceptibility of smax1D, containing a degradation-insensitive form of SMAX1, further confirmed the SMAX1 function in the resistance. The relationship between the accumulation of SMAX1/SMXLs and disease resistance suggested that the inhibitory activity of SMAX1 to resistance requires SMXL6/7/8. Moreover, exogenous application of KAR2 enhanced resistance against Pst, but KAR-induced resistance depended on salicylic acid (SA) signaling. Inhibition of karrikin signaling delayed SA-mediated defense responses and inhibited pathogen-induced protein biosynthesis. Together, we propose that the MAX2-KAI2-SMAX1 complex regulates resistance with the assistance of SMXL6/7/8 and SA signaling and that SMAX1/SMXLs possibly form a multimeric complex with their target transcription factors to fine-tune immune responses. This article is protected by copyright. All rights reserved.
ESTHER : Zheng_2023_J.Integr.Plant.Biol__
PubMedSearch : Zheng_2023_J.Integr.Plant.Biol__
PubMedID: 36738234

Title : Isolation and Identification of Efficient Malathion-Degrading Bacteria from Deep-Sea Hydrothermal Sediment - Ma_2022_Microorganisms_10_
Author(s) : Ma L , Dai X , Ai G , Zheng X , Zhang Y , Pan C , Hu M , Jiang C , Wang L , Dong Z
Ref : Microorganisms , 10 : , 2022
Abstract : The genetic and metabolic diversity of deep-sea microorganisms play important roles in phosphorus and sulfur cycles in the ocean, distinguishing them from terrestrial counterparts. Malathion is a representative organophosphorus component in herbicides, pesticides, and insecticides and is analogues of neurotoxic agent. Malathion has been one of the best-selling generic organophosphate insecticides from 1980 to 2012. Most of the sprayed malathion has migrated by surface runoff to ocean sinks, and it is highly toxic to aquatic organisms. Hitherto, there is no report on bacterial cultures capable of degrading malathion isolated from deep-sea sediment. In this study, eight bacterial strains, isolated from sediments from deep-sea hydrothermal regions, were identified as malathion degradators. Two of the tested strains, Pseudidiomarina homiensis strain FG2 and Pseudidiomarina sp. strain CB1, can completely degrade an initial concentration of 500 mg/L malathion within 36 h. Since the two strains have abundant carboxylesterases (CEs) genes, malathion monocarboxylic acid (MMC alpha and MMC beta) and dibasic carboxylic acid were detected as key intermediate metabolites of malathion degradation, and the pathway of malathion degradation between the two strains was identified as a passage from malathion monocarboxylic acid to malathion dicarboxylic acid.
ESTHER : Ma_2022_Microorganisms_10_
PubMedSearch : Ma_2022_Microorganisms_10_
PubMedID: 36144399

Title : Monoacylglycerol Lipase (MAGL) Inhibition Impedes the Osteosarcoma Progression by Regulating Epithelial Mesenchymal Transition - Gong_2022_Tohoku.J.Exp.Med_256_19
Author(s) : Gong X , Zheng X , Huang Y , Song W , Chen G , Chen T
Ref : Tohoku J Exp Med , 256 :19 , 2022
Abstract : Osteosarcoma is a primary malignancy of mesenchymal origin, and its metastasis and multidrug resistance remain major problems affecting the therapeutic effect. This study aimed to evaluate the efficacy and underlying mechanism of monoacylglycerol lipase (MAGL) on osteosarcoma progression. MAGL expression was downregulated by shMAGL or JZL184 (an MAGL inhibitor) and upregulated through plasmid. RT-PCR and Western blot were utilized to determine the expression of target molecules. CCK-8 assay, transwell assay and ROS assay were performed to investigate the inhibitory effect of MAGL on the growth and metastasis of osteosarcoma cells. The role of JZL184 on tumor growth was examined in cisplatin-resistant MG-63 (MG-63/R) xenograft model. MAGL was highly expressed in osteosarcoma cells and tissues. MAGL knockdown significantly impeded the proliferation, clone formation, invasion and migration of MG-63 cells, whereas opposite result was observed in 143B cells with MAGL overexpression. Likewise, an MAGL inhibitor JZL184 displayed reduced viability, clone formation, invasion and migration of osteosarcoma cells. Western blot of the epithelial mesenchymal transition (EMT)-related proteins indicated that MAGL knockdown or JZL184 could upregulated E-cadherin expression and downregulated vimentin expression. In vitro and in vivo experiments indicated that JZL184 re-sensitized MG-63/R cells to cisplatin. In summary, MAGL regulated osteosarcoma by modulating EMT, and JZL184 might be a promising agent for osteosarcoma patients who are resistant to cisplatin.
ESTHER : Gong_2022_Tohoku.J.Exp.Med_256_19
PubMedSearch : Gong_2022_Tohoku.J.Exp.Med_256_19
PubMedID: 35067491

Title : Activity-Based Protein Profiling Probe for the Detection of Enzymes Catalyzing Polysorbate Degradation - Liu_2022_Anal.Chem_94_8625
Author(s) : Liu GY , Nie S , Zheng X , Li N
Ref : Analytical Chemistry , 94 :8625 , 2022
Abstract : Polysorbates are nonionic surfactants that have been widely used in biotherapeutic formulations to prevent protein aggregation and denaturation. However, polysorbates are subject to degradation after prolonged storage if certain lipases are present in the biotherapeutic product. Because the degradation of polysorbates compromises the shelf life of biotherapeutics and leads to the formation of undesirable products such as protein aggregates and subvisible particles, it is important to identify the active enzymes that catalyze polysorbate hydrolysis. In this study, we developed a novel fluorophosphonate activity-based protein profiling (ABPP) probe (termed the REGN probe), which mimics the structure of polysorbate and targets lipases catalyzing polysorbate degradation. We demonstrated that the REGN probe could enrich certain lipases from Chinese hamster ovary (CHO) cell lysate by more than 100-fold compared with direct tryptic digestion. Furthermore, we found that the REGN probe had higher lipase enrichment efficiency than commercially available ABPP probes including fluorophosphonate-biotin (FP-biotin) and FP-desthiobiotin. Remarkably, the REGN probe can enrich several lipases that cannot be labeled by commercial probes, such as lysosomal acid lipase and cytosolic phospholipase A2. Additionally, we showed that lipases with abundances as low as 0.08 ppm in drug substances were detected by the REGN probe enrichment and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Collectively, we have developed a novel ABPP probe with higher enrichment efficiency and broader coverage for lipases compared with commercial probes, and this probe can be used to detect the trace level of lipases in biotherapeutic products and to facilitate their development and manufacturing.
ESTHER : Liu_2022_Anal.Chem_94_8625
PubMedSearch : Liu_2022_Anal.Chem_94_8625
PubMedID: 35679579

Title : Recovery of dopaminergic system after cocaine exposure and impact of a long-acting cocaine hydrolase - Deng_2022_Addict.Biol_27_e13179
Author(s) : Deng J , Zhang T , Zheng X , Shang L , Zhan CG , Zheng F
Ref : Addict Biol , 27 :e13179 , 2022
Abstract : Dysregulation of dopamine transporters (DAT) within the dopaminergic system is an important biomarker of cocaine exposure. Depending on cocaine amount in-taken, one-time exposure in rats could lead to most (>95% of total) of DAT translocating to plasma membrane of the dopaminergic neurons compared to normal DAT distribution (~5.7% on the plasma membrane). Without further cocaine exposure, the time course of striatal DAT distribution, in terms of intracellular and plasma membrane fractions of DAT, represents a recovery process of the dopaminergic system. In this study, we demonstrated that after an acute cocaine exposure of 20 mg/kg (i.p.), the initial recovery process from days 1 to 15 in rats was relatively faster (from >95% on day 1 to ~35.4% on day 15). However, complete recovery of the striatal DAT distribution may take about 60 days. In another situation, with repeated cocaine exposures for once every other day for a total of 17 doses of 20 mg/kg cocaine (i.p.) from days 0 to 32, the complete recovery of striatal DAT distribution may take an even longer time (about 90 days), which represents a consequence of chronic cocaine use. Further, we demonstrated that a highly efficient Fc-fused cocaine hydrolase, CocH5-Fc(M6), effectively blocked cocaine-induced hyperactivity and DAT trafficking with repeated cocaine exposures by maintaining a plasma CocH5-Fc(M6) concentration <=58.7 +/- 2.9 nM in rats. The cocaine hydrolase protected dopaminergic system and helped the cocaine-altered DAT distribution to recover by preventing the dopaminergic system from further damage by cocaine.
ESTHER : Deng_2022_Addict.Biol_27_e13179
PubMedSearch : Deng_2022_Addict.Biol_27_e13179
PubMedID: 35754103

Title : Development of a Highly Efficient Long-Acting Cocaine Hydrolase Entity to Accelerate Cocaine Metabolism - Zheng_2022_Bioconjug.Chem__
Author(s) : Zheng F , Jin Z , Deng J , Chen X , Zheng X , Wang G , Kim K , Shang L , Zhou Z , Zhan CG
Ref : Bioconjug Chem , : , 2022
Abstract : It is particularly challenging to develop a truly effective pharmacotherapy for cocaine use disorder (CUD) treatment. Accelerating cocaine metabolism via hydrolysis at cocaine benzoyl ester using an efficient cocaine hydrolase (CocH) is known as a promising pharmacotherapeutic approach to CUD treatment. Preclinical and clinical studies on our first CocH (CocH1), in its human serum albumin-fused form known as TV-1380, have demonstrated the promise of a general concept of CocH-based pharmacotherapy for CUD treatment. However, the biological half-life of TV-1380 (t(1/2) = 8 h in rats, associated with t(1/2) = 43-77 h in humans) is not long enough for practical treatment of cocaine dependence, which requires enzyme injection for no more than once weekly. Through protein fusion of a human butyrylcholinesterase mutant (denoted as CocH5) with a mutant (denoted as Fc(M6)) of Fc from human IgG1, we have designed, prepared, and tested a new fusion protein (denoted as CocH5-Fc(M6)) for its pharmacokinetic profile and in vivo catalytic activity against (-)-cocaine. CocH5-Fc(M6) represents the currently most efficient long-acting cocaine hydrolase with both the highest catalytic activity against (-)-cocaine and the longest elimination half-life (t(1/2) = 229 +/- 5 h) in rats. As a result, even at a single modest dose of 3 mg/kg, CocH5-Fc(M6) can significantly and effectively accelerate the metabolism of cocaine in rats for at least 60 days. In addition, -70 nM CocH5-Fc(M6) in plasma was able to completely block the toxicity and physiological effects induced by intraperitoneal injection of a lethal dose of cocaine (60 mg/kg).
ESTHER : Zheng_2022_Bioconjug.Chem__
PubMedSearch : Zheng_2022_Bioconjug.Chem__
PubMedID: 35767675

Title : Effects of alcohol on metabolism and toxicity of cocaine in rats - Shang_2022_Toxicol.Rep_9_1586
Author(s) : Shang L , Zheng X , Zhang T , Deng J , Zhan CG , Zheng F
Ref : Toxicol Rep , 9 :1586 , 2022
Abstract : As most cocaine users drink alcohol, it is interesting to understand how a non-lethal dose of alcohol affects the metabolism and toxicity of cocaine. In this study, we examined the correlation between dose-dependent toxicity and the metabolism/pharmacokinetic (PK) profile of cocaine with or without alcohol (ethanol, 1sg/kg) co-administration in rats. The cocaine toxicity in rats with or without alcohol co-administration is characterized by not only the commonly used LD(50), but also the average times for the appearance of convulsion and death as well as total toxicity level (TTL) in the blood. All these data have consistently demonstrated that co-administration of alcohol increased cocaine toxicity, and that the alcohol-enhanced toxicity of cocaine is mainly attributed to the observed two additional metabolites (cocaethylene and norcocaethylene - products of chemical reactions of cocaine with alcohol catalyzed by metabolic enzymes carboxylesterase-1 and liver microsomal cytochrome P450 3A4) that are more toxic than cocaine itself. So, evaluation of the substance TTL should account for the blood levels of not only cocaine itself, but also its all toxic metabolites. In addition, for rats died of a lethal dose of cocaine (60 or 100smg/kg) combined with 1sg/kg alcohol, we also determined the TTL at the time of death, demonstrating that death would occur once the TTL reached a threshold (~16smicroM).
ESTHER : Shang_2022_Toxicol.Rep_9_1586
PubMedSearch : Shang_2022_Toxicol.Rep_9_1586
PubMedID: 36518391

Title : The juvenile hormone epoxide hydrolase homolog in Penaeus vannamei plays immune-related functions - Liu_2022_Dev.Comp.Immunol_132_104410
Author(s) : Liu Z , Huang Z , Zheng X , Zheng Z , Yao D , Zhang Y , Aweya JJ
Ref : Dev Comp Immunol , 132 :104410 , 2022
Abstract : Juvenile hormone epoxide hydrolase (JHEH) participates in the degradation of juvenile hormone and also involved in the development and molting process in insects. Here, the JHEH homolog in Pennaus vannamei was cloned and found to consist of a full-length cDNA of 2543 bp and an open reading frame (ORF) of 1386 bp. Transcripts of PvJHEH1 were expressed in most tissues of healthy shrimp with the highest found in the hepatopancreas and lowest in hemocytes. Both Gram-negative (Vibrio parahaemolyticus) and Gram-positive (Streptococcus iniae) bacteria induced PvJHEH1 expression in shrimp hemocytes and hepatopancreas, suggesting the involvement of PvJHEH1 in P. vannamei immune responses. Moreover, the mRNA levels of ecdysone inducible nuclear transcription factor PvE75 and crustacean hyperglycemic hormone (PvCHH), two endocrine-related genes with roles in shrimp innate immune response, decreased significantly in shrimp hemocytes after PvJHEH1 knockdown. Shrimp survival was also affected after PvJHEH1 knockdown followed by V. parahaemolyticus challenge, indicating that JHEH1 plays an essential role in shrimp survival during bacterial infection.
ESTHER : Liu_2022_Dev.Comp.Immunol_132_104410
PubMedSearch : Liu_2022_Dev.Comp.Immunol_132_104410
PubMedID: 35398160
Gene_locus related to this paper: penva-a0a3r7m6s0

Title : Lipase-catalyzed hydrazine insertion for the synthesis of N'-alkyl benzohydrazides - Yu_2022_Biotechnol.Appl.Biochem__
Author(s) : Yu Y , Li F , Li J , Zheng X , Tian H , Mahmut Z , Du Y , Dai Y , Wang L
Ref : Biotechnol Appl Biochem , : , 2022
Abstract : N'-alkyl benzohydrazides are classic organic compounds that have been widely utilized in organic chemistry. In this study, an efficient method was developed for the synthesis of N'-alkyl benzohydrazides by hydrazine insertion catalyzed by lipase. Under the optimal conditions (Morita-Baylis-Hillman ketone [1 mmol], phenylhydrazine [1.3 mmol], N,N-dimethylformamide [2 mL], lipase [20 mg], room temperature, 12 h), satisfactory yields (71%-97%) and substrate tolerance were obtained when porcine pancreatic lipase was used as biocatalyst. These findings imply the great potential for the lipase-catalyzed synthesis of N'-alkyl benzohydrazides and extend the utilization of lipase in organic chemistry. This article is protected by copyright. All rights reserved.
ESTHER : Yu_2022_Biotechnol.Appl.Biochem__
PubMedSearch : Yu_2022_Biotechnol.Appl.Biochem__
PubMedID: 35285069

Title : Application of deep eutectic solvent-based extraction coupled with an S-CQD fluorescent sensor for the determination of pirimicarb in cereals - Jing_2021_Food.Chem_370_131360
Author(s) : Jing X , Wu J , Wang H , Guo L , Zheng X , Wang X , Wang S
Ref : Food Chem , 370 :131360 , 2021
Abstract : A novel deep eutectic solvent-based extraction and sulfur-doped carbon quantum dots (S-CQDs) serving as fluorescence probes to detect pirimicarb in cereals were established. The deep eutectic solvent was synthesized using choline chloride and butanediol, achieving direct and efficient extraction of pirimicarb residue in the cereals. The fluorescence quenching of S-CQDs was caused by the electrostatic interaction between the negatively charged S-CQDs and positively charged thiocholine, which was the hydrolysate of acetylthiocholine. The fluorescence of S-CQDs was enhanced as the activity of acetylcholinesterase (AChE) was inhibited by pirimicarb, achieving the detection of pirimicarb in the cereal samples. The limit of detection (LOD) was 0.006 microg mL(-1). The recovery ranged from 96.6% to 108.2%. This extraction and detection method of pirimicarb based on an environmentally friendly DES and S-CQD fluorescent sensor maintains good stability and convenience, offering a promising strategy for extracting and testing harmful substances in food samples.
ESTHER : Jing_2021_Food.Chem_370_131360
PubMedSearch : Jing_2021_Food.Chem_370_131360
PubMedID: 34662796

Title : Multiple transcriptomic profiling: potential novel metabolism-related genes predict prepubertal testis damage caused by DEHP exposure - Kang_2021_Environ.Sci.Pollut.Res.Int__
Author(s) : Kang L , Chen J , Wang J , Zhao T , Wei Y , Wu Y , Han L , Zheng X , Shen L , Long C , Wei G , Wu S
Ref : Environ Sci Pollut Res Int , : , 2021
Abstract : The toxic effect of di(2-ethylhexyl) phthalate (DEHP) on prepubertal testes was examined in this study. We treated 3-week-old male mice with 4.8 mg/kg/day (milligram/kilogram/day) (no observed adverse effect level), 30 mg/kg/day (high exposure dose relative to humans), 100 mg/kg/day (level causing a reproductive system disorder), and 500 mg/kg/day (dose causing a multigenerational reproductive system disorder) of DEHP via gavage. Obvious abnormalities in the testicular organ coefficient, spermatogenic epithelium, and testosterone levels occurred in the 500 mg/kg DEHP group. Ribonucleic acid sequencing (RNA-seq) showed that differentially expressed genes (DEGs) in each group could enrich reproduction and reproductive process terms according to the gene ontology (GO) results, and coenrichment of metabolism pathway was observed by the Reactome pathway analysis. Through the analysis of common genes in the metabolism pathway, we discovered that DEHP exposure at 4.8 to 500 mg/kg or 100 mg/kg caused the same damages to the prepubertal testis. In general, we identified two key transcriptional biomarkers (fatty acid binding protein 3 (Fabp3) and carboxylesterase (Ces) 1d), which provided new insight into the gene regulatory mechanism associated with DEHP exposure and will contribute to the prediction and diagnosis of prepuberty testis injury caused by DEHP.
ESTHER : Kang_2021_Environ.Sci.Pollut.Res.Int__
PubMedSearch : Kang_2021_Environ.Sci.Pollut.Res.Int__
PubMedID: 34595713

Title : Monoterpene indole alkaloids with diverse skeletons from the stems of Rauvolfia vomitoria and their acetylcholinesterase inhibitory activities - Zhan_2020_Phytochemistry_177_112450
Author(s) : Zhan G , Miao R , Zhang F , Hao X , Zheng X , Zhang H , Zhang X , Guo Z
Ref : Phytochemistry , 177 :112450 , 2020
Abstract : Nine undescribed monoterpene indole alkaloids, rauvomitorine A-I, including an unprecedented C-9-methoxymethylene-sarpagine framework alkaloid, two rare suaveoline framework type alkaloids, and six yohimbine framework type alkaloids, as well as eleven known alkaloids, were isolated from the stems of Rauvolfia vomitoria Afzel. (Apocynaceae). The structures of the unreported alkaloids were elucidated by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis with Cu Kalpha radiation. Rauvomitorine A with an unreported framework type represents the first example of C-9-methoxymethylene-sarpagine alkaloids and its plausible biosynthetic pathway was proposed. All the isolated alkaloids were evaluated their acetylcholinesterase inhibitory (AChE) activities and cytotoxicity against five cancer cell lines and some of them exhibited potential anti-AChE activities with IC50 values ranging from 49.76 to 186.62 muM. Importantly, this is the first report of the AChE inhibitory activities on suaveoline framework type alkaloids, suggesting this type of alkaloids may be valuable sources for the discovery of AChE inhibitory agents. A preliminary structure-activity relationship for AChE inhibitory activities of the isolated alkaloids is also discussed, providing some clues to designing lead compounds for AChE inhibitors.
ESTHER : Zhan_2020_Phytochemistry_177_112450
PubMedSearch : Zhan_2020_Phytochemistry_177_112450
PubMedID: 32580106

Title : Catalytic activities of cocaine hydrolases against the most toxic cocaine metabolite norcocaethylene - Zheng_2020_Org.Biomol.Chem__
Author(s) : Zheng X , Chen X , Zhang T , Zhan M , Zhan CG , Zheng F
Ref : Org Biomol Chem , : , 2020
Abstract : A majority of cocaine users also consume alcohol. The concurrent use of cocaine and alcohol produces the pharmacologically active metabolites cocaethylene and norcocaethylene, in addition to norcocaine. Both cocaethylene and norcocaethylene are more toxic than cocaine itself. Hence, a truly valuable cocaine-metabolizing enzyme for cocaine abuse/overdose treatment should be effective for the hydrolysis of not only cocaine, but also its metabolites norcocaine, cocaethylene, and norcocaethylene. However, there has been no report on enzymes capable of hydrolyzing norcocaethylene (the most toxic metabolite of cocaine). The catalytic efficiency parameters (kcat and KM) of human butyrylcholinesterase (BChE) and two mutants (known as cocaine hydrolases E14-3 and E12-7) against norcocaethylene have been characterized in the present study for the first time, and they are compared with those against cocaine. According to the obtained kinetic data, wild-type human BChE showed a similar catalytic efficiency against norcocaethylene (kcat = 9.5 min-1, KM = 11.7 muM, and kcat/KM = 8.12 x 105 M-1 min-1) to that against (-)-cocaine (kcat = 4.1 min-1, KM = 4.5 muM, and kcat/KM = 9.1 x 105 M-1 min-1). E14-3 and E12-7 showed an improved catalytic activity against norcocaethylene compared to wild-type BChE. E12-7 showed a 39-fold improved catalytic efficiency against norcocaethylene (kcat = 210 min-1, KM = 6.6 muM, and kcat/KM = 3.18 x 107 M-1 min-1). It has been demonstrated that E12-7 as an exogenous enzyme can efficiently metabolize norcocaethylene in rats.
ESTHER : Zheng_2020_Org.Biomol.Chem__
PubMedSearch : Zheng_2020_Org.Biomol.Chem__
PubMedID: 32101217

Title : A novel feruloyl esterase with high rosmarinic acid hydrolysis activity from Bacillus pumilus W3 - Liang_2020_Int.J.Biol.Macromol_161_525
Author(s) : Liang W , Xiong T , Wang X , Deng H , Bai Y , Fan TP , Zheng X , Cai Y
Ref : Int J Biol Macromol , 161 :525 , 2020
Abstract : A novel feruloyl esterase (BpFae12) with rosmarinic acid (RA) hydrolysis activity was isolated from Bacillus pumilus W3 and expressed in Escherichia coli BL21 (DE3). With RA as a substrate, the optimal pH and temperature of BpFae12 were pH 8.0 and 50 degreesC, respectively. The specific enzyme activity was 12.8 U.mg(-1). BpFae12 showed the highest activity and substrate affinity toward RA (V(max) of 13.13 U.mg(-1), K(m) of 0.41 mM). Moreover, it also presented strong hydrolysis performance against chlorogenic acid (190.17 U.mg(-1)). RA was effectively Hydrolyzed into more bioactive caffeic acid and 3,4-dihydroxyphenyllactic acid by BpFae12, which have potential applications in the food industry.
ESTHER : Liang_2020_Int.J.Biol.Macromol_161_525
PubMedSearch : Liang_2020_Int.J.Biol.Macromol_161_525
PubMedID: 32531366
Gene_locus related to this paper: 9baci-BpFae12

Title : Selenoprotein F knockout leads to glucose and lipid metabolism disorders in mice - Zheng_2020_J.Biol.Inorg.Chem_25_1009
Author(s) : Zheng X , Ren B , Li X , Yan H , Xie Q , Liu H , Zhou J , Tian J , Huang K
Ref : J Biol Inorg Chem , 25 :1009 , 2020
Abstract : Selenoprotein F (Selenof), an endoplasmic reticulum (ER)-resident protein, is considered to be involved in glycoprotein folding and quality control in the ER. However, its function has not yet been thoroughly addressed. In this study, proteomics analysis revealed that Selenof deficiency in mice led to the differential expression of hepatic proteins associated with glucose and lipid metabolism. The phenotype analysis revealed that Selenof knockout mice showed glucose intolerance and insulin reduction, even with a normal diet. Additionally, Selenof knockout exacerbated high-fat diet-induced obesity, hyperglycemia, glucose intolerance, and hepatic steatosis. Furthermore, lipoprotein lipase and carboxylesterase 1D, two glycoproteins involved in lipid metabolism, were significantly decreased in the liver of Selenof knockout mice with a normal or high-fat diet. Collectively, these findings suggested that Selenof deficiency might cause the perturbation of glycoprotein quality control and thus contribute to glucose and lipid metabolism disorders, implying a novel biological function of Selenof.
ESTHER : Zheng_2020_J.Biol.Inorg.Chem_25_1009
PubMedSearch : Zheng_2020_J.Biol.Inorg.Chem_25_1009
PubMedID: 32995962

Title : Different EPHX1 methylation levels in promoter area between carbamazepine-resistant epilepsy group and carbamazepine-sensitive epilepsy group in Chinese population - Lv_2019_BMC.Neurol_19_114
Author(s) : Lv Y , Zheng X , Shi M , Wang Z , Cui L
Ref : BMC Neurol , 19 :114 , 2019
Abstract : BACKGROUND: Epigenetics underlying refractory epilepsy is poorly understood. DNA methylation may affect gene expression in epilepsy patients without affecting DNA sequences. Herein, we investigated the association between Carbamazepine-resistant (CBZ-resistant) epilepsy and EPHX1 methylation in a northern Han Chinese population, and conducted an analysis of clinical risk factors for CBZ-resistant epilepsy. METHODS: Seventy-five northern Han Chinese patients participated in this research. 25 cases were CBZ-resistant epilepsy, 25 cases were CBZ-sensitive epilepsy and the remaining 25 cases were controls. Using a CpG searcher was to make a prediction of CpG islands; bisulfite sequencing PCR (BSP) was applied to test the methylation of EPHX1. We then did statistical analysis between clinical parameters and EPHX1 methylation. RESULTS: There was no difference between CBZ-resistant patients, CBZ-sensitive patients and healthy controls in matched age and gender. However, a significant difference of methylation levels located in NC_000001.11 (225,806,929.....225807108) of the EPHX1 promoter was found in CBZ-resistant patients, which was much higher than CBZ-sensitive and controls. Additionally, there was a significant positive correlation between seizure frequency, disease course and EPHX1 methylation in CBZ-resistant group. CONCLUSION: Methylation levels in EPHX1 promoter associated with CBZ-resistant epilepsy significantly. EPHX1 methylation may be the potential marker for CBZ resistance prior to the CBZ therapy and potential target for treatments.
ESTHER : Lv_2019_BMC.Neurol_19_114
PubMedSearch : Lv_2019_BMC.Neurol_19_114
PubMedID: 31164100

Title : Development of the hidden multifunctional agents for Alzheimer's disease - Huang_2019_Eur.J.Med.Chem_177_247
Author(s) : Huang W , Liang M , Li Q , Zheng X , Zhang C , Wang Q , Tang L , Zhang Z , Wang B , Shen Z
Ref : Eur Journal of Medicinal Chemistry , 177 :247 , 2019
Abstract : Alzheimer's disease (AD) is a chronic, fatal and complex neurodegenerative disorder, which is characterized by cholinergic system dysregulation, metal dyshomeostasis, amyloid-beta (Abeta) aggregation, etc. Therefore in most cases, single-target or single-functional agents are insufficient to achieve the desirable effect against AD. Multi-Target-Directed Ligand (MTDL), which is rationally designed to simultaneously hit multiple targets to improve the pharmacological profiles, has been developed as a promising approach for drug discovery against AD. To identify the multifunctional agents for AD, we developed an innovative method to successfully conceal the metal chelator into acetylcholinesterase (AChE) inhibitor. Briefly, the "hidden" agents first cross the Blood Brain Barrier (BBB) to inhibit the function of AChE, and the metal chelator will then be released via the enzymatic hydrolysis by AChE. Therefore, the AChE inhibitor, in this case, is not only a single-target agent against AD, but also a carrier of the metal chelator. In this study a total of 14 quinoline derivatives were synthesized and biologically evaluated. Both in vitro and in vivo results demonstrated that compound 9b could cross the BBB efficiently, then release 8a, the metabolite of 9b, into brain. In vitro, 9b had a potent AChE inhibitory activity, while 8a displayed a significant metal ion chelating function, therefore in combination, both 9b and 8a exhibited a considerable inhibition of Abeta aggregation, one of the observations that plays important roles in the pathogenesis of AD. The efficacy of 9b against AD was further investigated in both a zebrafish model and two different mice models.
ESTHER : Huang_2019_Eur.J.Med.Chem_177_247
PubMedSearch : Huang_2019_Eur.J.Med.Chem_177_247
PubMedID: 31158742

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 : Expression and characterisation of feruloyl esterases from Lactobacillus fermentum JN248 and release of ferulic acid from wheat bran - Deng_2019_Int.J.Biol.Macromol_138_272
Author(s) : Deng H , Jia P , Jiang J , Bai Y , Fan TP , Zheng X , Cai Y
Ref : Int J Biol Macromol , 138 :272 , 2019
Abstract : Genes encoding six feruloyl esterases (FAEs; lbff0997, lbff0272, lbff1432, lbff1695, lbff1849, lbff0153) from Lactobacillus fermentum JN248 were cloned, overexpressed and characterised. Maximum enzyme activity was observed at 35 degrees C for recombinant FAEs LFFae0997, LFFae0272 and LFFae0153, at 30 degrees C for LFFae1695, and at 40 degrees C for LFFae1432and LFFae1849. For five of the enzymes, optimal activity was observed at pH7.0 or pH8.0, and high thermostability was measured up to 55 degrees C. By contrast, LFFae1432 lost less than 10.0% activity after incubation at 40 degrees C for 2h, and pH stability was highest between pH7.0 and pH9.0. In addition, LFFae1432 was the most robust esterase, with a higher affinity and hydrolytic activity against synthetic esters. The enzymes released ferulic acids (FAs) from de-starched wheat bran (DSWB), and 60.7% of the total alkali-extractable FAs were released when LFFae1432 was added alone, compared with less than 10% for the other enzymes. The amount of FAs released by FAEs increased when combined with xylanase. These FAEs could serve as promising biocatalysts for biodegradation, and LFFae1432 may hold promise for potential industrial applications.
ESTHER : Deng_2019_Int.J.Biol.Macromol_138_272
PubMedSearch : Deng_2019_Int.J.Biol.Macromol_138_272
PubMedID: 31306699

Title : Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer's Disease - Wu_2018_Molecules_23_
Author(s) : Wu W , Liang X , Xie G , Chen L , Liu W , Luo G , Zhang P , Yu L , Zheng X , Ji H , Zhang C , Yi W
Ref : Molecules , 23 : , 2018
Abstract : A series of novel ligustrazine derivatives 8a(-)r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer's disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC50 values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC50 BuChE/IC50 AChE = 2.91 x 10(6); for 8r, IC50 BuChE/IC50 AChE = 1.32 x 10(7)). Of note, 8q and 8r also presented potent inhibitory activities against Abeta aggregation, with IC50 values of 17.36 microM and 49.14 microM, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 muM. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest.
ESTHER : Wu_2018_Molecules_23_
PubMedSearch : Wu_2018_Molecules_23_
PubMedID: 30301153

Title : One-step methodology for the direct covalent capture of GPCRs from complex matrices onto solid surfaces based on the bioorthogonal reaction between haloalkane dehalogenase and chloroalkanes - Zeng_2018_Chem.Sci_9_446
Author(s) : Zeng K , Li Q , Wang J , Yin G , Zhang Y , Xiao C , Fan T , Zhao X , Zheng X
Ref : Chem Sci , 9 :446 , 2018
Abstract : Protein immobilization techniques play an important role in the development of assays for disease diagnosis and drug discovery. However, many of these approaches are not applicable to transmembrane proteins. G protein-coupled receptors (GPCRs) are the largest protein superfamily encoded by the human genome and are targeted by a quarter of all prescription drugs. GPCRs are highly dynamic and sensitive to changes in the ambient environment, and current immobilization methodologies are not suitable for GPCRs. We used haloalkane dehalogenase (Halo) as an immobilization tag fused to the beta2-adrenoceptor (beta2-AR), angiotensin II type 1 (AT1) and angiotensin II type 2 (AT2) receptors. The engineered Halo-tag covalently binds to a specific substrate chloroalkane through Asp 106 in the catalytic pocket. The Halo-tagged GPCRs were expressed in Escherichia coli at a suitable yield. Accordingly, we loaded cell lysate containing Halo-tagged GPCRs onto a macroporous silica gel coated with chloroalkane. Morphological characterization indicated a homogeneous monolayer of immobilized Halo-tagged GPCRs on the silica gel surface. The immobilized receptors proved to be surrounded by specific bound phospholipids including PG C18:1/C18:1. We observed a radio-ligand binding ability and ligand-induced conformational changes in the immobilized GPCRs, suggesting the preservation of bioactivity. This method is a one-step approach for the specific immobilization of GPCRs from cell lysates and validates that immobilized receptors retain canonical ligand binding capacity. Our immobilization strategy circumvents labor-intensive purification procedures and minimizes loss of activity. The immobilized receptors can be applied to high-throughput drug and interaction partner screening for GPCRs.
ESTHER : Zeng_2018_Chem.Sci_9_446
PubMedSearch : Zeng_2018_Chem.Sci_9_446
PubMedID: 29629116

Title : Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer's Disease - Mao_2018_ACS.Chem.Neurosci_9_328
Author(s) : Mao F , Wang H , Ni W , Zheng X , Wang M , Bao K , Ling D , Li X , Xu Y , Zhang H , Li J
Ref : ACS Chem Neurosci , 9 :328 , 2018
Abstract : Through drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer's disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Importantly, 1w.Cit (citrate of 1w) could reverse the cognitive dysfunction of scopolamine-induced AD mice and exhibited an excellent effect on enhancing cAMP response element-binding protein (CREB) phosphorylation in vivo, a crucial factor in memory formation and synaptic plasticity. Moreover, the molecular docking simulations of 1w with hAChE and hPDE5A confirmed that our design strategy was rational. In summary, our research provides a potential selective dual-target AChE/PDE5 inhibitor as a good candidate drug for the treatment of AD, and it could also be regarded as a small molecule probe to validate the novel AD therapeutic approach in vivo.
ESTHER : Mao_2018_ACS.Chem.Neurosci_9_328
PubMedSearch : Mao_2018_ACS.Chem.Neurosci_9_328
PubMedID: 29068218

Title : Novel Tadalafil Derivatives Ameliorates Scopolamine-Induced Cognitive Impairment in Mice via Inhibition of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) - Ni_2018_ACS.Chem.Neurosci_9_1625
Author(s) : Ni W , Wang H , Li X , Zheng X , Wang M , Zhang J , Gong Q , Ling D , Mao F , Zhang H , Li J
Ref : ACS Chem Neurosci , 9 :1625 , 2018
Abstract : On the basis of the drug-repositioning and redeveloping strategy, first-generation dual-target inhibitors of acetylcholinesterase (AChE) and phosphodiesterase 5 (PDE5) have been recently reported as a potentially novel therapeutic method for the treatment of Alzheimer's disease (AD), and the lead compound 2 has proven this method was feasible in AD mouse models. In this study, our work focused on exploring alternative novel tadalafil derivatives (3a-s). Among the 19 analogues, compound 3c exhibited good selective dual-target AChE/PDE5 inhibition and good blood-brain barrier (BBB) permeability. Moreover, its citrate (3c.Cit) possessed improved water solubility and good effects against scopolamine-induced cognitive impairment with inhibition of cortical AChE activities and enhancement of cAMP response element-binding protein (CREB) phosphorylation ex vivo.
ESTHER : Ni_2018_ACS.Chem.Neurosci_9_1625
PubMedSearch : Ni_2018_ACS.Chem.Neurosci_9_1625
PubMedID: 29616790

Title : Rational Design of a Red-Emissive Fluorophore with AIE and ESIPT Characteristics and Its Application in Light-Up Sensing of Esterase - Peng_2017_Anal.Chem_89_3162
Author(s) : Peng L , Xu S , Zheng X , Cheng X , Zhang R , Liu J , Liu B , Tong A
Ref : Analytical Chemistry , 89 :3162 , 2017
Abstract : The development of red fluorophores with efficient solid-state emission is still challenging. Herein, a red fluorophore 1 with aggregation-induced emission (AIE) and excited-state intramolecular proton transfer (ESIPT) characteristics is rationally designed and facilely synthesized by attaching an electron-donor diethylamine and an electron-acceptor maleonitrile group to salicyladazine. In contrast to many red fluorophores which undergo serious aggregation-caused quenching (ACQ), compound 1 emits bright red fluorescence (lambdaem = 650 nm, PhiF = 24.3%) in the solid state with a large Stokes shift of 174 nm. Interestingly, control compounds 2 and 3, which have similar structures as 1, exhibit obvious aggregation-caused quenching (ACQ) characteristics. The difference in the crystal structures of 1, 2, and 3 reveals that the interplanar spacing among molecules plays a decisive role in realizing the AIE characteristics of 1. Moreover, when the hydroxyl group of 1 was substituted by an esterase reactive acetoxyl, a fluorescence light-up probe 4 was developed for sensing of esterase based on the selective reaction between 4 and esterase to generate the AIE and ESIPT active molecule 1. The linear range for in vitro quantification of esterase is 0.01-0.15 U/mL with a detection limit of 0.005 U/mL. Probe 4 was also successfully applied to image esterase in mitochondria of living cells.
ESTHER : Peng_2017_Anal.Chem_89_3162
PubMedSearch : Peng_2017_Anal.Chem_89_3162
PubMedID: 28192960

Title : Metabolic Enzymes of Cocaine Metabolite Benzoylecgonine - Chen_2016_ACS.Chem.Biol_11_2186
Author(s) : Chen X , Zheng X , Zhan M , Zhou Z , Zhan CG , Zheng F
Ref : ACS Chemical Biology , 11 :2186 , 2016
Abstract : Cocaine is one of the most addictive drugs without a U.S. Food and Drug Administration (FDA)-approved medication. Enzyme therapy using an efficient cocaine-metabolizing enzyme is recognized as the most promising approach to cocaine overdose treatment. The actual enzyme, known as RBP-8000, under current clinical development for cocaine overdose treatment is our previously designed T172R/G173Q mutant of bacterial cocaine esterase (CocE). The T172R/G173Q mutant is effective in hydrolyzing cocaine but inactive against benzoylecgonine (a major, biologically active metabolite of cocaine). Unlike cocaine itself, benzoylecgonine has an unusually stable zwitterion structure resistant to further hydrolysis in the body and environment. In fact, benzoylecgonine can last in the body for a very long time (a few days) and, thus, is responsible for the long-term toxicity of cocaine and a commonly used marker for drug addiction diagnosis in pre-employment drug tests. Because CocE and its mutants are all active against cocaine and inactive against benzoylecgonine, one might simply assume that other enzymes that are active against cocaine are also inactive against benzoylecgonine. Here, through combined computational modeling and experimental studies, we demonstrate for the first time that human butyrylcholinesterase (BChE) is actually active against benzoylecgonine, and that a rationally designed BChE mutant can not only more efficiently accelerate cocaine hydrolysis but also significantly hydrolyze benzoylecgonine in vitro and in vivo. This sets the stage for advanced studies to design more efficient mutant enzymes valuable for the development of an ideal cocaine overdose enzyme therapy and for benzoylecgonine detoxification in the environment.
ESTHER : Chen_2016_ACS.Chem.Biol_11_2186
PubMedSearch : Chen_2016_ACS.Chem.Biol_11_2186
PubMedID: 27224254

Title : Development of Multifunctional Pyrimidinylthiourea Derivatives as Potential Anti-Alzheimer Agents - Li_2016_J.Med.Chem_59_8326
Author(s) : Li X , Wang H , Lu Z , Zheng X , Ni W , Zhu J , Fu Y , Lian F , Zhang N , Li J , Zhang H , Mao F
Ref : Journal of Medicinal Chemistry , 59 :8326 , 2016
Abstract : Starting from a screening-hit compound, via structure modifications and optimizations, a series of nonfused and nonassembly pyrimidinylthiourea derivatives (2-5) was designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease. Biological activity results demonstrated that compounds 5r and 5t exhibited potent inhibition and excellent selectivity toward acetylcholinesterase (AChE, 5r, IC50 = 0.204 muM, SI > 196; 5t, IC50 = 0.067 muM, SI > 597), specific metal-chelating ability, significant antioxidant effects, modulation of metal-induced Abeta aggregation, inhibition of ROS production by copper redox cycle, low cytotoxicity, and moderate neuroprotection to human neuroblastoma SH-SY5Y cells. Moreover, compound 5r displayed appropriate blood-brain barrier (BBB) permeability both in vitro and in vivo and could improve memory and cognitive function of scopolamine-induced amnesia mice. The multifunctional profiles of 5r and its effectivity in AD mice highlight these structurally distinct pyrimidinylthiourea derivatives as prospective prototypes in the research of innovative multifunctional drugs for Alzheimer's disease.
ESTHER : Li_2016_J.Med.Chem_59_8326
PubMedSearch : Li_2016_J.Med.Chem_59_8326
PubMedID: 27552582

Title : Characterization of a Desiccation Stress Induced Lipase Gene from Brassica napus L. - Zhang_2016_J.Agr.Sci.Tech_18_1129
Author(s) : Zhang H , Zhou J , Zheng X , Zhang Z , Wang Z , Tan X
Ref : J Agr Sci Tech , 18 :1129 , 2016
Abstract : Lipases are known to have important functions in many physiological processes in plants. Here, we cloned a lipase gene via Rapid Amplification of cDNA Ends (RACE) technique from Brassica napus L., designated as BnDIL1 (B. napus Desiccation-Induced Lipase 1). The lipase enzyme activity was confirmed by estimating the lipase activity and reduced lipids content in Saccharomyces cerevisiae (pep4) transformant. Two B. napus lines with different oil contents were employed to examine the transcription profiles of BnDIL1 during the processes of seed morphogenesis, maturation, dormancy, pregermination and germination. The transcription level of lipid degradation pathway was enhanced during the processes of seed maturation, dormancy, pregermination and germination, and was higher in seeds of low oil-contents line than that of high oil-contents line. However, BnDIL1 was significantly activated when seed desiccation started. Both slow desiccation and -fast desiccation- treatments on seedlings dramatically activated the transcription of BnDIL1, while only -slow desiccation- stress, which would induce the cell apoptosis, significantly activated the transcription of lipid degradation gene. This result demonstrated that BnDIL1 in B. napus was desiccation stress dependent gene rather than fatty acids degradation gene.
ESTHER : Zhang_2016_J.Agr.Sci.Tech_18_1129
PubMedSearch : Zhang_2016_J.Agr.Sci.Tech_18_1129
PubMedID:

Title : Effects of a cocaine hydrolase engineered from human butyrylcholinesterase on metabolic profile of cocaine in rats - Chen_2016_Chem.Biol.Interact_259_104
Author(s) : Chen X , Zheng X , Zhou Z , Zhan CG , Zheng F
Ref : Chemico-Biological Interactions , 259 :104 , 2016
Abstract : Accelerating cocaine metabolism through enzymatic hydrolysis at cocaine benzoyl ester is recognized as a promising therapeutic approach for cocaine abuse treatment. Our more recently designed A199S/F227A/S287G/A328W/Y332G mutant of human BChE, denoted as cocaine hydrolase-3 (CocH3), has a considerably improved catalytic efficiency against cocaine and has been proven active in blocking cocaine-induced toxicity and physiological effects. In the present study, we have further characterized the effects of CocH3 on the detailed metabolic profile of cocaine in rats administrated intravenously (IV) with 5 mg/kg cocaine, demonstrating that IV administration of 0.15 mg/kg CocH3 dramatically changed the metabolic profile of cocaine. Without CocH3 administration, the dominant cocaine-metabolizing pathway in rats was cocaine methyl ester hydrolysis to benzoylecgonine (BZE). With the CocH3 administration, the dominant cocaine-metabolizing pathway in rats became cocaine benzoyl ester hydrolysis to ecgonine methyl ester (EME), and the other two metabolic pathways (i.e. cocaine methyl ester hydrolysis to BZE and cocaine oxidation to norcocaine) became insignificant. The CocH3-catalyzed cocaine benzoyl ester hydrolysis to EME was so efficient such that the measured maximum blood cocaine concentration ( approximately 38 ng/ml) was significantly lower than the threshold blood cocaine concentration ( approximately 72 ng/ml) required to produce any measurable physiological effects.
ESTHER : Chen_2016_Chem.Biol.Interact_259_104
PubMedSearch : Chen_2016_Chem.Biol.Interact_259_104
PubMedID: 27154495

Title : Potential anti-obesity effects of a long-acting cocaine hydrolase - Zheng_2016_Chem.Biol.Interact_259_99
Author(s) : Zheng X , Deng J , Zhang T , Yao J , Zheng F , Zhan CG
Ref : Chemico-Biological Interactions , 259 :99 , 2016
Abstract : A long-acting cocaine hydrolase, known as CocH3-Fc(M3), engineered from human butyrylcholinesterase (BChE) was tested, in this study, for its potential anti-obesity effects. Mice on a high-fat diet gained significantly less body weight when treated weekly with 1 mg/kg CocH3-Fc(M3) compared to control mice, though their food intake was similar. There is no correlation between the average body weight and the average food intake, which is consistent with the previously reported observation in BChE knockout mice. In addition, molecular modeling was carried out to understand how ghrelin binds with CocH3, showing that ghrelin binds with CocH3 in a similar mode as ghrelin binding with wild-type human BChE. The similar binding structure mode explains why CocH3 has a similar catalytic activity against ghrelin.
ESTHER : Zheng_2016_Chem.Biol.Interact_259_99
PubMedSearch : Zheng_2016_Chem.Biol.Interact_259_99
PubMedID: 27163854

Title : Discovery of novel feruloyl esterase activity of BioH in Escherichia coli BL21(DE3) - Kang_2016_Biotechnol.Lett_38_1009
Author(s) : Kang L , Bai Y , Cai Y , Zheng X
Ref : Biotechnol Lett , 38 :1009 , 2016
Abstract : OBJECTIVES: To characterize a novel feruloyl esterase from Escherichia coli BL21 DE3.
RESULTS: The gene encoding BioH was cloned and overexpressed in E. coli. The protein was purified and its catalytic activity was assessed. BioH exhibited feruloyl esterase activity toward a broad range of substrates, and the corresponding kinetic constants for the methyl ferulate, ethyl ferulate, and methyl p-coumarate substrates were: K m values of 0.48, 6.3, and 1.9 mM, respectively, and k cat /K m values of 9.3, 3.8, and 3.8 mM(-1) s(-1), respectively.
CONCLUSIONS: Feruloyl esterase from E. coli was expressed for the first time. BioH was confirmed to be a feruloyl esterase.
ESTHER : Kang_2016_Biotechnol.Lett_38_1009
PubMedSearch : Kang_2016_Biotechnol.Lett_38_1009
PubMedID: 26956238

Title : Structure activity relationship studies on chemically non-reactive glycine sulfonamide inhibitors of diacylglycerol lipase - Chupak_2016_Bioorg.Med.Chem_24_1455
Author(s) : Chupak LS , Zheng X , Hu S , Huang Y , Ding M , Lewis MA , Westphal RS , Blat Y , McClure A , Gentles RG
Ref : Bioorganic & Medicinal Chemistry , 24 :1455 , 2016
Abstract : N-Benzylic-substituted glycine sulfonamides that reversibly inhibit diacylglycerol (DAG) lipases are reported. Detailed herein are the structure activity relationships, profiling characteristics and physico-chemical properties for the first reported series of DAG lipase (DAGL) inhibitors that function without covalent attachment to the enzyme. Highly potent examples are presented that represent valuable tool compounds for studying DAGL inhibition and constitute important leads for future medicinal chemistry efforts.
ESTHER : Chupak_2016_Bioorg.Med.Chem_24_1455
PubMedSearch : Chupak_2016_Bioorg.Med.Chem_24_1455
PubMedID: 26917221

Title : Genome analysis of three Pneumocystis species reveals adaptation mechanisms to life exclusively in mammalian hosts - Ma_2016_Nat.Commun_7_10740
Author(s) : Ma L , Chen Z , Huang da W , Kutty G , Ishihara M , Wang H , Abouelleil A , Bishop L , Davey E , Deng R , Deng X , Fan L , Fantoni G , FitzGerald M , Gogineni E , Goldberg JM , Handley G , Hu X , Huber C , Jiao X , Jones K , Levin JZ , Liu Y , Macdonald P , Melnikov A , Raley C , Sassi M , Sherman BT , Song X , Sykes S , Tran B , Walsh L , Xia Y , Yang J , Young S , Zeng Q , Zheng X , Stephens R , Nusbaum C , Birren BW , Azadi P , Lempicki RA , Cuomo CA , Kovacs JA
Ref : Nat Commun , 7 :10740 , 2016
Abstract : Pneumocystis jirovecii is a major cause of life-threatening pneumonia in immunosuppressed patients including transplant recipients and those with HIV/AIDS, yet surprisingly little is known about the biology of this fungal pathogen. Here we report near complete genome assemblies for three Pneumocystis species that infect humans, rats and mice. Pneumocystis genomes are highly compact relative to other fungi, with substantial reductions of ribosomal RNA genes, transporters, transcription factors and many metabolic pathways, but contain expansions of surface proteins, especially a unique and complex surface glycoprotein superfamily, as well as proteases and RNA processing proteins. Unexpectedly, the key fungal cell wall components chitin and outer chain N-mannans are absent, based on genome content and experimental validation. Our findings suggest that Pneumocystis has developed unique mechanisms of adaptation to life exclusively in mammalian hosts, including dependence on the lungs for gas and nutrients and highly efficient strategies to escape both host innate and acquired immune defenses.
ESTHER : Ma_2016_Nat.Commun_7_10740
PubMedSearch : Ma_2016_Nat.Commun_7_10740
PubMedID: 26899007
Gene_locus related to this paper: pnec8-a0a0w4zi95 , pnemu-m7nra0 , pnej8-l0pgn2 , pnemu-m7nsb0

Title : Intranasal H102 Peptide-Loaded Liposomes for Brain Delivery to Treat Alzheimer's Disease - Zheng_2015_Pharm.Res_32_3837
Author(s) : Zheng X , Shao X , Zhang C , Tan Y , Liu Q , Wan X , Zhang Q , Xu S , Jiang X
Ref : Pharm Res , 32 :3837 , 2015
Abstract : PURPOSE: H102, a novel beta-sheet breaker peptide, was encapsulated into liposomes to reduce its degradation and increase its brain penetration through intranasal administration for the treatment of Alzheimer's disease (AD).
METHODS: The H102 liposomes were prepared using a modified thin film hydration method, and their transport characteristics were tested on Calu-3 cell monolayers. The pharmacokinetics in rats' blood and brains were also investigated. Behavioral experiments were performed to evaluate the improvements on AD rats' spatial memory impairment. The neuroprotective effects were tested by detecting acetylcholinesterase (AchE), choline acetyltransferase (ChAT) and insulin degrading enzyme (IDE) activity and conducting histological assays. The safety was evaluated on rats' nasal mucosa and cilia.
RESULTS: The liposomes prepared could penetrate Calu-3 cell monolayers consistently. After intranasal administration, H102 could be effectively delivered to the brain, and the AUC of H102 liposomes in the hippocampus was 2.92-fold larger than that of solution group. H102 liposomes could excellently ameliorate spatial memory impairment of AD model rats, increase the activities of ChAT and IDE and inhibit plaque deposition, even in a lower dosage compared with H102 intranasal solution. H102 nasal formulations showed no toxicity on nasal mucosa.
CONCLUSIONS: The H102-loaded liposome prepared in this study for nasal administration is stable, effective and safe, which has great potential for AD treatment.
ESTHER : Zheng_2015_Pharm.Res_32_3837
PubMedSearch : Zheng_2015_Pharm.Res_32_3837
PubMedID: 26113236

Title : Kinetic characterization of a cocaine hydrolase engineered from mouse butyrylcholinesterase - Chen_2015_Biochem.J_466_243
Author(s) : Chen X , Huang X , Geng L , Xue L , Hou S , Zheng X , Brimijoin S , Zheng F , Zhan CG
Ref : Biochemical Journal , 466 :243 , 2015
Abstract : Mouse butyrylcholinesterase (mBChE) and an mBChE-based cocaine hydrolase (mCocH, i.e. the A199S/S227A/S287G/A328W/Y332G mutant) have been characterized for their catalytic activities against cocaine, i.e. naturally occurring (-)-cocaine, in comparison with the corresponding human BChE (hBChE) and an hBChE-based cocaine hydrolase (hCocH, i.e. the A199S/F227A/S287G/A328W/Y332G mutant). It has been demonstrated that mCocH and hCocH have improved the catalytic efficiency of mBChE and hBChE against (-)-cocaine by ~8- and ~2000-fold respectively, although the catalytic efficiencies of mCocH and hCocH against other substrates, including acetylcholine (ACh) and butyrylthiocholine (BTC), are close to those of the corresponding wild-type enzymes mBChE and hBChE. According to the kinetic data, the catalytic efficiency (kcat/KM) of mBChE against (-)-cocaine is comparable with that of hBChE, but the catalytic efficiency of mCocH against (-)-cocaine is remarkably lower than that of hCocH by ~250-fold. The remarkable difference in the catalytic activity between mCocH and hCocH is consistent with the difference between the enzyme-(-)-cocaine binding modes obtained from molecular modelling. Further, both mBChE and hBChE demonstrated substrate activation for all of the examined substrates [(-)-cocaine, ACh and BTC] at high concentrations, whereas both mCocH and hCocH showed substrate inhibition for all three substrates at high concentrations. The amino-acid mutations have remarkably converted substrate activation of the enzymes into substrate inhibition, implying that the rate-determining step of the reaction in mCocH and hCocH might be different from that in mBChE and hBChE.
ESTHER : Chen_2015_Biochem.J_466_243
PubMedSearch : Chen_2015_Biochem.J_466_243
PubMedID: 25486543
Gene_locus related to this paper: human-BCHE

Title : Kinetic characterization of human butyrylcholinesterase mutants for the hydrolysis of cocaethylene - Hou_2014_Biochem.J_460_447
Author(s) : Hou S , Zhan M , Zheng X , Zhan CG , Zheng F
Ref : Biochemical Journal , 460 :447 , 2014
Abstract : It is known that the majority of cocaine users also consume alcohol. Alcohol can react with cocaine to produce a significantly more cytotoxic compound, cocaethylene. Hence a truly valuable cocaine-metabolizing enzyme as treatment for cocaine abuse/overdose should be efficient for not only cocaine itself, but also cocaethylene. The catalytic parameters (kcat and KM) of human BChE (butyrylcholinesterase) and two mutants (known as cocaine hydrolases E14-3 and E12-7) for cocaethylene are characterized in the present study, for the first time, in comparison with those for cocaine. On the basis of the obtained kinetic data, wild-type human BChE has a lower catalytic activity for cocaethylene (kcat=3.3 min-1, KM=7.5 muM and kcat/KM=4.40x105 M-1.min-1) compared with its catalytic activity for (-)-cocaine. E14-3 and E12-7 have a considerably improved catalytic activity against cocaethylene compared with the wild-type BChE. E12-7 is identified as the most efficient enzyme for hydrolysing cocaethylene in addition to its high activity for (-)-cocaine. E12-7 has an 861-fold improved catalytic efficiency for cocaethylene (kcat=3600 min-1, KM=9.5 muM and kcat/KM=3.79x108 M-1.min-1). It has been demonstrated that E12-7 as an exogenous enzyme can indeed rapidly metabolize cocaethylene in rats. Further kinetic modelling has suggested that E12-7 with an identical concentration as that of the endogenous BChE in human plasma can effectively eliminate (-)-cocaine, cocaethylene and norcocaine in simplified kinetic models of cocaine abuse and overdose associated with the concurrent use of cocaine and alcohol.
ESTHER : Hou_2014_Biochem.J_460_447
PubMedSearch : Hou_2014_Biochem.J_460_447
PubMedID: 24870023

Title : Probing the molecular determinant of the lipase-specific foldase Lif26 for the interaction with its cognate Lip26 - Zheng_2012_Int.J.Biol.Macromol_53C_54
Author(s) : Zheng X , Tian J , Wu N , Fan Y
Ref : Int J Biol Macromol , 53C :54 , 2012
Abstract : As a steric chaperone, the lipase-specific foldase Lif26 from Acinetobacter sp. XMZ-26 is required for correct folding of the lipase Lip26 in in vivo co-expression and in vitro refolding systems. Lif26 interacts with Lip26 as determined by yeast two hybrid assays in vivo and GST pull-down experiments in vitro. To study the molecular determinants of the interaction between Lif26 and Lip26, a homology model-based screening of residues, molecular dynamics (MD) simulation-based calculation of interaction energies, and site-directed mutagenesis to alter individual screened residues were applied. One conserved amino acid in the C-terminal mini-domain of Lif26, Arg332, was involved in the interaction with Lip26. Arg332 could not be replaced by any other residue, based on saturated site-directed mutagenesis, and it formed a conserved and stable salt bridge with Glu112 of Lip26, which may contribute to binding specificity. The residues surrounding Arg332, such as Trp288 in alpha9, likely stabilized Arg332 in the proper conformation for the interaction with Lip26.
ESTHER : Zheng_2012_Int.J.Biol.Macromol_53C_54
PubMedSearch : Zheng_2012_Int.J.Biol.Macromol_53C_54
PubMedID: 23153763
Gene_locus related to this paper: 9gamm-d7nn81

Title : Crystal structure of a novel esterase Rv0045c from Mycobacterium tuberculosis - Zheng_2011_PLoS.One_6_e20506
Author(s) : Zheng X , Guo J , Xu L , Li H , Zhang D , Zhang K , Sun F , Wen T , Liu S , Pang H
Ref : PLoS ONE , 6 :e20506 , 2011
Abstract : There are at least 250 enzymes in Mycobacterium tuberculosis (M. tuberculosis) involved in lipid metabolism. Some of the enzymes are required for bacterial survival and full virulence. The esterase Rv0045c shares little amino acid sequence similarity with other members of the esterase/lipase family. Here, we report the 3D structure of Rv0045c. Our studies demonstrated that Rv0045c is a novel member of alpha/beta hydrolase fold family. The structure of esterase Rv0045c contains two distinct domains: the alpha/beta fold domain and the cap domain. The active site of esterase Rv0045c is highly conserved and comprised of two residues: Ser154 and His309. We proposed that Rv0045c probably employs two kinds of enzymatic mechanisms when hydrolyzing C-O ester bonds within substrates. The structure provides insight into the hydrolysis mechanism of the C-O ester bond, and will be helpful in understanding the ester/lipid metabolism in M. tuberculosis.
ESTHER : Zheng_2011_PLoS.One_6_e20506
PubMedSearch : Zheng_2011_PLoS.One_6_e20506
PubMedID: 21637775
Gene_locus related to this paper: myctu-RV0045C

Title : Drug-like leads for steric discrimination between substrate and inhibitors of human acetylcholinesterase - Wildman_2011_Chem.Biol.Drug.Des_78_495
Author(s) : Wildman SA , Zheng X , Sept D , Auletta JT , Rosenberry TL , Marshall GR
Ref : Chemical Biology Drug Des , 78 :495 , 2011
Abstract : Protection of the enzyme acetylcholinesterase (AChE) from the toxic effects of organophosphate insecticides and chemical warfare agents (OPs) may be provided by inhibitors that bind at the peripheral binding site (P-site) near the mouth of the active-site gorge. Compounds that bind to this site may selectively block access to the acylation site (A-site) catalytic serine for OPs, but not acetylcholine itself. To identify such compounds, we employed a virtual screening approach using AutoDock 4.2 and AutoDock Vina, confirmed using compounds experimentally known to bind specifically to either the A-site or P-site. Both programs demonstrated the ability to correctly predict the binding site. Virtual screening of the NCI Diversity Set II was conducted using the apo form of the enzyme, and with acetylcholine bound at the crystallographic locations in the A-site only and in both and A- and P-sites. The docking identified 32 compounds that were obtained for testing, and one was demonstrated to bind specifically to the P-site in an inhibitor competition assay.
ESTHER : Wildman_2011_Chem.Biol.Drug.Des_78_495
PubMedSearch : Wildman_2011_Chem.Biol.Drug.Des_78_495
PubMedID: 21668653

Title : A novel cold-adapted lipase from Acinetobacter sp. XMZ-26: gene cloning and characterisation - Zheng_2011_Appl.Microbiol.Biotechnol_90_971
Author(s) : Zheng X , Chu X , Zhang W , Wu N , Fan Y
Ref : Applied Microbiology & Biotechnology , 90 :971 , 2011
Abstract : Acinetobacter sp. XMZ-26 (ACCC 05422) was isolated from soil samples obtained from glaciers in Xinjiang Province, China. The partial nucleotide sequence of a lipase gene was obtained by touchdown PCR using degenerate primers designed based on the conserved domains of cold-adapted lipases. Subsequently, a complete gene sequence encoding a 317 amino acid polypeptide was identified. Our novel lipase gene, lipA, was overexpressed in Escherichia coli. The recombinant protein (LipA) was purified by Ni-affinity chromatography, and then deeply characterised. The LipA resulted to hydrolyse pNP esters of fatty acids with acyl chain length from C2 to C16, and the preferred substrate was pNP octanoate showing a k(cat) = 560.52 +/- 28.32 s(-1), K(m) = 0.075 +/6 0.008 mM, and a k(cat)/K(m) = 7,377.29 +/- 118.88 s(-1) mM(-1). Maximal LipA activity was observed at a temperature of 15 C and pH 10.0 using pNP decanoate as substrate. That LipA peaked at such a low temperature and remained most activity between 5 C and 35 C indicated that it was a cold-adapted enzyme. Remarkably, this lipase retained much of its activity in the presence of commercial detergents and organic solvents, including Ninol, Triton X-100, methanol, PEG-600, and DMSO. This cold-adapted lipase may find applications in the detergent industry and organic synthesis.
ESTHER : Zheng_2011_Appl.Microbiol.Biotechnol_90_971
PubMedSearch : Zheng_2011_Appl.Microbiol.Biotechnol_90_971
PubMedID: 21336927

Title : [Selective isolation and diversity of cold-adapted lipase-producing strains from permafrost soil at the terminus of a glacier in the Tianshan Mountains] - Xu_2011_Wei.Sheng.Wu.Xue.Bao_51_233
Author(s) : Xu Y , Wang D , Shi X , Zheng X , Zhou H , Liu Y , Ni Y
Ref : Wei Sheng Wu Xue Bao , 51 :233 , 2011
Abstract : OBJECTIVE: The diversity of culturable lipase-producing bacterial strains from permafrost soils at the terminus of a glacier in the Tianshan Mountains was investigated. Isolation and molecular phylogenetic analysis were performed to expand our knowledge on diversity of psychrotrophic and psychrophilic bacteria. In addition, efforts were made focusing on screening for cold active lipases. METHODS: Lipase-producing bacterial strains were detected on tween 80 and olive oil plates, respectively. Identity and genetic diversity of strains isolated were determined by spatial 16S rRNA gene sequences and rep-PCR fingerprint. The physiological tests were carried out to determine the phonotypic differences between strains showing high similarity of 16S rRNA gene sequences. RESULTS: Of the total 17 bacterial stains exhibiting cold-adapted lipase activity, we found that only 8 stains were able to hydrolyze olive oil. Based on 16S rRNA gene sequences, the lipase-producing bacterial isolates fell in five phylogenetic groups: subclasses (, ( and ( of Proteobacteria, Actinobacteria, and the Cytophaga-Flexibacter-Bacteroides (CFB) phylum. Nearly 59% of the isolates were affiliated with the genus Pseudomonas. CONCLUSION: The results enrich our knowledge on the psychrotrophic bacterial diversity and biogeographic distribution of cold active lipases-producing bacteria in cold environments.
ESTHER : Xu_2011_Wei.Sheng.Wu.Xue.Bao_51_233
PubMedSearch : Xu_2011_Wei.Sheng.Wu.Xue.Bao_51_233
PubMedID: 21574385

Title : Direct detection of the hydrolysis of nerve agent model compounds using a fluorescent probe - Zheng_2010_Chem.Biol.Interact_187_330
Author(s) : Zheng X , Okolotowicz K , Wang B , MacDonald M , Cashman JR , Zhang J
Ref : Chemico-Biological Interactions , 187 :330 , 2010
Abstract : Nerve agents are highly toxic organophosphorus compounds (OPs) that are used as chemical warfare agents. Developing a catalytic bioscavenger to efficiently detoxify nerve agents in the bloodstream of affected individuals has been recognized as an attractive approach to prevent nerve agent toxicity. However, the search for nerve agent catalysts has been hindered by the lack of efficient direct assays for nerve agent hydrolysis. In addition, authentic nerve agents are restricted and access to use for experiments by the general research community is prohibited. Herein we report development of a method that combines use of novel nerve agent model compounds possessing a thiocholine leaving group that reacts with the fluorescent thio-detection probe, BES-Thio, to afford detection of sub-micromolar amounts of nerve agent model compounds hydrolysis products. The detection sensitivity of BES-Thio assay was approximately 10 times better than the Ellman assay. This developed method is useful as a direct, sensitive screening method for evaluating OP hydrolysis efficiency from catalytic cholinesterases. When the assay was assembled in the presence of oxime, OP-inhibited cholinesterases that were able to be reactivated by specific oxime showed oxime-assisted enzyme-mediated OP hydrolysis. Therefore, this method is also useful to screen oxime analogs to identify novel agents that can reactivate OP-inhibited cholinesterases or to screen various enzymes to identify pseudo-catalytic bioscavengers that can be readily reactivated by clinically approved oximes.
ESTHER : Zheng_2010_Chem.Biol.Interact_187_330
PubMedSearch : Zheng_2010_Chem.Biol.Interact_187_330
PubMedID: 20097185

Title : Crystallization and preliminary X-ray analysis of a novel esterase Rv0045c from Mycobacterium tuberculosis. - Xu_2010_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_66_1579
Author(s) : Xu L , Guo J , Zheng X , Wen T , Sun F , Liu S , Pang H
Ref : Acta Crystallographica Sect F Struct Biol Cryst Commun , 66 :1579 , 2010
Abstract : The Rv0045c protein is predicted to be an esterase that is involved in lipid metabolism in Mycobacterium tuberculosis. The protein was overproduced in Escherichia coli, purified and crystallized using the hanging-drop vapour-diffusion method. The Rv0045c protein crystals diffracted to a resolution of 2.7A using a synchrotron-radiation source and belonged to space group P3(1) or P3(2), with unit-cell parameters a=b=73.465, c=48.064A, alpha=beta=90, =120deg. Purified SeMet-labelled Rv0045c protein was also crystallized and formed crystals that diffracted to a resolution of 3.0A using an in-house X-ray radiation source.
ESTHER : Xu_2010_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_66_1579
PubMedSearch : Xu_2010_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_66_1579
PubMedID: 21139199
Gene_locus related to this paper: myctu-RV0045C

Title : Characterization of a novel esterase Rv0045c from Mycobacterium tuberculosis - Guo_2010_PLoS.One_5_
Author(s) : Guo J , Zheng X , Xu L , Liu Z , Xu K , Li S , Wen T , Liu S , Pang H
Ref : PLoS ONE , 5 : , 2010
Abstract : BACKGROUND: It was proposed that there are at least 250 enzymes in M. tuberculosis involved in lipid metabolism. Rv0045c was predicted to be a hydrolase by amino acid sequence similarity, although its precise biochemical characterization and function remained to be defined. METHODOLOGY/PRINCIPAL FINDINGS: We expressed the Rv0045c protein to high levels in E. coli and purified the protein to high purity. We confirmed that the prepared protein was the Rv0045c protein by mass spectrometry analysis. Circular dichroism spectroscopy analysis showed that the protein possessed abundant beta-sheet secondary structure, and confirmed that its conformation was stable in the range pH 6.0-10.0 and at temperatures <= 40 degrees C. Enzyme activity analysis indicated that the Rv0045c protein could efficiently hydrolyze short chain p-nitrophenyl esters (C(2)-C(8)), and its suitable substrate was p-nitrophenyl caproate (C(6)) with optimal catalytic conditions of 39 degrees C and pH 8.0. CONCLUSIONS/SIGNIFICANCE: Our results demonstrated that the Rv0045c protein is a novel esterase. These experiments will be helpful in understanding ester/lipid metabolism related to M. tuberculosis.
ESTHER : Guo_2010_PLoS.One_5_
PubMedSearch : Guo_2010_PLoS.One_5_
PubMedID: 20957207
Gene_locus related to this paper: myctu-RV0045C

Title : Protective effects of galantamine against Abeta-induced PC12 cell apoptosis by preventing mitochondrial dysfunction and endoplasmic reticulum stress - Liu_2010_Neurochem.Int_57_588
Author(s) : Liu X , Xu K , Yan M , Wang Y , Zheng X
Ref : Neurochem Int , 57 :588 , 2010
Abstract : Amyloid beta (Abeta) is considered to be responsible for the pathogenesis of Alzheimer's disease (AD). Mitochondrial and ER apoptotic pathways are considered to be involved in this process. Galantamine is an acetylcholinesterase (AChE) inhibitor widely used for patients with AD. In this study, we investigated the neuroprotective effects of galantamine on Abeta(25-35)-induced apoptosis in PC12 cells and the underlying mechanisms. Exposure of PC12 cells to 20 microM Abeta(25-35) caused significant cell viability loss and apoptosis, Abeta aggregation, mitochondrial and ER morphological changes, as well as mitochondrial membrane potential dissipation, reactive oxygen species (ROS) production, intracellular calcium elevation, and cytochrome c release from mitochondria. Pretreatment with 10 microM galantamine for 24 h prior to Abeta(25-35) exposure significantly reduced Abeta(25-35)-induced apoptosis not only by preventing Abeta aggregation, mitochondrial and ER morphological changes, mitochondrial membrane potential dissipation, ROS production, intracellular calcium elevation, and cytochrome c release, but also via reversing Bcl-2/Bax ratio and suppressing the activity of GADD153, Grp78/94, caspase-9, caspase-12, and caspase-3. All these data indicate that galantamine protects PC12 cells against Abeta(25-35)-induced apoptosis by preventing mitochondrial dysfunction and endoplasmic reticulum (ER) stress.
ESTHER : Liu_2010_Neurochem.Int_57_588
PubMedSearch : Liu_2010_Neurochem.Int_57_588
PubMedID: 20655346

Title : Chemical synthesis of two series of nerve agent model compounds and their stereoselective interaction with human acetylcholinesterase and human butyrylcholinesterase - Barakat_2009_Chem.Res.Toxicol_22_1669
Author(s) : Barakat NH , Zheng X , Gilley CB , MacDonald M , Okolotowicz K , Cashman JR , Vyas S , Beck JM , Hadad CM , Zhang J
Ref : Chemical Research in Toxicology , 22 :1669 , 2009
Abstract : Both G and V type nerve agents possess a center of chirality about phosphorus. The S(p) enantiomers are generally more potent inhibitors than their R(p) counterparts toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). To develop model compounds with defined centers of chirality that mimic the target nerve agent structures, we synthesized both the S(p) and the R(p) stereoisomers of two series of G type nerve agent model compounds in enantiomerically enriched form. The two series of model compounds contained identical substituents on the phosphorus as the G type agents, except that thiomethyl (CH(3)-S-) and thiocholine [(CH(3))(3)NCH(2)CH(2)-S-] groups were used to replace the traditional nerve agent leaving groups (i.e., fluoro for GB, GF, and GD and cyano for GA). Inhibition kinetic studies of the thiomethyl- and thiocholine-substituted series of nerve agent model compounds revealed that the S(p) enantiomers of both series of compounds showed greater inhibition potency toward AChE and BChE. The level of stereoselectivity, as indicated by the ratio of the bimolecular inhibition rate constants between S(p) and R(p) enantiomers, was greatest for the GF model compounds in both series. The thiocholine analogues were much more potent than the corresponding thiomethyl analogues. With the exception of the GA model compounds, both series showed greater potency against AChE than BChE. The stereoselectivity (i.e., S(p) > R(p)), enzyme selectivity, and dynamic range of inhibition potency contributed from these two series of compounds suggest that the combined application of these model compounds will provide useful research tools for understanding interactions of nerve agents with cholinesterase and other enzymes involved in nerve agent and organophosphate pharmacology. The potential of and limitations for using these model compounds in the development of biological therapeutics against nerve agent toxicity are also discussed.
ESTHER : Barakat_2009_Chem.Res.Toxicol_22_1669
PubMedSearch : Barakat_2009_Chem.Res.Toxicol_22_1669
PubMedID: 19715346

Title : Multilocus analysis of nucleotide variation of Oryza sativa and its wild relatives: severe bottleneck during domestication of rice - Zhu_2007_Mol.Biol.Evol_24_875
Author(s) : Zhu Q , Zheng X , Luo J , Gaut BS , Ge S
Ref : Molecular Biology Evolution , 24 :875 , 2007
Abstract : Varying degrees of reduction of genetic diversity in crops relative to their wild progenitors occurred during the process of domestication. Such information, however, has not been available for the Asian cultivated rice (Oryza sativa) despite its importance as a staple food and a model organism. To reveal levels and patterns of nucleotide diversity and to elucidate the genetic relationship and demographic history of O. sativa and its close relatives (Oryza rufipogon and Oryza nivara), we investigated nucleotide diversity data from 10 unlinked nuclear loci in species-wide samples of these species. The results indicated that O. rufipogon and O. nivara possessed comparable levels of nucleotide variation ((sil) = 0.0077 approximately 0.0095) compared with the relatives of other crops. In contrast, nucleotide diversity of O. sativa was as low as (sil) = 0.0024 and even lower ((sil) = 0.0021 for indica and 0.0011 for japonica), if we consider the 2 subspecies separately. Overall, only 20-10% of the diversity in the wild species was retained in 2 subspecies of the cultivated rice (indica and japonica), respectively. Because statistic tests did not reject the assumption of neutrality for all 10 loci, we further used coalescent to simulate bottlenecks under various lengths and population sizes to better understand the domestication process. Consistent with the dramatic reduction in nucleotide diversity, we detected a severe domestication bottleneck and demonstrated that the sequence diversity currently found in the rice genome could be explained by a founding population of 1,500 individuals if the initial domestication event occurred over a 3,000-year period. Phylogenetic analyses revealed close genetic relationships and ambiguous species boundary of O. rufipogon and O. nivara, providing additional evidence to treat them as 2 ecotypes of a single species. Lowest linkage disequilibrium (LD) was found in the perennial O. rufipogon where the r(2) value dropped to a negligible level within 400 bp, and the highest in the japonica rice where LD extended to the entirely sequenced region ( approximately 900 bp), implying that LD mapping by genome scans may not be feasible in wild rice due to the high density of markers needed.
ESTHER : Zhu_2007_Mol.Biol.Evol_24_875
PubMedSearch : Zhu_2007_Mol.Biol.Evol_24_875
PubMedID: 17218640
Gene_locus related to this paper: orysa-cbp1

Title : A whole-genome assembly of Drosophila - Myers_2000_Science_287_2196
Author(s) : Myers EW , Sutton GG , Delcher AL , Dew IM , Fasulo DP , Flanigan MJ , Kravitz SA , Mobarry CM , Reinert KH , Remington KA , Anson EL , Bolanos RA , Chou HH , Jordan CM , Halpern AL , Lonardi S , Beasley EM , Brandon RC , Chen L , Dunn PJ , Lai Z , Liang Y , Nusskern DR , Zhan M , Zhang Q , Zheng X , Rubin GM , Adams MD , Venter JC
Ref : Science , 287 :2196 , 2000
Abstract : We report on the quality of a whole-genome assembly of Drosophila melanogaster and the nature of the computer algorithms that accomplished it. Three independent external data sources essentially agree with and support the assembly's sequence and ordering of contigs across the euchromatic portion of the genome. In addition, there are isolated contigs that we believe represent nonrepetitive pockets within the heterochromatin of the centromeres. Comparison with a previously sequenced 2.9- megabase region indicates that sequencing accuracy within nonrepetitive segments is greater than 99. 99% without manual curation. As such, this initial reconstruction of the Drosophila sequence should be of substantial value to the scientific community.
ESTHER : Myers_2000_Science_287_2196
PubMedSearch : Myers_2000_Science_287_2196
PubMedID: 10731133

Title : [Cochleogram for assessing hair cells and efferent fibers in carboplatin-treated ear] - Ding_1999_Lin.Chuang.Er.Bi.Yan.Hou.Ke.Za.Zhi_13_510
Author(s) : Ding D , Li M , Zheng X
Ref : Lin Chuang Er Bi Yan Hou Ke Za Zhi , 13 :510 , 1999
Abstract : OBJECTIVE: This paper describes a convenient histochemical technique that allows one to simultaneously assess the cochlear efferent neurons and inner (IHCs) and outer hair cells (OHCs). METHOD: Selective labeling of the sensory cells and efferent fibers was carried out by first labeling the hair cells for dehydrogenase activity and then staining the efferent fibers for acetylcholinesterase activity. Double-labeled specimens were prepared as a surface preparation and counts were made of the number of hair cells and the number of discreate fiber bundles crossing the tunnel of Corti along the entire length of the cochlea. RESULT: The utility of this technique for assessing ototoxic damage was demonstrated by constructing cochleograms showing the percentage of missing hair cells and tunnel-crossing efferent fibers in chinchillas treated with carboplatin. In the region of the cochlea associated with most IHC loss and a part of OHC missing showed by succinate dehydrogenase in the region of hair cells; however, the loss of tunnel-crossing efferent fibers showed by acetylcholinesterase staining was closely correlated with the percentage of OHC loss. But, if only damage the IHC, the efferent fibers showed normal. CONCLUSION: These results suggest that carboplatin damaged efferent systems may be due to the damage of OHC.
ESTHER : Ding_1999_Lin.Chuang.Er.Bi.Yan.Hou.Ke.Za.Zhi_13_510
PubMedSearch : Ding_1999_Lin.Chuang.Er.Bi.Yan.Hou.Ke.Za.Zhi_13_510
PubMedID: 12541378

Title : [Environmental pollution, human exposure and its health effect of sodium pentachlorophenate in schistosomiasis prevalent area] - Zheng_1997_Wei.Sheng.Yan.Jiu_26_24
Author(s) : Zheng X , Feng Y , Jiang X , Lu H , Wan Y , Fang YQ , Li YP , Huang XY , Li ZL , Fu WZ , Wang XH , Lin YZ , Zhang Z
Ref : Wei Sheng Yan Jiu , 26 :24 , 1997
Abstract : Sodium pentachlorophenate (Na-PCP) has been used in China for years as an molluscacide to kill oncomelania, which is an intermediate host of Schistosome. To evaluate the effects of its long-term successive usage on environment, human exposure and health, studies were carried out in Sichuan, Jiangxi, Jiangsu and Fujian provinces, with a time gap of more than one month between sample collection and last spray of Na-PCP. Results indicated that PCP contents in surface water, soil, sediment, animals and plants were significantly higher in studied areas than in control areas. The daily intake and the content in urine of PCP were also sigificantify higher in studied areas. But, there was no difference on physical and biochemical examinations except that a 22%-28% decrease of blood cholinesterase activity was found in studied areas. The health effect of impurities in Na-PCP, dioxins and furans, was assessed and discussed.
ESTHER : Zheng_1997_Wei.Sheng.Yan.Jiu_26_24
PubMedSearch : Zheng_1997_Wei.Sheng.Yan.Jiu_26_24
PubMedID: 15747456