Tang W

References (27)

Title : Inhibiting PLA2G7 reverses the immunosuppressive function of intratumoral macrophages and augments immunotherapy response in hepatocellular carcinoma - Zhang_2024_J.Immunother.Cancer_12_e008094
Author(s) : Zhang F , Liu W , Meng F , Jiang Q , Tang W , Liu Z , Lin X , Xue R , Zhang S , Dong L
Ref : J Immunother Cancer , 12 : , 2024
Abstract : BACKGROUND: Hepatocellular carcinoma (HCC) is an exceptionally immunosuppressive malignancy characterized by limited treatment options and a dismal prognosis. Macrophages constitute the primary and heterogeneous immune cell population within the HCC microenvironment. Our objective is to identify distinct subsets of macrophages implicated in the progression of HCC and their resistance to immunotherapy. METHODS: Intratumoral macrophage-specific marker genes were identified via single-cell RNA sequencing analyses. The clinical relevance of phospholipase A2 Group VII (PLA2G7), a pivotal enzyme in phospholipid metabolism, was assessed in patients with HCC through immunohistochemistry and immunofluorescence. Flow cytometry and an in vitro co-culture system were used to elucidate the specific role of PLA2G7 in macrophages. Orthotopic and subcutaneous HCC mouse models were employed to evaluate the potential of the PLA2G7 inhibitor in complementing immune checkpoint blockade (ICB) therapy. RESULTS: Single-cell RNA sequencing analyses disclosed predominant PLA2G7 expression in intratumoral macrophages within the HCC microenvironment. The macrophage-specific PLA2G7 was significantly correlated with poorer prognosis and immunotherapy resistance in patients with HCC. PLA2G7(high) macrophages represent a highly immunosuppressive subset and impede CD8 T-cell activation. Pharmacological inhibition of PLA2G7 by darapladib improved the therapeutic efficacy of anti-programmed cell death protein 1 antibodies in the HCC mouse models. CONCLUSIONS: Macrophage-specific PLA2G7 serves as a novel biomarker capable of prognosticating immunotherapy responsiveness and inhibiting PLA2G7 has the potential to enhance the efficacy of ICB therapy for HCC.
ESTHER : Zhang_2024_J.Immunother.Cancer_12_e008094
PubMedSearch : Zhang_2024_J.Immunother.Cancer_12_e008094
PubMedID: 38272562
Gene_locus related to this paper: human-PLA2G7

Title : Serum alkaline phosphatase was independently associated with depression in patients with cerebrovascular disease - Tao_2023_Front.Psychiatry_14_1184673
Author(s) : Tao X , Yang C , He J , Liu Q , Wu S , Tang W , Wang J
Ref : Front Psychiatry , 14 :1184673 , 2023
Abstract : BACKGROUND AND PURPOSE: Blood markers have important value in the diagnosis of depressive disorders. Serum alkaline phosphatase (ALP) not only predicts stroke recurrence and poor functional prognosis in cerebrovascular disease (CVD) patients but also increases significantly in middle-aged women with depression. Thus, it has not been reported whether serum ALP is associated with the development of depression and/or vascular depression (VDe) in CVD patients. METHODS: This was a cross-sectional study of 353 CVD patients (stroke patients, n = 291; cerebral small vessel disease (CSVD) patients, n = 62). Baseline demographic information, fasting blood markers (such as blood counts, liver function, kidney function and lipids), and brain CT/MRI scans were collected. CVD patients were divided into non-depression, suspected vascular depression (SVD), and positive vascular depression (PVD) groups according to their Hamilton Rating Scale for Depression (HAMD) scores. Univariate analysis of baseline data, blood markers, and the prevalence of lesions (> 1.5 cm) was performed. Subsequently, the diagnostic performance of the univariate and combined variables for SVD and PVD was analyzed using binary logistic regression. The diagnostic value of the multivariate model for VDe was analyzed by ordinal logistic regression. RESULTS: (1) Serum ALP (p = 0.003) and hypersensitive C-reactive protein (hs-CRP, p = 0.001) concentrations increased as HAMD scores increased, and the prevalence of brain atrophy (p = 0.016) and lesions in the basal ganglia (p = 0.001) and parietal (p = 0.001), temporal (p = 0.002), and frontal lobes (p = 0.003) also increased, whereas the concentrations of hemoglobin (Hb, p = 0.003), cholinesterase (ChE, p = 0.001), and high-density lipoprotein cholesterol (HDL-C, p = 0.005) declined. Among these variables, hs-CRP (r = 0.218, p < 0.001) had a weak positively association with HAMD scores, and ChE (r = -0.226, p < 0.001) had a weak negative association. (2) The combination of Hb, hs-CRP, ChE, ALP, and HDL-C improved diagnostic performance for VDe [AUC = 0.775, 95% CI (0.706, 0.844), p < 0.001]. (3) Hb (OR = 0.986, p = 0.049), ChE (OR = 0.999, p = 0.020), ALP (OR = 1.017, p = 0.003), and basal ganglia lesions (OR = 2.197, p < 0.001) were important factors impacting VDe development. After adjusting for Hb, hs-CRP, ChE, HDL-C, lesions in the above mentioned four locations, sex, age and the prevalence of CSVD and brain atrophy, ALP [OR = 1.016, 95% CI (1.005, 1.027), p = 0.004] was independently associated with VDe. CONCLUSION: Hb, hs-CRP, ChE, ALP, and HDL-C concentrations are potential blood markers of depression in CVD patients and, when combined, may improve diagnostic performance for VDe. Serum ALP was independently associated with VDe in patients with CVD.
ESTHER : Tao_2023_Front.Psychiatry_14_1184673
PubMedSearch : Tao_2023_Front.Psychiatry_14_1184673
PubMedID: 37469359

Title : Microtiter plate-based chemistry and in situ screening: SuFEx-enabled lead discovery of selective AChE inhibitors - Tang_2023_J.Enzyme.Inhib.Med.Chem_38_2237213
Author(s) : Tang K , Li HH , Wu C , Zhang SL , Yang JG , Tang W , Qin HL
Ref : J Enzyme Inhib Med Chem , 38 :2237213 , 2023
Abstract : Sulphur fluoride exchange (SuFEx) is a category of click chemistry that enables covalent linking of modular units through sulphur connective hubs. Here, we reported an efficient synthesis and in situ screening method for building a library of sulphonamides on the picomolar scale by SuFEx reaction between a sulphonyl fluoride (RSO(2)F) core and primary or secondary amines. This biocompatible SuFEx reaction would allow us to rapidly synthesise sulphonamide molecules, and evaluate their ChE inhibitory activity. Compound T14-A24 was identified as a reversible, competitive, and selective AChE inhibitor (K(i) = 22 nM). The drug-like evaluation showed that T14-A24 had benign BBB penetration, remarkable neuroprotective effect, and safe toxicological profile. In vivo behavioural study showed that T14-A24 treatment improved the Abeta(1 - 42)-induced cognitive impairment, significantly prevented the effects of Abeta(1 - 42) toxicity. Therefore, this SuFEx click reaction can accelerate the discovery of lead compounds.
ESTHER : Tang_2023_J.Enzyme.Inhib.Med.Chem_38_2237213
PubMedSearch : Tang_2023_J.Enzyme.Inhib.Med.Chem_38_2237213
PubMedID: 37501629

Title : Sulfur-fluoride exchange (SuFEx)-enabled lead discovery of AChE inhibitors by fragment linking strategies - Zhang_2023_Eur.J.Med.Chem_257_115502
Author(s) : Zhang Z , Zhang SL , Wu C , Li HH , Zha L , Shi J , Liu X , Qin HL , Tang W
Ref : Eur Journal of Medicinal Chemistry , 257 :115502 , 2023
Abstract : SuFEx click chemistry has been a method for the rapid synthesis of functional molecules with desirable properties. Here, we demonstrated a workflow that allows for in situ synthesis of sulfonamide inhibitors based on SuFEx reaction for high-throughput testing of their cholinesterase activity. According to fragment-based drug discovery (FBDD), sulfonyl fluorides [R-SO(2)F] with moderate activity were identified as fragment hits, rapidly diversified into 102 analogs in SuFEx reactions, and the sulfonamides were directly screened to yield drug-like inhibitors with 70-fold higher potency (IC(50) = 94 nM). Moreover, the improved molecule J8-A34 can ameliorate cognitive function in Abeta(1-42)-induced mouse model. Since this SuFEx linkage reaction succeeds on picomole scale for direct screening, this methodology can accelerate the development of robust biological probes and drug candidates.
ESTHER : Zhang_2023_Eur.J.Med.Chem_257_115502
PubMedSearch : Zhang_2023_Eur.J.Med.Chem_257_115502
PubMedID: 37224761

Title : Aporphines: A privileged scaffold in CNS drug discovery - Zhu_2023_Eur.J.Med.Chem_256_115414
Author(s) : Zhu R , Jiang G , Tang W , Zhao X , Chen F , Zhang X , Ye N
Ref : Eur Journal of Medicinal Chemistry , 256 :115414 , 2023
Abstract : Aporphine alkaloids embedded in 4H-dibenzo[de,g]quinoline four-ring structures belong to one of the largest subclasses of isoquinoline alkaloids. Aporphine is a privileged scaffold in the field of organic synthesis and medicinal chemistry for the discovery of new therapeutic agents for central nervous system (CNS) diseases, cancer, metabolic syndrome, and other diseases. In the past few decades, aporphine has attracted continuing interest to be widely used to develop selective or multitarget directed ligands (MTDLs) targeting the CNS (e.g., dopamine D(1/2/5), serotonin 5-HT(1A/2A/2C) and 5-HT(7), adrenergic alpha/beta receptors, and cholinesterase enzymes), thereby serving as valuable pharmacological probes for mechanism studies or as potential leads for CNS drug discovery. The aims of the present review are to highlight the diverse CNS activities of aporphines, discuss their SAR, and briefly summarize general synthetic routes, which will pave the way for the design and development of new aporphine derivatives as promising CNS active drugs in the future.
ESTHER : Zhu_2023_Eur.J.Med.Chem_256_115414
PubMedSearch : Zhu_2023_Eur.J.Med.Chem_256_115414
PubMedID: 37172474

Title : Fluorosulfate-containing pyrazole heterocycles as selective BuChE inhibitors: structure-activity relationship and biological evaluation for the treatment of Alzheimer's disease - Li_2022_J.Enzyme.Inhib.Med.Chem_37_2099
Author(s) : Li HH , Wu C , Zhang SL , Yang JG , Qin HL , Tang W
Ref : J Enzyme Inhib Med Chem , 37 :2099 , 2022
Abstract : Novel scaffolds are expected to treat Alzheimer's disease, pyrazole-5-fluorosulfates were found as selective BuChE inhibitors. Compounds K1-K26 were assayed for ChE inhibitory activity, amongst them, compound K3 showed potent BuChE and hBuChE inhibition (IC(50) = 0.79 microM and 6.59 microM). SAR analysis showed that 1-, 3-, 4-subtituent and 5-fluorosulfate of pyrazole ring affected BuChE inhibitory activity. Molecular docking showed that the fluorosulfate increased the binding affinity of hBuChE through Pi-sulphur interaction. Compound K3 was a reversible, mixed and non-competitive BuChE inhibitor (K(i) = 0.77 microM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. In vivo behavioural study showed that K3 treatment improved the Abeta(1 - 42)-induced cognitive impairment, and significantly prevented the effects of Abeta(1 - 42) toxicity. Therefore, selective BuChE inhibitor K3 has potential to be further developed as AD therapeutics.
ESTHER : Li_2022_J.Enzyme.Inhib.Med.Chem_37_2099
PubMedSearch : Li_2022_J.Enzyme.Inhib.Med.Chem_37_2099
PubMedID: 35899776

Title : The monoacylglycerol lipase inhibitor, JZL184, has comparable effects to therapeutic hypothermia, attenuating global cerebral injury in a rat model of cardiac arrest - Xu_2022_Biomed.Pharmacother_156_113847
Author(s) : Xu J , Zheng G , Hu J , Ge W , Bradley JL , Ornato JP , Tang W
Ref : Biomed Pharmacother , 156 :113847 , 2022
Abstract : Post-resuscitation cerebral ischemia-reperfusion injury (IRI) is a vital contributor to poor neurological prognosis. Exploring novel therapeutics that attenuate cerebral IRI is of great significance. Inflammation plays a role in the development of cerebral IRI after successful cardiopulmonary resuscitation (CPR). Monoacylglycerol lipase (MAGL) is an enzyme that is predominantly responsible for the metabolism of endocannabinoid 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) metabolites, which are associated with inflammation. Therefore, we investigated the efficacy of the MAGL inhibitor, JZL184, on cerebral IRI and further compared the effects to therapeutic hypothermia (TH). Thirty-six rats were randomized into three groups: 1) JZL184; 2) Control; 3) TH (N = 12 for each group). Animals underwent 6 min of ventricular fibrillation (VF) followed with 8 min of CPR. After return of spontaneous circulation (ROSC), rats received an intraperitoneal injection of JZL184 (16 mg/kg) or DMSO (20 mg/ml) or body cooling was initiated. Cerebral microcirculation, brain edema, blood brain barrier (BBB) permeability, serum neuron-specific enolase (NSE), S-100beta, interleukin-6 (IL-6) and interleukin-10 (IL-10) were quantified at 6 h post ROSC. Compared to control, treatment with JZL184 or TH was associated with significantly ameliorated cerebral microcirculation, mitigated brain edema, attenuated BBB permeability, decreased serum levels of NSE, S-100beta and IL-6, and increased serum IL-10 levels (p < 0.05). There was no significant difference in the above measurements between JZL184 and TH. JZL184 has comparable neuroprotective effects to therapeutic hypothermia on global cerebral IRI in a rat model of cardiac arrest (CA).
ESTHER : Xu_2022_Biomed.Pharmacother_156_113847
PubMedSearch : Xu_2022_Biomed.Pharmacother_156_113847
PubMedID: 36252353

Title : Phytochemical Properties and In Vitro Biological Activities of Phenolic Compounds from Flower of Clitoria ternatea L - Li_2022_Molecules_27_6336
Author(s) : Li C , Tang W , Chen S , He J , Li X , Zhu X , Li H , Peng Y
Ref : Molecules , 27 :6336 , 2022
Abstract : Phenolic compounds from the flower of Clitoria ternatea L. (PCFCTL) were extracted using a high-speed shearing extraction technique and purified by AB-8 macroporous resins, and the phytochemical composition of the purified phenolic compounds from the flower of Clitoria ternatea L. (PPCFCTL) was then analyzed. Subsequently, its bioactivities including antioxidant properties, enzyme inhibitory activities, and antiproliferative activities against several tumor cell lines were evaluated. Results indicated that the contents of total phenolics, flavonoids, flavonols, flavanols, and phenolic acids in PPCFCTL were increased by 3.29, 4.11, 2.74, 2.43, and 2.96-fold, respectively, compared with those before being purified by AB-8 macroporous resins. The results showed PPCFCTL have significant antioxidant ability (measured by reducing power, RP, and ferric reducing antioxidant power method, FRAP) and good DPPH, ABTS(+), and superoxide anion radical scavenging activities. They can also significantly inhibit lipase, alpha-amylase, and alpha-glucosidase. In addition, morphological changes of HeLa, HepG2, and NCI-H460 tumor cells demonstrated the superior antitumor performance of PPCFCTL. However, the acetylcholinesterase inhibitory activity was relatively weak. These findings suggest that PPCFCTL have important potential as natural antioxidant, antilipidemic, anti-glycemic and antineoplastic agents in health-promoting foods.
ESTHER : Li_2022_Molecules_27_6336
PubMedSearch : Li_2022_Molecules_27_6336
PubMedID: 36234873

Title : Structure-activity relationship, in vitro and in vivo evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease - Wu_2021_J.Enzyme.Inhib.Med.Chem_36_1860
Author(s) : Wu C , Zhang G , Zhang ZW , Jiang X , Zhang Z , Li H , Qin HL , Tang W
Ref : J Enzyme Inhib Med Chem , 36 :1860 , 2021
Abstract : To discover novel scaffolds as leads against dementia, a series of delta-aryl-1,3-dienesulfonyl fluorides with alpha-halo, alpha-aryl and alpha-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC(50) = 0.021 microM for eqBChE, 3.62 microM for hBuChE). SAR of BuChE inhibition showed: (i) o- > m- > p-; -OCH(3) > -CH(3) > -Cl (-Br) for delta-aryl; (ii) alpha-Br > alpha-Cl, alpha-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (K(i) = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the Abeta(1-42)-induced cognitive dysfunction to the normal level, and the assessment of total amount of Abeta(1-42) confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.
ESTHER : Wu_2021_J.Enzyme.Inhib.Med.Chem_36_1860
PubMedSearch : Wu_2021_J.Enzyme.Inhib.Med.Chem_36_1860
PubMedID: 34425715

Title : Glycerol is Released from a New Path in MGL Lipase Catalytic Process - Lan_2021_J.Chem.Inf.Model__
Author(s) : Lan D , Li S , Tang W , Zhao Z , Luo M , Yuan S , Xu J , Wang Y
Ref : J Chem Inf Model , : , 2021
Abstract : Traditionally, it is believed that the substrate and products of a monoacylglycerol lipase (MGL) share the same path to enter and exit the catalytic site. Glycerol (a product of MGL), however, was recently hypothesized to be released through a different path. In order to improve the catalytic efficacy and thermo-stability of MGL, it is important to articulate the pathways of a MGL products releasing. In this study, with structure biological approaches, biochemical experiments, and in silico methods, we prove that glycerol is released from a different path in the catalytic site indeed. The fatty acid (another product of MGL) does share the same binding path with the substrate. This discovery paves a new road to design MGL inhibitors or optimize MGL catalytic efficacy.
ESTHER : Lan_2021_J.Chem.Inf.Model__
PubMedSearch : Lan_2021_J.Chem.Inf.Model__
PubMedID: 34873908

Title : Novel cannabidiol-carbamate hybrids as selective BuChE inhibitors: Docking-based fragment reassembly for the development of potential therapeutic agents against Alzheimer's disease - Jiang_2021_Eur.J.Med.Chem_223_113735
Author(s) : Jiang X , Zhang Z , Zuo J , Wu C , Zha L , Xu Y , Wang S , Shi J , Liu XH , Zhang J , Tang W
Ref : Eur Journal of Medicinal Chemistry , 223 :113735 , 2021
Abstract : Cannabidiol (CBD) and rivastigmine have been launched as drugs for treating dementia and cholinesterases (ChEs) are ideal drug targets. This study focused on developing novel ChE inhibitors as drug leads against dementia through molecular modeling and fragment reassembly approaches. A potent carbamate fragment binding to active site gorge of BuChE was found via a docking-based structural splicing approach, thus, 17 novel compounds were designed by structural reassembly. Compound C16 was identified as a highly selective potent BuChE inhibitor (IC(50) = 5.3 nM, SI > 4000), superior to CBD (IC(50) = 0.67 microM). C16 possessed BBB penetrating ability, benign safety, neuroprotection, antioxidant and pseudo-irreversible BuChE inhibition (K(d) = 13 nM, k(2) = 0.26 min(-1)), showing good drug-like properties. In vivo studies confirmed that C16 significantly ameliorated the scopolamine-induced cognition impairment, almost entirely recovered the Abeta(1-42) (icv)-impaired cognitive function to the normal level, showed better behavioral performance than donepezil and good anti-amyloidogenic effect. Hence, the potential BuChE inhibitor C16 can be developed as a promising disease-modifying treatment of AD.
ESTHER : Jiang_2021_Eur.J.Med.Chem_223_113735
PubMedSearch : Jiang_2021_Eur.J.Med.Chem_223_113735
PubMedID: 34371367

Title : Novel pyridine-containing sultones: Structure-activity relationship and biological evaluation as selective AChE inhibitors for the treatment of Alzheimer's disease - Tang_2021_ChemMedChem__
Author(s) : Tang W , Zhang H , Wu C , Chen X , Zhang Z , Jiang X , Qin HL
Ref : ChemMedChem , : , 2021
Abstract : Novel pyridine-containing sultones were synthesized and evaluated for their ChE inhibitory activity. Most of compounds showed selective AChE inhibitory activity. The structure-activity relationship (SAR) showed: (i) fused pyridine-containing sultones increased the AChE inhibition, series B > series A ; (ii) series B with halo-phenyl had better activity. Compound B4 was identified as a selective AChE inhibitor (IC 50 = 8.93 microM), which was nicely fallen into Tc AChE via hydrogen interactions between delta-pyridylsultone scaffold with Asp72, Ser122, Phe288, Phe290 and Trp84. Compound B4 showed reversible and non-competitive ( K i = 7.67 microM) AChE inhibition, nontoxicity and remarkable neuro-protective activity. In vivo studies confirmed that compound B4 significantly ameliorates performances of scopolamine-treated C57BL/6J mice, suggesting a significant benefit of AChE inhibition for a disease-modifying treatment of AD.
ESTHER : Tang_2021_ChemMedChem__
PubMedSearch : Tang_2021_ChemMedChem__
PubMedID: 34036731

Title : Metabolic degradation of lentinan in liver mediated by CYP450 enzymes and epoxide hydrolase - Zheng_2021_Carbohydr.Polym_253_117255
Author(s) : Zheng Z , Zhang Y , Liu Y , Wang J , Cui Z , Pan X , Tang W , Wang K
Ref : Carbohydr Polym , 253 :117255 , 2021
Abstract : Lentinan (LNT), a typical triple helix beta-glucan, has been widely used as drug and biomaterial. However, its pharmacokinetics in vivo is rarely reported, which severely limits its further development and application. The aim of this study is to establish a sensitive method for detecting LNT in biosamples and to evaluate the plasma level, tissue distribution and metabolic degradation of LNT in rats. 5-([4,6-Dichlorotriazin-2-yl] amino) fluorescein (DTAF) was labelled to LNT. After purification and identification, FLNT was intravenously administered to rats at dose of 32 mg/kg. LNT was predominantly incorporated into the liver and liver microsomes were used to study the degradation mechanism of LNT in the liver. The results showed that two cytochrome P450 (CYP450) enzymes subtypes (CYP2D6 and CYP2C9), as well as epoxide hydrolase, were involved in the metabolic degradation of LNT. These findings provide a pharmacokinetic reference for further study and application of LNT and other beta-glucans.
ESTHER : Zheng_2021_Carbohydr.Polym_253_117255
PubMedSearch : Zheng_2021_Carbohydr.Polym_253_117255
PubMedID: 33279005

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

Title : The structure-based optimization of delta-sultone-fused pyrazoles as selective BuChE inhibitors - Zhang_2020_Eur.J.Med.Chem_201_112273
Author(s) : Zhang Z , Min J , Chen M , Jiang X , Xu Y , Qin H , Tang W
Ref : Eur Journal of Medicinal Chemistry , 201 :112273 , 2020
Abstract : Structure-based optimization was conducted to improve the potency and selectivity of BuChE inhibitors with delta-sulfonolactone-fused pyrazole scaffold. By mimicking the hydrophobic interactions of donepezil at PAS, the introduction of a tertiary benzylamine at 5-position can significantly increase BuChE inhibitory activity. Compounds C4 and C6 were identified as high selective nanomolar BuChE inhibitors (IC50 = 8.3 and 7.7 nM, respectively), which exhibited mild antioxidant capacity, nontoxicity, lipophilicity and neuroprotective activity. Kinetic studies showed that BuChE inhibition of compound C6 was mixed-type against BuChE (Ki = 24 nM) and >2000-fold selectivity for BuChE over AChE. The proposed binding mode of new inhibitors was consistent with the results of structure-activity relationship analysis.
ESTHER : Zhang_2020_Eur.J.Med.Chem_201_112273
PubMedSearch : Zhang_2020_Eur.J.Med.Chem_201_112273
PubMedID: 32569925

Title : Efficient Preservation of Acetylcholinesterase at Room Temperature for Facile Detection of Organophosphorus Pesticide - Tang_2019_Anal.Sci_35_401
Author(s) : Tang W , Yang J , Wang F , Li Z
Ref : Anal Sci , 35 :401 , 2019
Abstract : A simple and inexpensive strategy is reported to facilitate the detection of an organophosphorus pesticide by acetylcholinesterase (AChE). Pullulan is able to preserve AChE at room temperature, but the activity of conserved AChE varies significantly depending on the time, stir and volume of solution to dissolve it. The reason is that AChE entrapped in pullulan tablet remains in an inactive state to avoid denaturalization and deactivation. There is a reactivation process to gradually recover the enzyme activity during dissolution of the tablet. Stirring would interrupt this procedure and lead to a loss of enzyme activity. Dissolution of the tablet for 5 min with a volume of 15 muL could facilitate full recovery of AChE activity. The feasibility of activated AChE for organophosphorus pesticide detection was evaluated using malaoxon. These results contribute to the understanding of preservation mechanism by pullulan and the development of easy-to-use enzyme assays.
ESTHER : Tang_2019_Anal.Sci_35_401
PubMedSearch : Tang_2019_Anal.Sci_35_401
PubMedID: 30555106

Title : A Flexible Acetylcholinesterase-Modified Graphene for Chiral Pesticide Sensor - Zhang_2019_J.Am.Chem.Soc_141_14643
Author(s) : Zhang Y , Liu X , Qiu S , Zhang Q , Tang W , Liu H , Guo Y , Ma Y , Guo X , Liu Y
Ref : Journal of the American Chemical Society , 141 :14643 , 2019
Abstract : Sensors based on graphene are promising devices for chemical and biological detection owing to their high sensitivity, biocompatibility, and low costs. However, for chiral recognition, which is very important in biological systems, graphene sensors remain unable to discriminate enantiomers. Here, using chiral pesticide molecules as an example, we realized a highly sensitive graphene chiral sensor by modification with acetylcholinesterase (AChE). Quantum chemical simulations indicate that the inhibition effect of the enantiomer on AChE was transferred to graphene, which allowed for the electrical detection of chiral molecules. Under an operating voltage of 1 V, the sensitivity of the device reached 0.34 mug/L and 0.32 mug/L for (+)/(-)-methamidophos, respectively, which is much higher than by circular dichroism (6.90 mg/L and 5.16 mg/L, respectively). Furthermore, real-time, rapid detection was realized by combining with smartphones and wireless transmission.
ESTHER : Zhang_2019_J.Am.Chem.Soc_141_14643
PubMedSearch : Zhang_2019_J.Am.Chem.Soc_141_14643
PubMedID: 31448915

Title : Thiocholine-triggered reaction in personal glucose meters for portable quantitative detection of organophosphorus pesticide - Tang_2019_Anal.Chim.Acta_1060_97
Author(s) : Tang W , Yang J , Wang F , Wang J , Li Z
Ref : Anal Chim Acta , 1060 :97 , 2019
Abstract : A portable and user-friendly method using personal glucose meters for on-site quantitative detection of organophosphorus pesticide (OP) was developed. The inhibition of organophosphorus compounds on acetylcholinesterase (AChE) leads to reduced yields of thiocholine formed by the enzymatic hydrolysis of acetylthiocholine chloride. Ferricyanide ([Fe(CN)6](3-)), the mediator used in glucose test strips for electron transfer to the electrode, can be rapidly reduced to ferrocyanide ([Fe(CN)6](4-)) by thiocholine. This reaction enables direct measurement of thiocholine by personal glucose meters in the same way as measuring the glucose in blood, offering an interesting choice to quantify OP. After incubation of AChE for 30min and enzymatic reaction of 10min, the yield of thiocholine was measured by a personal glucose meter, achieving detection limit of 5mugL(-1) for paraoxon. The proposed method was successfully applied to the detection in apples and cucumbers, presenting promising potential for on-site OP detection in food samples.
ESTHER : Tang_2019_Anal.Chim.Acta_1060_97
PubMedSearch : Tang_2019_Anal.Chim.Acta_1060_97
PubMedID: 30902336

Title : Novel chromanone-dithiocarbamate hybrids as multifunctional AChE inhibitors with beta-amyloid anti-aggregation properties for the treatment of Alzheimer's disease - Jiang_2019_Bioorg.Chem_89_103027
Author(s) : Jiang N , Ding J , Liu J , Sun X , Zhang Z , Mo Z , Li X , Yin H , Tang W , Xie SS
Ref : Bioorg Chem , 89 :103027 , 2019
Abstract : By connecting chromanone with dithiocarbamate moieties through flexible linkers, a series of hybrids as novel multifunctional AChE inhibitors have been designed and synthesized. Most of these compounds displayed strong and excellently selective inhibition to eeAChE as well as potent inhibition to self- and AChE-induced Abeta aggregation. Among them, compound 6c showed the best activity to inhibit eeAChE (IC50=0.10muM) and AChE-induced Abeta aggregation (33.02% at 100muM), and could effectively inhibit self-induced Abeta aggregation (38.25% at 25muM). Kinetic analysis and docking study indicated that compound 6c could target both the CAS and PAS, suggesting that it was a dual binding site inhibitor for AChE. Besides, it exhibited good ability to penetrate the BBB and low neurotoxicity in SH-SY5Y cells. More importantly, compound 6c was well tolerated in mice (2500mg/kg, po) and could attenuate the memory impairment in a scopolamine-induced mouse model. Overall, these results highlight 6c as a promising multifunctional agent for treating AD and also demonstrate that the dithiocarbamate is a valid scaffold for design of multifunctional AChE inhibitors.
ESTHER : Jiang_2019_Bioorg.Chem_89_103027
PubMedSearch : Jiang_2019_Bioorg.Chem_89_103027
PubMedID: 31176237

Title : A Thermostable Monoacylglycerol Lipase from Marine Geobacillus sp. 12AMOR1: Biochemical Characterization and Mutagenesis Study - Tang_2019_Int.J.Mol.Sci_20_
Author(s) : Tang W , Lan D , Zhao Z , Li S , Li X , Wang Y
Ref : Int J Mol Sci , 20 : , 2019
Abstract : Lipases with unique substrate specificity are highly desired in biotechnological applications. In this study, a putative marine Geobacillus sp. monoacylglycerol lipase (GMGL) encoded gene was identified by a genomic mining strategy. The gene was expressed in Escherichia coli as a His-tag fusion protein and purified by affinity chromatography with a yield of 264 mg per liter fermentation broth. The recombinant GMGL shows the highest hydrolysis activity at 60 degrees C and pH 8.0, and the half-life was 60 min at 70 degrees C. The GMGL is active on monoacylglycerol (MAG) substrate but not diacylglycerol (DAG) or triacylglycerol (TAG), and produces MAG as the single product in the esterification reaction. Modeling structure analysis showed that the catalytic triad is formed by Ser97, Asp196 and His226, and the flexible cap region is constituted by residues from Ala120 to Thr160. A mutagenesis study on Leu142, Ile145 and Ile170 located in the substrate binding tunnel revealed that these residues were related with its substrate specificity. The kcat/Km value toward the pNP-C6 substrate in mutants Leu142Ala, Ile145Ala and Ile170Phe increased to 2.3-, 1.4- and 2.2-fold as compared to that of the wild type, respectively.
ESTHER : Tang_2019_Int.J.Mol.Sci_20_
PubMedSearch : Tang_2019_Int.J.Mol.Sci_20_
PubMedID: 30759774
Gene_locus related to this paper: 9baci-a0a0g3xxb4

Title : Discovery of delta-sultone-fused pyrazoles for treating Alzheimer's disease: Design, synthesis, biological evaluation and SAR studies - Xu_2019_Eur.J.Med.Chem_181_111598
Author(s) : Xu Y , Zhang Z , Jiang X , Chen X , Wang Z , Alsulami H , Qin HL , Tang W
Ref : Eur Journal of Medicinal Chemistry , 181 :111598 , 2019
Abstract : A class of novel delta-sulfonolactone-fused pyrazole scaffold was prepared via sulfur (VI) fluoride exchange (SuFEx) chemistry using aryl sulfonyl fluorides and pyrazolones. Enzyme screening revealed their cholinesterase inhibitory activity, among them, compounds 4a, 5a and 5d were identified as highly selective submicromolar BuChE inhibitors (IC50=0.20, 0.46 and 0.42muM, respectively), which exhibited nontoxicity, lipophilicity and remarkable neuroprotective activity. Kinetic studies showed that BuChE inhibition of compounds 5a and 5d was reversible, mixed-type and non-competitive inhibition against BuChE (Ki=145nM and 60nM, respectively). Compound 5d can be accommodated into hBuChE via pi-S interaction and hydrophobic interactions. The title compounds are potentially symptomatic treatment in progressive Alzheimer's disease.
ESTHER : Xu_2019_Eur.J.Med.Chem_181_111598
PubMedSearch : Xu_2019_Eur.J.Med.Chem_181_111598
PubMedID: 31415981

Title : Characterization of a novel cold active and salt tolerant esterase from Zunongwangia profunda - Rahman_2016_Enzyme.Microb.Technol_85_1
Author(s) : Rahman MA , Culsum U , Tang W , Zhang SW , Wu G , Liu Z
Ref : Enzyme Microb Technol , 85 :1 , 2016
Abstract : A novel cold active esterase, EstLiu was cloned from the marine bacterium Zunongwangia profunda, overexpressed in E. coli BL21 (DE3) and purified by glutathione-S transferase (GST) affinity chromatography. The mature esterase EstLiu sequence encodes a protein of 273 amino acids residues, with a predicted molecular weight of 30KDa and containing the classical pentapeptidase motif from position 156 to 160 with the catalytic triad Ser158-Asp211-His243. Although, EstLiu showed 64% similarity with the hypothetical esterase from Chryseobacterium sp. StRB126 (WP_045498424), phylogenetic analysis showed it had no similarity with any of the established family of lipases/esterases, suggesting that it could be considered as a new family. The purified enzyme showed broad substrate specificity with the highest hydrolytic activity against p-nitrophenyl butyrate (C4). EstLiu showed remarkable activity (75%) at 0 degrees Cand the optimal activity at pH 8.0 and 30 degrees C with good thermostability and quickened inactivation above 60 degrees C. EstLiu retained 81, 103, 67 and 78% of its original activity at 50% (v/v) in ethanol, isopropanol, DMSO and ethylene glycol, respectively. In the presence of Tween 20, Tween 80 and Triton X-100, EstLiu showed 88, 100 and 117% of relative activity. It is also co-factor independent. The high activity at low temperature and desirable stability in organic solvents and salts of this novel family esterase represents a good evidence of novel biocatalyst. Overall, this novel enzyme showed better activity than previously reported esterases in extreme reaction conditions and could promote the reaction in both aqueous and non-aqueous conditions, indicating its great potential for industrial applications.
ESTHER : Rahman_2016_Enzyme.Microb.Technol_85_1
PubMedSearch : Rahman_2016_Enzyme.Microb.Technol_85_1
PubMedID: 26920474

Title : Independent Prognostic Factors for Acute Organophosphorus Pesticide Poisoning - Tang_2016_Respir.Care_61_965
Author(s) : Tang W , Ruan F , Chen Q , Chen S , Shao X , Gao J , Zhang M
Ref : Respir Care , 61 :965 , 2016
Abstract : BACKGROUND: Acute organophosphorus pesticide poisoning (AOPP) is becoming a significant problem and a potential cause of human mortality because of the abuse of organophosphate compounds. This study aims to determine the independent prognostic factors of AOPP by using multivariate logistic regression analysis.
METHODS: The clinical data for 71 subjects with AOPP admitted to our hospital were retrospectively analyzed. This information included the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, 6-h post-admission blood lactate levels, post-admission 6-h lactate clearance rates, admission blood cholinesterase levels, 6-h post-admission blood cholinesterase levels, cholinesterase activity, blood pH, and other factors. Univariate analysis and multivariate logistic regression analyses were conducted to identify all prognostic factors and independent prognostic factors, respectively. A receiver operating characteristic curve was plotted to analyze the testing power of independent prognostic factors.
RESULTS: Twelve of 71 subjects died. Admission blood lactate levels, 6-h post-admission blood lactate levels, post-admission 6-h lactate clearance rates, blood pH, and APACHE II scores were identified as prognostic factors for AOPP according to the univariate analysis, whereas only 6-h post-admission blood lactate levels, post-admission 6-h lactate clearance rates, and blood pH were independent prognostic factors identified by multivariate logistic regression analysis. The receiver operating characteristic analysis suggested that post-admission 6-h lactate clearance rates were of moderate diagnostic value.
CONCLUSIONS: High 6-h post-admission blood lactate levels, low blood pH, and low post-admission 6-h lactate clearance rates were independent prognostic factors identified by multivariate logistic regression analysis.
ESTHER : Tang_2016_Respir.Care_61_965
PubMedSearch : Tang_2016_Respir.Care_61_965
PubMedID: 27048625

Title : Deletion of soluble epoxide hydrolase attenuates cardiac hypertrophy via down-regulation of cardiac fibroblasts-derived fibroblast growth factor-2 - Zhang_2014_Crit.Care.Med_42_e345
Author(s) : Zhang H , Wang T , Zhang K , Liu Y , Huang F , Zhu X , Wang MH , Tang W , Wang J , Huang H
Ref : Critical Care Medicine , 42 :e345 , 2014
Abstract : OBJECTIVE: Inhibition of soluble epoxide hydrolase (Ephx2) has been shown to play a protective role in cardiac hypertrophy, but the mechanism is not fully understood. We tested the hypothesis that deletion of soluble epoxide hydrolase attenuates cardiac hypertrophy via down-regulation of cardiac fibroblasts-derived fibroblast growth factor-2. DESIGN: Prospective, controlled, and randomized animal study. SETTING: University laboratory. SUBJECTS: Male wild-type C57BL/6 mice and Ephx2 (-/-) mice. INTERVENTIONS: Male wild-type or Ephx2 (-/-) mice were subjected to transverse aorta constriction surgery. MEASUREMENTS AND MAIN
RESULTS: Four weeks after transverse aorta constriction, Ephx2 (-/-) mice did not develop significant cardiac hypertrophy as that of wild-type mice, indicated by no changes in the ratio of heart weight/body weight and ventricular wall thickness after transverse aorta constriction. Cardiac fibroblast growth factor-2 increased in wild-type-transverse aorta constriction group but this did not change in Ephx2 (-/-)-transverse aorta constriction group, and the serum level of fibroblast growth factor-2 did not change in both groups. In vitro, cardiac fibroblasts were stimulated by angiotensin II to analyze the expression of fibroblast growth factor-2. The effect of increased fibroblast growth factor-2 from cardiac fibroblasts induced by angiotensin II was attenuated by soluble epoxide hydrolase deletion. ERK1/2, p38, and AKT kinase were involved in fibroblast growth factor-2 expression regulated by angiotensin II, and soluble epoxide hydrolase deletion lowered the phosphorylation of ERK1/2 not p38 or AKT to mediate fibroblast growth factor-2 expression. In addition, soluble epoxide hydrolase deletion did not attenuate cardiomyocytes hypertrophy induced by exogenous fibroblast growth factor-2.
CONCLUSIONS: Our present data demonstrated that deletion of soluble epoxide hydrolase prevented cardiac hypertrophy not only directly to cardiomyocytes but also to cardiac fibroblasts by reducing expression of fibroblast growth factor-2.
ESTHER : Zhang_2014_Crit.Care.Med_42_e345
PubMedSearch : Zhang_2014_Crit.Care.Med_42_e345
PubMedID: 24448199

Title : Associations of lipoprotein lipase gene polymorphisms with longitudinal plasma lipid trends in young adults: The Coronary Artery Risk Development in Young Adults (CARDIA) study - Tang_2010_Circ.Cardiovasc.Genet_3_179
Author(s) : Tang W , Apostol G , Schreiner PJ , Jacobs DR, Jr. , Boerwinkle E , Fornage M
Ref : Circ Cardiovasc Genet , 3 :179 , 2010
Abstract : BACKGROUND: Genome-wide association studies in European Americans have reported several single-nucleotide polymorphisms (SNPs) in the lipoprotein lipase gene associated with plasma levels of high-density lipoprotein cholesterol (HDL-C) and triglycerides. However, the influences of the lipoprotein lipase SNPs on longitudinal changes of these lipids have not been systematically examined. METHODS AND RESULTS: On the basis of data from 2045 African Americans and 2116 European Americans in the Coronary Artery Risk Development in Young Adults study, we investigated cross-sectional and longitudinal associations of lipids with 8 lipoprotein lipase SNPs, including the 2 that have been reported in genome-wide association studies. Plasma levels of HDL-C and triglycerides were measured at 7 examinations during 20 years of follow-up. In European Americans, rs328 (Ser447Stop), rs326, and rs13702 were significantly associated with cross-sectional interindividual variations in triglycerides and HDL-C (P<0.005) and with their longitudinal changes over time (P<0.05). The minor alleles in rs326, rs328, and rs13702 that predispose an individual to lower triglycerides and higher HDL-C levels at young adulthood further slow down the trajectory increase in triglycerides and decrease in HDL-C during 20 years of follow-up. In African Americans, these 3 SNPs were significantly associated with triglycerides, but only rs326 and rs13702 were associated with HDL-C (P<0.008). Rs328 showed a stronger association in European Americans than in African Americans, and adjustment for it did not remove all of the associations for the other SNPs. Longitudinal changes in either trait did not differ significantly by SNP genotypes in African Americans. CONCLUSIONS: Our data suggest that aging interacts with LPL gene variants to influence the longitudinal lipid variations, and there is population-related heterogeneity in the longitudinal associations.
ESTHER : Tang_2010_Circ.Cardiovasc.Genet_3_179
PubMedSearch : Tang_2010_Circ.Cardiovasc.Genet_3_179
PubMedID: 20150529

Title : The application of laser microdissection to in planta gene expression profiling of the maize anthracnose stalk rot fungus Colletotrichum graminicola - Tang_2006_Mol.Plant.Microbe.Interact_19_1240
Author(s) : Tang W , Coughlan S , Crane E , Beatty M , Duvick J
Ref : Mol Plant Microbe Interact , 19 :1240 , 2006
Abstract : Laser microdissection (LM) offers a potential means for deep sampling of a fungal plant-pathogen transcriptome during the infection process using whole-genome DNA microarrays. The use of a fluorescent protein-expressing fungus can greatly facilitate the identification of fungal structures for LM sampling. However, fixation methods that preserve both tissue histology and protein fluorescence, and that also yield RNA of suitable quality for microarray applications, have not been reported. We developed a microwave-accelerated acetone fixation, paraffin-embedding method that fulfills these requirements and used it to prepare mature maize stalk tissues infected with an Anemonia majano cyan fluorescent protein-expressing isolate of the anthracnose stalk rot fungus Colletotrichum graminicola. We successfully used LM to isolate individual maize cells associated with C. graminicola hyphae at an early stage of infection. The LM-derived RNA, after two-round linear amplification, was of sufficient quality and quantity for global expression profiling using a fungal microarray. Comparing replicated LM samples representing an early stage of stalk cell infection with samples from in vitro-germinated conidia, we identified 437 and 370 C. graminicola genes showing significant up- or downregulation, respectively. We confirmed the differential expression of several representative transcripts by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and documented extensive overlap of this dataset with a PCR-subtraction library enriched for C. graminicola transcripts in planta. Our results demonstrate that LM is feasible for in planta pathogen expression profiling and can reveal clues about fungal genes involved in pathogenesis. The method in this report may be advantageous for visualizing a variety of cellular features that depend on a high degree of histochemical preservation and RNA integrity prior to LM.
ESTHER : Tang_2006_Mol.Plant.Microbe.Interact_19_1240
PubMedSearch : Tang_2006_Mol.Plant.Microbe.Interact_19_1240
PubMedID: 17073306
Gene_locus related to this paper: colgm-e3qkn0

Title : An efficient enantioselective synthesis of (-)-galanthamine -
Author(s) : Trost BM , Tang W
Ref : Angew Chem Int Ed Engl , 41 :2795 , 2002
PubMedID: 12203489