Fu H

General

Full name : Fu Hongjun

First name : Hongjun

Mail : The Hong Kong Polytechnic University\; The Department of Applied Biology and Chemical Technology\; Room Y862\; 12\/F\; Block Y\; Hung Hom\; KLN\; Hong Kong

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Country : China

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References (30)

Title : Role of Mn-LIPA in Sex Hormone Regulation and Gonadal Development in the Oriental River Prawn, Macrobrachium nipponense - Cai_2024_Int.J.Mol.Sci_25_
Author(s) : Cai P , Zhang W , Jiang S , Xiong Y , Qiao H , Yuan H , Gao Z , Zhou Y , Jin S , Fu H
Ref : Int J Mol Sci , 25 : , 2024
Abstract : This study investigates the role of lysosomal acid lipase (LIPA) in sex hormone regulation and gonadal development in Macrobrachium nipponense. The full-length Mn-LIPA cDNA was cloned, and its expression patterns were analyzed using quantitative real-time PCR (qPCR) in various tissues and developmental stages. Higher expression levels were observed in the hepatopancreas, cerebral ganglion, and testes, indicating the potential involvement of Mn-LIPA in sex differentiation and gonadal development. In situ hybridization experiments revealed strong Mn-LIPA signaling in the spermatheca and hepatopancreas, suggesting their potential role in steroid synthesis (such as cholesterol, fatty acids, cholesteryl ester, and triglycerides) and sperm maturation. Increased expression levels of male-specific genes, such as insulin-like androgenic gland hormone (IAG), sperm gelatinase (SG), and mab-3-related transcription factor (Dmrt11E), were observed after dsMn-LIPA (double-stranded LIPA) injection, and significant inhibition of sperm development and maturation was observed histologically. Additionally, the relationship between Mn-LIPA and sex-related genes (IAG, SG, and Dmrt11E) and hormones (17beta-estradiol and 17alpha-methyltestosterone) was explored by administering sex hormones to male prawns, indicating that Mn-LIPA does not directly control the production of sex hormones but rather utilizes the property of hydrolyzing triglycerides and cholesterol to provide energy while influencing the synthesis and secretion of self-sex hormones. These findings provide valuable insights into the function of Mn-LIPA in M. nipponense and its potential implications for understanding sex differentiation and gonadal development in crustaceans. It provides an important theoretical basis for the realization of a monosex culture of M. nipponense.
ESTHER : Cai_2024_Int.J.Mol.Sci_25_
PubMedSearch : Cai_2024_Int.J.Mol.Sci_25_
PubMedID: 38338678

Title : [(18)F]MAGL-4-11 positron emission tomography molecular imaging of monoacylglycerol lipase changes in preclinical liver fibrosis models - Shao_2022_Acta.Pharm.Sin.B_12_308
Author(s) : Shao T , Chen Z , Rong J , Belov V , Chen J , Jeyarajan A , Deng X , Fu H , Yu Q , Rwema SH , Lin W , Papisov M , Josephson L , Chung RT , Liang SH
Ref : Acta Pharm Sin B , 12 :308 , 2022
Abstract : Monoacylglycerol lipase (MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol (2-AG) into the proinflammatory eicosanoid precursor arachidonic acid (AA). MAGL and other endogenous cannabinoid (EC) degrading enzymes are involved in the fibrogenic signaling pathways that induce hepatic stellate cell (HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an (18)F-labeled MAGL inhibitor ([(18)F]MAGL-4-11) for PET imaging and demonstrated highly specific binding in vitro and in vivo. In this study, we determined [(18)F]MAGL-4-11 PET enabled imaging MAGL levels in the bile duct ligation (BDL) and carbon tetrachloride (CCl(4)) models of liver cirrhosis; we also assessed the hepatic gene expression of the enzymes involved with EC system including MAGL, NAPE-PLD, FAAH and DAGL that as a function of disease severity in these models; [(18)F]MAGL-4-11 autoradiography was performed to assess tracer binding in frozen liver sections both in animal and human. [(18)F]MAGL-4-11 demonstrated reduced PET signals in early stages of fibrosis and further significantly decreased with disease progression compared with control mice. We confirmed MAGL and FAAH expression decreases with fibrosis severity, while its levels in normal liver tissue are high; in contrast, the EC synthetic enzymes NAPE-PLD and DAGL are enhanced in these different fibrosis models. In vitro autoradiography further supported that [(18)F]MAGL-4-11 bound specifically to MAGL in both animal and human fibrotic liver tissues. Our PET ligand [(18)F]MAGL-4-11 shows excellent sensitivity and specificity for MAGL visualization in vivo and accurately reflects the histological stages of liver fibrosis in preclinical models and human liver tissues.
ESTHER : Shao_2022_Acta.Pharm.Sin.B_12_308
PubMedSearch : Shao_2022_Acta.Pharm.Sin.B_12_308
PubMedID: 35127387

Title : Mechanism and biomass association of glucuronoyl esterase: an alpha\/beta hydrolase with potential in biomass conversion - Zong_2022_Nat.Commun_13_1449
Author(s) : Zong Z , Mazurkewich S , Pereira CS , Fu H , Cai W , Shao X , Skaf MS , Larsbrink J , Lo Leggio L
Ref : Nat Commun , 13 :1449 , 2022
Abstract : Glucuronoyl esterases (GEs) are alpha/beta serine hydrolases and a relatively new addition in the toolbox to reduce the recalcitrance of lignocellulose, the biggest obstacle in cost-effective utilization of this important renewable resource. While biochemical and structural characterization of GEs have progressed greatly recently, there have yet been no mechanistic studies shedding light onto the rate-limiting steps relevant for biomass conversion. The bacterial GE OtCE15A possesses a classical yet distinctive catalytic machinery, with easily identifiable catalytic Ser/His completed by two acidic residues (Glu and Asp) rather than one as in the classical triad, and an Arg side chain participating in the oxyanion hole. By QM/MM calculations, we identified deacylation as the decisive step in catalysis, and quantified the role of Asp, Glu and Arg, showing the latter to be particularly important. The results agree well with experimental and structural data. We further calculated the free-energy barrier of post-catalysis dissociation from a complex natural substrate, suggesting that in industrial settings non-catalytic processes may constitute the rate-limiting step, and pointing to future directions for enzyme engineering in biomass utilization.
ESTHER : Zong_2022_Nat.Commun_13_1449
PubMedSearch : Zong_2022_Nat.Commun_13_1449
PubMedID: 35304453
Gene_locus related to this paper: opitp-b1zmf4

Title : New perspective on the regulation of acetylcholinesterase via the aryl hydrocarbon receptor - Xie_2021_J.Neurochem_158_1254
Author(s) : Xie HQ , Ma Y , Fu H , Xu T , Luo Y , Liu Y , Chen Y , Xu L , Xia Y , Zhao B
Ref : Journal of Neurochemistry , 158 :1254 , 2021
Abstract : Acetylcholinesterase (AChE, EC 3.1.1.7) plays important roles in cholinergic neurotransmission and has been widely recognized as a biomarker for monitoring pollution by organophosphate (OP) and carbamate pesticides. Dioxin is an emerging environmental AChE disruptor and is a typical persistent organic pollutant with multiple toxic effects on the nervous system. Growing evidence has shown that there is a significant link between dioxin exposure and neurodegenerative diseases and neurodevelopmental disorders, most of which involve AChE and cholinergic dysfunctions. Therefore, an in-depth understanding of the effects of dioxin on AChE and the related mechanisms of action might help to shed light on the molecular bases of dioxin impacts on the nervous system. In the past decade, the effects of dioxins on AChE have been revealed in cultured cells of different origins and in rodent animal models. Unlike OP and carbamate pesticides, dioxin-induced AChE disturbance is not due to direct inhibition of enzymatic activity; instead, dioxin causes alterations of AChE expression in certain models. As a widely accepted mechanism for most dioxin effects, the aryl hydrocarbon receptor (AhR)-dependent pathway has become a research focus in studies on the mechanism of action of dioxin-induced AChE dysregulation. In this mini-review, the effects of dioxin on AChE and the diverse roles of the AhR pathway in AChE regulation are summarized. Additionally, the involvement of AhR in AChE regulation during different neurodevelopmental processes is discussed. These AhR-related findings might also provide new insight into AChE regulation triggered by diverse xenobiotics capable of interacting with AhR.
ESTHER : Xie_2021_J.Neurochem_158_1254
PubMedSearch : Xie_2021_J.Neurochem_158_1254
PubMedID: 33278027

Title : Promising tacrine\/huperzine A-based dimeric acetylcholinesterase inhibitors for neurodegenerative disorders: From relieving symptoms to modifying diseases through multitarget - Mak_2021_J.Neurochem__
Author(s) : Mak S , Li W , Fu H , Luo J , Cui W , Hu S , Pang Y , Carlier PR , Tsim KWK , Pi R , Han Y
Ref : Journal of Neurochemistry , : , 2021
Abstract : Neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, are devastating diseases in the elderly world, which are closely associated with progressive neuronal loss induced by a variety of genetic and/or environmental factors. Unfortunately, currently available treatments for neurodegenerative disorders can only relieve the symptoms but not modify the pathological processes. Over the past decades, our group by collaborating with Profs. Yuan-Ping Pang and Paul R. Carlier has developed three series of homo/hetero dimeric acetylcholinesterase inhibitors derived from tacrine and/or huperzine A. The representative dimers bis(3)-Cognitin (B3C), bis(12)-hupyridone, and tacrine(10)-hupyridone might possess disease-modifying effects through the modulation of N-methyl-d-aspartic acid receptors, the activation of myocyte enhancer factor 2D gene transcription, and the promotion of neurotrophic factor secretion. In this review, we summarize that the representative dimers, such as B3C, provide neuroprotection against a variety of neurotoxins via multiple targets, including the inhibitions of N-methyl-d-aspartic acid receptor with pathological-activated potential, neuronal nitric oxide synthase, and beta-amyloid cascades synergistically. More importantly, B3C might offer disease-modifying potentials by activating myocyte enhancer factor 2D transcription, inducing neuritogenesis, and promoting the expressions of neurotrophic factors in vitro and in vivo. Taken together, the novel dimers might offer synergistic disease-modifying effects, proving that dimerization might serve as one of the strategies to develop new generation of therapeutics for neurodegenerative disorders.
ESTHER : Mak_2021_J.Neurochem__
PubMedSearch : Mak_2021_J.Neurochem__
PubMedID: 33930191

Title : The basal transcription factor II H subunit Tfb5 is required for stress response and pathogenicity in the tangerine pathotype of Alternaria alternata - Fu_2020_Mol.Plant.Pathol_21_1337
Author(s) : Fu H , Chung KR , Gai Y , Mao L , Li H
Ref : Mol Plant Pathol , 21 :1337 , 2020
Abstract : The basal transcription factor II H (TFIIH) is a multicomponent complex. In the present study, we characterized a TFIIH subunit Tfb5 by analysing loss- and gain-of-function mutants to gain a better understanding of the molecular mechanisms underlying stress resistance and pathogenicity in the citrus fungal pathogen Alternaria alternata. Tfb5 deficiency mutants (deltaAatfb5) decreased sporulation and pigmentation, and were impaired in the maintenance of colony surface hydrophobicity and cell wall integrity. deltaAatfb5 increased sensitivity to ultraviolet light, DNA-damaging agents, and oxidants. The expression of Aatfb5 was up-regulated in the wild type upon infection in citrus leaves, implicating the requirement of Aatfb5 in fungal pathogenesis. Biochemical and virulence assays revealed that deltaAatfb5 was defective in toxin production and cellwall-degrading enzymes, and failed to induce necrotic lesions on detached citrus leaves. Aatfb5 fused with green fluorescent protein (GFP) was localized in the cytoplasm and nucleus and physically interacted with another subunit, Tfb2, based on yeast two-hybrid and co-immunoprecipitation analyses. Transcriptome and Antibiotics & Secondary Metabolite Analysis Shell (antiSMASH) analyses revealed the positive and negative roles of Aatfb5 in the production of various secondary metabolites and in the regulation of many metabolic and biosynthetic processes in A. alternata. Aatfb5 may play a negative role in oxidative phosphorylation and a positive role in peroxisome biosynthesis. Two cutinase-coding genes (AaCut2 and AaCut15) required for full virulence were down-regulated in deltaAatfb5. Overall, this study expands our understanding of how A. alternata uses the basal transcription factor to deal with stress and achieve successful infection in the plant host.
ESTHER : Fu_2020_Mol.Plant.Pathol_21_1337
PubMedSearch : Fu_2020_Mol.Plant.Pathol_21_1337
PubMedID: 32776683

Title : 2,3,7,8-Tetrachlorodibenzo-p-dioxin and up-regulation of neurofilament expression in neuronal cells: Evaluation of AhR and MAPK pathways - Chen_2020_Environ.Int_134_105193
Author(s) : Chen Y , Xie HQ , Sha R , Xu T , Zhang S , Fu H , Xia Y , Liu YY , Xu L , Zhao B
Ref : Environ Int , 134 :105193 , 2020
Abstract : Dioxin exposure is reported to affect nervous system development and increase the risk of neurodegenerative diseases. Generally, dioxin exerts its neurotoxicity via aryl hydrocarbon receptor (AhR). Neurofilament (NF) light (NFL) protein is a biomarker for both neuronal differentiation and neurodegeneration and its expression is controlled by the mitogen-activated protein kinase (MAPK) pathway. However, the effects of dioxin on NFL expression and involved mechanisms are incompletely understood. We aimed to investigate the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on NFL expression and elucidate the underlining signaling pathways and their potential crosstalk, specifically between MAPK and AhR pathway. We employed primary cultured rat cortical neurons to evaluate the effect of TCDD exposure on NFL expression. We also used nerve growth factor (NGF)-treated PC12 cells with specific inhibitors to investigate the involvement of and potential crosstalk between the MAPK pathway and the AhR pathway in mediating the effects of TCDD on NFL expression. After TCDD exposure, NFL mRNA and protein levels were upregulated in cultured neurons. NFL protein was preferentially found in the cell body compared with neurites of the cultured neurons. In PC12 cells, TCDD enhanced both NGF-induced NFL expression and phosphorylation of ERK1/2 and p38. The addition of MAPK-pathway inhibitors (PD98059 and SB230580) partially blocked the TCDD-induced NFL upregulation. CH223191, an AhR antagonist, reversed the upregulation of NFL and phosphorylation of ERK1/2 and p38 induced by TCDD. This study demonstrated TCDD-induced upregulation of NFL in cultured neurons, with protein retained in the cell body. TCDD action was dependent on activation of AhR and MAPK, while crosstalk was found between these two signaling pathways.
ESTHER : Chen_2020_Environ.Int_134_105193
PubMedSearch : Chen_2020_Environ.Int_134_105193
PubMedID: 31775093

Title : Spectroscopic and molecular modeling investigation on inhibition effect of nitroaromatic compounds on acetylcholinesterase activity - Chen_2019_Chemosphere_236_124365
Author(s) : Chen Y , Wang M , Fu H , Qu X , Zhang Z , Kang F , Zhu D
Ref : Chemosphere , 236 :124365 , 2019
Abstract : Nitroaromatic compounds (NACs) are widely distributed in the environment and are considered toxic or carcinogenic. However, little attention has been paid to the binding interactions between NACs and biomacromolecules (e.g., proteins). Here we investigated the effects of three model NACs, nitrobenzene (NB), 1,3-dinitrobenzene (DNB), and 1,3,5-trinitrobenzene (TNB), on the activity of acetylcholinesterase (AChE). The presence of NACs (up to 0.5mM) effectively suppressed the AChE-catalyzed hydrolysis of acetylthiocholine iodide, with the suppression effect increasing with the nitro-group substitution (TNB>DNB>NB). Consistently, the UV absorption of AChE at 206nm arising from the skeleton structure decreased by the addition NACs, and the decrease exhibited the same compound sequence, reflecting the perturbing interactions with the skeleton enzyme structure. However, no changes were made on the secondary structure of AChE, as evidenced by the circular dichroism analysis. The fluorescence quenching analysis of AChE demonstrated that NB and DNB interacted with both tryptophan (Trp) and tyrosine (Tyr) residues, whereas TNB interacted only with Trp. The UV absorption and fluorescence quenching analyses both reflected that the interactions with the non-skeleton aromatic amino acids were weak. (1)H NMR analysis confirmed the strong pi-pi coupling interactions between TNB and model Trp. Molecular simulation indicated that the DNB or TNB molecule was sandwiched between Trp84 and Phe330 at the catalytic site via pi-pi coupling interactions. The findings highlight the importance of specific interactions of NACs with proteins to cause them to malfunction.
ESTHER : Chen_2019_Chemosphere_236_124365
PubMedSearch : Chen_2019_Chemosphere_236_124365
PubMedID: 31325829

Title : Design, Synthesis, and Evaluation of (18)F-Labeled Monoacylglycerol Lipase Inhibitors as Novel Positron Emission Tomography Probes - Chen_2019_J.Med.Chem_62_8866
Author(s) : Chen Z , Mori W , Fu H , Schafroth MA , Hatori A , Shao T , Zhang G , Van RS , Zhang Y , Hu K , Fujinaga M , Wang L , Belov V , Ogasawara D , Giffenig P , Deng X , Rong J , Yu Q , Zhang X , Papisov MI , Shao Y , Collier TL , Ma JA , Cravatt BF , Josephson L , Zhang MR , Liang SH
Ref : Journal of Medicinal Chemistry , 62 :8866 , 2019
Abstract : Dysfunction of monoacylglycerol lipase (MAGL) is associated with several psychopathological disorders, including drug addiction and neurodegenerative diseases. Herein we design, synthesize, and evaluate several irreversible fluorine-containing MAGL inhibitors for positron emission tomography (PET) ligand development. Compound 6 (identified from a therapeutic agent) was advanced for (18)F-labeling via a novel spirocyclic iodonium ylide (SCIDY) strategy, which demonstrated high brain permeability and excellent specific binding. This work supports further development of novel (18)F-labeled MAGL PET probes.
ESTHER : Chen_2019_J.Med.Chem_62_8866
PubMedSearch : Chen_2019_J.Med.Chem_62_8866
PubMedID: 31518130

Title : Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a Tail Switching Strategy on a Piperazinyl Azetidine Skeleton - Chen_2019_J.Med.Chem_62_3336
Author(s) : Chen Z , Mori W , Deng X , Cheng R , Ogasawara D , Zhang G , Schafroth MA , Dahl K , Fu H , Hatori A , Shao T , Zhang Y , Yamasaki T , Zhang X , Rong J , Yu Q , Hu K , Fujinaga M , Xie L , Kumata K , Gou Y , Chen J , Gu S , Bao L , Wang L , Collier TL , Vasdev N , Shao Y , Ma JA , Cravatt BF , Fowler C , Josephson L , Zhang MR , Liang SH
Ref : Journal of Medicinal Chemistry , 62 :3336 , 2019
Abstract : Monoacylglycerol lipase (MAGL) is a serine hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions, including chronic pain, inflammation, cancer, and neurodegeneration. Herein, we disclose a novel array of reversible and irreversible MAGL inhibitors by means of "tail switching" on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with (11)C or (18)F. [(11)C]8 ([(11)C]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [(11)C]17 ([(11)C]PAD) and [(18)F]37 ([(18)F]MAGL-4-11) also demonstrated excellent in vivo binding specificity toward MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography tracers with tunability in reversible and irreversible binding mechanisms.
ESTHER : Chen_2019_J.Med.Chem_62_3336
PubMedSearch : Chen_2019_J.Med.Chem_62_3336
PubMedID: 30829483
Gene_locus related to this paper: human-MGLL

Title : Csn5 Is Required for the Conidiogenesis and Pathogenesis of the Alternaria alternata Tangerine Pathotype - Wang_2018_Front.Microbiol_9_508
Author(s) : Wang M , Yang X , Ruan R , Fu H , Li H
Ref : Front Microbiol , 9 :508 , 2018
Abstract : The COP9 signalosome (CSN) is a highly conserved protein complex involved in the ubiquitin-proteasome system. Its metalloisopeptidase activity resides in subunit 5 (CSN5). Functions of csn5 in phytopathogenic fungi are poorly understood. Here, we knocked out the csn5 ortholog (Aacsn5) in the tangerine pathotype of Alternaria alternata. The deltaAacsn5 mutant showed a moderately reduced growth rate compared to the wildtype strain and was unable to produce conidia. The growth of deltaAacsn5 mutant was not affected in response to oxidative and osmotic stresses. Virulence assays revealed that deltaAacsn5 induced no or significantly reduced necrotic lesions on detached citrus leaves. The defects in hyphal growth, conidial sporulation, and pathogenicity of deltaAacsn5 were restored by genetic complementation of the mutant with wildtype Aacsn5. To explore the molecular mechanisms of conidiation and pathogenesis underlying Aacsn5 regulation, we systematically examined the transcriptomes of both deltaAacsn5 and the wildtype. Generally, 881 genes were overexpressed and 777 were underexpressed in the deltaAacsn5 mutant during conidiation while 694 overexpressed and 993 underexpressed during infection. During asexual development, genes related to the transport processes and nitrogen metabolism were significantly downregulated; the expression of csn1-4 and csn7 in deltaAacsn5 was significantly elevated; secondary metabolism gene clusters were broadly affected; especially, the transcript level of the whole of cluster 28 and 30 was strongly induced. During infection, the expression of the host-specific ACT toxin gene cluster which controls the biosynthesis of the citrus specific toxin was significantly repressed; many other SM clusters with unknown products were also regulated; 86 out of 373 carbohydrate-active enzymes responsible for breaking down the plant dead tissues showed uniquely decreased expression. Taken together, our results expand our understanding of the roles of csn5 on conidiation and pathogenicity in plant pathogenic fungi and provide a foundation for future investigations.
ESTHER : Wang_2018_Front.Microbiol_9_508
PubMedSearch : Wang_2018_Front.Microbiol_9_508
PubMedID: 29616013
Gene_locus related to this paper: altal-actt2

Title : Clinical diagnostic significance of prealbumin, cholinesterase and retinol binding protein in liver cirrhosis combined with encephalopathy - Tan_2018_Br.J.Biomed.Sci__1
Author(s) : Tan L , Meng Y , Zeng T , Wang Q , Long T , Wu S , Guan X , Fu H , Zheng W , Tian Y , Chen J , Yu J , Wu Y , Li H , Cao L
Ref : Br J Biomed Sci , :1 , 2018
Abstract : OBJECTIVE: Hepatic encephalopathy is a common consequence of liver cirrhosis, but diagnosis can be difficult as it is based on clinical criteria alone. We hypothesised that serum prealbumin, cholinesterase and retinol binding protein (RBP) can help support the diagnosis of hepatic encephalopathy. METHODS: We enrolled 306 cirrhotic patients (110 with encephalopathy), 100 chronic hepatitis B patients and 50 healthy controls, measuring routine liver function tests (ALT, AST, GGT, ALP, and bilirubin), albumin, prothrombin time, prealbumin, cholinesterase and RBP by routine methods. Logistic regression analysis and areas under the receiver operating characteristic curves (AUCs) were used to find predictive factors for hepatic encephalopathy. RESULTS: There were differences in all laboratory indices between the three groups (all p < 0.001). In univariate analysis, albumin, prothrombin time, prealbumin, cholinesterase and RBP were significantly altered in those with encephalopathy (p < 0.01), but only prealbumin, cholinesterase and RBP levels were significant predictors in multivariate analysis, and each was linked to the severity of liver fibrosis defined by the Child-Pugh score (all p < 0.001). The AUCs (95% CI) of prealbumin, cholinesterase and RBP for diagnosing liver cirrhosis with hepatic encephalopathy were comparable at 0.85 (81-90), 0.81 (0.76-0.85) and 0.81 (0.76-0.86), respectively (all p < 0.01). CONCLUSIONS: Serum prealbumin, cholinesterase and RBP levels are of potential clinical value in diagnosis of liver cirrhosis complicated by encephalopathy.
ESTHER : Tan_2018_Br.J.Biomed.Sci__1
PubMedSearch : Tan_2018_Br.J.Biomed.Sci__1
PubMedID: 30392460

Title : Acetylcholinesterase Is a Potential Biomarker for a Broad Spectrum of Organic Environmental Pollutants - Fu_2018_Environ.Sci.Technol_52_8065
Author(s) : Fu H , Xia Y , Chen Y , Xu T , Xu L , Guo Z , Xu H , Xie HQ , Zhao B
Ref : Environ Sci Technol , 52 :8065 , 2018
Abstract : Acetylcholinesterase (AChE, EC 3.1.1.7) is a classical biomarker for monitoring contamination and intoxication of organophosphate (OP) and carbamate pesticides. In addition to these classical environmental AChE inhibitors, other organic toxic substances have been found to alter AChE activity in various species. These emerging organic AChE disruptors include certain persistent organic pollutants (POPs), polycyclic aromatic hydrocarbons (PAHs), and wildly used chemicals, most of which have received considerable public health concern in recent years. It is necessary to re-evaluate the environmental significances of AChE in terms of these toxic substances. Therefore, the present review is aiming to summarize correlations of AChE activity of certain organisms with the level of the contaminants in particular habitats, disruptions of AChE activity upon treatment with the emerging disruptors in vivo and in vitro, and action mechanisms underlying the effects on AChE. Over 40 chemicals belonging to six main categories were reviewed, including 12 POPs listed in the Stockholm Convention. AChE activity in certain organisms has been found to be well correlated with the contamination level of certain persistent pesticides and PAHs in particular habitats. Moreover, it has been documented that most of the listed toxic chemicals could inhibit AChE activity in diverse species ranging from invertebrates to mammals. Besides directly inactivating AChE, the mechanisms in terms of interference with the biosynthesis have been recognized for some emerging AChE disruptors, particularly for dioxins. The collected evidence suggests that AChE could serve as a potential biomarker for a diverse spectrum of organic environmental pollutants.
ESTHER : Fu_2018_Environ.Sci.Technol_52_8065
PubMedSearch : Fu_2018_Environ.Sci.Technol_52_8065
PubMedID: 29995397

Title : 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces alterations in myogenic differentiation of C2C12 cells - Xie_2018_Environ.Pollut_235_965
Author(s) : Xie HQ , Xia Y , Xu T , Chen Y , Fu H , Li Y , Luo Y , Xu L , Tsim KWK , Zhao B
Ref : Environ Pollut , 235 :965 , 2018
Abstract : Dioxin-induced toxicities that affect the development of the motor system have been proposed since many years. However, cellular evidence and the molecular basis for the effects are limited. In this study, a cultured mouse myoblast cell line, C2C12, was utilized to examine the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on myogenic differentiation and expression of acetylcholinesterase (AChE), a neuromuscular transmission-related gene. The results showed that TCDD exposure at 10(-10)M repressed the myotube formation of C2C12cells by disturbing the fusion process and suppressing the expression of myosin heavy chain, a myobute structural protein, and not by induction of cytotoxicity. Furthermore, TCDD dose dependently suppressed the transcriptional expression and enzymatic activity of AChE during the myogenic differentiation, particularly in the middle stage. However, the administration of aryl hydrocarbon receptor antagonists, CH223191 and alpha-naphthoflavone, did not completely reverse the TCDD-induced downregulation of muscular AChE during myogenic differentiation. These findings suggest that low dose exposure to dioxin may result in disturbances of muscle differentiation and neuromuscular transmission.
ESTHER : Xie_2018_Environ.Pollut_235_965
PubMedSearch : Xie_2018_Environ.Pollut_235_965
PubMedID: 29751400

Title : Evaluation of Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors as Potential Anti-Alzheimer's Disease Agents Using Pharmacophore, 3D-QSAR, and Molecular Docking Approaches - Pang_2017_Molecules_22_
Author(s) : Pang X , Fu H , Yang S , Wang L , Liu AL , Wu S , Du GH
Ref : Molecules , 22 : , 2017
Abstract : DL0410, containing biphenyl and piperidine skeletons, was identified as an acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor through high-throughput screening assays, and further studies affirmed its efficacy and safety for Alzheimer's disease treatment. In our study, a series of novel DL0410 derivatives were evaluated for inhibitory activities towards AChE and BuChE. Among these derivatives, compounds 6-1 and 7-6 showed stronger AChE and BuChE inhibitory activities than DL0410. Then, pharmacophore modeling and three-dimensional quantitative structure activity relationship (3D-QSAR) models were performed. The R(2) of AChE and BuChE 3D-QSAR models for training set were found to be 0.925 and 0.883, while that of the test set were 0.850 and 0.881, respectively. Next, molecular docking methods were utilized to explore the putative binding modes. Compounds 6-1 and 7-6 could interact with the amino acid residues in the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE/BuChE, which was similar with DL0410. Kinetics studies also suggested that the three compounds were all mixed-types of inhibitors. In addition, compound 6-1 showed better absorption and blood brain barrier permeability. These studies provide better insight into the inhibitory behaviors of DL0410 derivatives, which is beneficial for rational design of AChE and BuChE inhibitors in the future.
ESTHER : Pang_2017_Molecules_22_
PubMedSearch : Pang_2017_Molecules_22_
PubMedID: 28933746

Title : Design, Synthesis, and Biological Evaluation of a New Series of Biphenyl\/Bibenzyl Derivatives Functioning as Dual Inhibitors of Acetylcholinesterase and Butyrylcholinesterase - Wang_2017_Molecules_22_
Author(s) : Wang DM , Feng B , Fu H , Liu AL , Wang L , Du GH , Wu S
Ref : Molecules , 22 : , 2017
Abstract : Alzheimer's disease (AD), the most common form of dementia in adults, is a progressive neurodegenerative disorder of the brain characterized by loss of memory and steady deterioration of cognition. Here, a series of symmetrical molecules containing biphenyl/bibenzyl scaffolds (12-36) were designed, synthesized, and evaluated for their ability to inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A biological evaluation showed that most of these biphenyl derivatives were potent AChE and BuChE inhibitors. Among them, compound 15 displayed the greatest ability to inhibit BuChE (IC50 = 0.74 microM) and was also a good AChE inhibitor (IC50 = 1.18 microM). Compound 19 was not only a potent AChE inhibitor (IC50 = 0.096 microM), but also a mild BuChE inhibitor (IC50 =1.25 microM). Overall, these results suggested that compound 19 may be a promising agent in the treatment of AD.
ESTHER : Wang_2017_Molecules_22_
PubMedSearch : Wang_2017_Molecules_22_
PubMedID: 28117700

Title : Vagus Nerve Attenuates Hepatocyte Apoptosis upon Ischemia-Reperfusion via alpha7 Nicotinic Acetylcholine Receptor on Kupffer Cells in Mice - Ni_2016_Anesthesiology_125_1005
Author(s) : Ni M , Fu H , Huang F , Zhao T , Chen JK , Li DJ , Shen FM
Ref : Anesthesiology , 125 :1005 , 2016
Abstract : BACKGROUND: Hepatic ischemia-reperfusion (HIR) injury is a complication of liver surgery. As much as 50% of hepatocytes undergo apoptosis within the first 24 h of reperfusion. The neurotransmitters of the vagus nerve can activate alpha7 nicotinic acetylcholine receptor (alpha7nAChR) on macrophages. The function of Kupffer cells (KCs) determines HIR injury. We hypothesize that the vagus nerve could attenuate HIR-induced hepatocyte apoptosis by activating alpha7nAChR on KCs.
METHODS: Hepatic vagotomized C57BL/6J mice, KC-eliminated C57BL/6J mice, and alpha7nAChR mice were used for HIR. Primary KCs and hepatocytes were subjected to hypoxia/reoxygenation (HR). Liver injury, hepatocyte apoptosis, reactive oxygen species (ROS) production, and soluble CD163 were measured.
RESULTS: Hepatic vagotomy and alpha7nAChR caused higher levels of alanine transaminase and liver caspase-3 and -8 activity by HIR. Activating alpha7nAChR attenuated these changes in wild-type but not in the alpha7nAChR mice. Furthermore, activating alpha7nAChR diminished hepatic injury and reduced liver apoptosis by HIR in vagotomized mice. In vitro, activating alpha7nAChR reduced apoptosis of hepatocytes cocultured with KCs that suffered HR. Similar to the effects by catalase, activating alpha7nAChR on KCs reduced ROS and H2O2 by HR. The supernatant from KCs, with alpha7nAChR activated or catalase treated, prevented hepatocyte apoptosis by HR. Finally, KC elimination reduced HIR-induced H2O2 production in mice. Activating alpha7nAChR significantly attenuated soluble CD163 both in mice by HIR (serum: 240 +/- 34 vs. 446 +/- 72; mean +/- SD; n = 8; P < 0.01) and in KCs by HR (supernatant: 4.23 +/- 0.06 vs. 5.60 +/- 0.18; n = 3; P < 0.01).
CONCLUSIONS: The vagus nerve could minimize HIR-induced liver apoptosis through activating alpha7nAChR on KCs possibly by preventing their excessive ROS production.
ESTHER : Ni_2016_Anesthesiology_125_1005
PubMedSearch : Ni_2016_Anesthesiology_125_1005
PubMedID: 27560466

Title : 2,3,7,8-Tetrachlorodibenzo-p-dioxin suppress AChE activity in NGF treated PC12 cells - XuL_2016_Chem.Biol.Interact_259_282
Author(s) : Xu L , Chen Y , Xie HQ , Xu T , Fu H , Zhang S , Tsim KWK , Bi CWC , Zhao B
Ref : Chemico-Biological Interactions , 259 :282 , 2016
Abstract : PC12 is a well studied cell model for neuronal differentiation. AChE is also considered as a marker for neuronal differentiation. In this study, we detected the change of AChE activity during the NGF induced differentiation of PC 12 cells, and targeted on the ratio of the activity of AChE on the cell surface, and found that NGF mainly increased the intracellular AChE activity. Dioxin is a kind of persistent organic pollutants which have extreme impact on human health and widely distributed all over the world. Recently, AChE was reported as a target of the toxicity of dioxin. Here we investigated the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on AChE activity in the PC12 cells, and found that at the later stage of differentiation, TCDD could decrease the AChE activity. This down regulation might not related to transcriptional regulation.
ESTHER : XuL_2016_Chem.Biol.Interact_259_282
PubMedSearch : XuL_2016_Chem.Biol.Interact_259_282
PubMedID: 27502150

Title : Differential distribution of heparan sulfate glycoforms and elevated expression of heparan sulfate biosynthetic enzyme genes in the brain of mucopolysaccharidosis IIIB mice - McCarty_2011_Metab.Brain.Dis_26_9
Author(s) : McCarty DM , DiRosario J , Gulaid K , Killedar S , Oosterhof A , van Kuppevelt TH , Martin PT , Fu H
Ref : Metabolic Brain Disease , 26 :9 , 2011
Abstract : The primary pathology in mucopolysaccharidosis (MPS) IIIB is lysosomal storage of heparan sulfate (HS) glycosaminoglycans, leading to complex neuropathology and dysfunction, for which the detailed mechanisms remain unclear. Using antibodies that recognize specific HS glycoforms, we demonstrate differential cell-specific and domain-specific lysosomal HS-GAG distribution in MPS IIIB mouse brain. We also describe a novel neuron-specific brain HS epitope with broad, non-specific increase in the expression in all neurons in MPS IIIB mouse brain, including cerebellar granule neurons, which do not exhibit lysosomal storage pathology. This suggests that biosynthesis of certain HS glycoforms is enhanced throughout the CNS of MPS IIIB mice. Such a conclusion is further supported by demonstration of increased expression of multiple genes encoding enzymes essential in HS biosynthesis, including HS sulfotransferases and epimerases, as well as FGFs, for which HS serves as a co-receptor, in MPS IIIB brain. These data suggest that lysosomal storage of HS may lead to the increase in HS biosyntheses, which may contribute to the neuropathology of MPS IIIB by exacerbating the lysosomal HS storage.
ESTHER : McCarty_2011_Metab.Brain.Dis_26_9
PubMedSearch : McCarty_2011_Metab.Brain.Dis_26_9
PubMedID: 21225451

Title : Pathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin - Luo_2010_J.Biol.Chem_285_19947
Author(s) : Luo J , Li W , Zhao Y , Fu H , Ma DL , Tang J , Li C , Peoples RW , Li F , Wang Q , Huang P , Xia J , Pang Y , Han Y
Ref : Journal of Biological Chemistry , 285 :19947 , 2010
Abstract : Uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and gamma-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [(3)H]MK-801 with a K(i) value of 0.27 mum, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. More interestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced long-term potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation.
ESTHER : Luo_2010_J.Biol.Chem_285_19947
PubMedSearch : Luo_2010_J.Biol.Chem_285_19947
PubMedID: 20404346

Title : Synthesis and characterization of branched polymers from lipase-catalyzed trimethylolpropane copolymerizations - Kulshrestha_2007_Biomacromolecules_8_1794
Author(s) : Kulshrestha AS , Gao W , Fu H , Gross RA
Ref : Biomacromolecules , 8 :1794 , 2007
Abstract : Lipase-catalyzed terpolymerizations were performed with the monomers trimethylolpropane (B3), 1,8-octanediol (B2), and adipic acid (A2). Polymerizations were performed in bulk, at 70 degrees C, for 42 h, using immobilized lipase B from Candida antartica (Novozyme-435) as a catalyst. To determine the substitution pattern of trimethylolpropane (TMP) in copolymers, model compounds with variable degrees of acetylation were synthesized. Inverse-gated 13C NMR spectra were recorded to first determine the chemical shift positions for mono-, di-, and trisubstituted TMP units and, subsequently, to determine substitution of TMP units along chains. Variation of TMP in the monomer feed gave copolymers with degrees of branching (DB) from 20% to 67%. In one example, a hyperbranched copolyester with 53 mol % TMP adipate units was formed in 80% yield, with Mw 14 100 (relative to polystyrene standards), Mw/Mn 5.3, and DB 36%. Thermal and crystalline properties of the copolyesters were studied by thermogravimetric analysis and differential scanning calorimetry.
ESTHER : Kulshrestha_2007_Biomacromolecules_8_1794
PubMedSearch : Kulshrestha_2007_Biomacromolecules_8_1794
PubMedID: 17477567

Title : Mitochondrial proteomic analysis and characterization of the intracellular mechanisms of bis(7)-tacrine in protecting against glutamate-induced excitotoxicity in primary cultured neurons - Fu_2007_J.Proteome.Res_6_2435
Author(s) : Fu H , Li W , Liu Y , Lao Y , Liu W , Chen C , Yu H , Lee NT , Chang DC , Li P , Pang Y , Tsim KWK , Li M , Han Y
Ref : J Proteome Res , 6 :2435 , 2007
Abstract : Increasing evidence supports that the mitochondrial dysfunction, mainly caused by abnormal changes in mitochondrial proteins, plays a pivotal role in glutamate-induced excitotoxicity, which is closely associated with the pathogenesis of acute and chronic neurodegenerative disorders, such as stroke and Alzheimer's disease. In this study, post-treatment of cerebellar granule neurons with bis(7)-tacrine significantly reversed declines in mitochondrial membrane potential, ATP production, and neuronal cell death induced by glutamate. Moreover, this reversal was independent of NMDA antagonism, acetylcholinesterase inhibition, and cholinergic pathways. Using two-dimensional differential in-gel electrophoresis, we conducted a comparative analysis of mitochondrial protein patterns. In all, 29 proteins exhibiting significant differences in their abundances were identified in the glutamate-treated group when compared with the control. The expression patterns in 22 out of these proteins could be reversed by post-treatment with bis(7)-tacrine. Most of the differentially expressed proteins are involved in energy metabolism, oxidative stress, and apoptosis. In particular, the altered patterns of four of these proteins were further validated by Western blot analysis. Our findings suggest that multiple signaling pathways initiated by the altered mitochondrial proteins may mediate glutamate-induced excitotoxicity and also offer potentially useful intracellular targets for the neuroprotection provided by bis(7)-tacrine.
ESTHER : Fu_2007_J.Proteome.Res_6_2435
PubMedSearch : Fu_2007_J.Proteome.Res_6_2435
PubMedID: 17530875

Title : Pancreatic lipase-inhibiting triterpenoid saponins from fruits of Acanthopanax senticosus - Li_2007_Chem.Pharm.Bull.(Tokyo)_55_1087
Author(s) : Li F , Li W , Fu H , Zhang Q , Koike K
Ref : Chem Pharm Bull (Tokyo) , 55 :1087 , 2007
Abstract : Sixteen triterpenoid saponins were isolated from the fruits of Acanthopanax senticosus, including a new compound, acanthopanaxoside E (1), which was established as 3-O-beta-D-glucuronopyranosyl echinocystic acid 28-O-beta-D-glucopyranoside on the basis of various spectroscopic analyses and chemical degradation. By using a pancreatic lipase-inhibiting assay system, the crude saponin fraction showed inhibitory activity on pancreatic lipase, which is a key enzyme in lipid digestion. Among the isolated compounds, silphioside F (2), copteroside B (3), hederagenin 3-O-beta-D-glucuronopyranoside 6'-O-methyl ester (4) and gypsogenin 3-O-beta-D-glucuronopyranoside (5) showed inhibitory activity toward pancreatic lipase with IC(50) values of 0.22, 0.25, 0.26 and 0.29 mM, respectively, and the free carboxylic acid groups in position 28 within their chemical structures were required for enhancement of pancreatic lipase inhibition.
ESTHER : Li_2007_Chem.Pharm.Bull.(Tokyo)_55_1087
PubMedSearch : Li_2007_Chem.Pharm.Bull.(Tokyo)_55_1087
PubMedID: 17603209

Title : Bis(7)-tacrine attenuates beta amyloid-induced neuronal apoptosis by regulating L-type calcium channels - Fu_2006_J.Neurochem_98_1400
Author(s) : Fu H , Li W , Lao Y , Luo J , Lee NT , Kan KK , Tsang HW , Tsim KWK , Pang Y , Li Z , Chang DC , Li M , Han Y
Ref : Journal of Neurochemistry , 98 :1400 , 2006
Abstract : Beta amyloid protein (Abeta) and acetylcholinesterase (AChE) have been shown to be closely implicated in the pathogenesis of Alzheimer's disease. In the current study, we investigated the effects of bis(7)-tacrine, a novel dimeric AChE inhibitor, on Abeta-induced neurotoxicity in primary cortical neurons. Bis(7)-tacrine, but not other AChE inhibitors, elicited a marked reduction of both fibrillar and soluble oligomeric forms of Abeta-induced apoptosis as evidenced by chromatin condensation and DNA specific fragmentation. Both nicotinic and muscarinic receptor antagonists failed to block the effects of bis(7)-tacrine. Instead, nimodipine, a blocker of L-type voltage-dependent Ca2+ channels (VDCCs), attenuated Abeta neurotoxicity, whereas N-, P/Q- or R-type VDCCs blockers and ionotropic glutamate receptor antagonists did not. Fluorescence Ca2+ imaging assay revealed that, similar to nimodipine, bis(7)-tacrine reversed Abeta-triggered intracellular Ca2+ increase, which was mainly contributed by the extracellular Ca2+ instead of endoplasmic reticulum and mitochondria Ca2+. Concurrently, using whole cell patch-clamping technique, it was found that bis(7)-tacrine significantly reduced the augmentation of high voltage-activated inward calcium currents induced by Abeta. These results suggest that bis(7)-tacrine attenuates Abeta-induced neuronal apoptosis by regulating L-type VDCCs, offers a novel modality as to how the agent exerts neuroprotective effects.
ESTHER : Fu_2006_J.Neurochem_98_1400
PubMedSearch : Fu_2006_J.Neurochem_98_1400
PubMedID: 16771827

Title : Neuroprotection via inhibition of nitric oxide synthase by bis(7)-tacrine - Li_2006_Neuroreport_17_471
Author(s) : Li W , Lee NT , Fu H , Kan KK , Pang Y , Li M , Tsim KWK , Li X , Han Y
Ref : Neuroreport , 17 :471 , 2006
Abstract : Here we report that bis(7)-tacrine, a novel acetylcholinesterase inhibitor, exerts neuroprotective effects by inhibition of nitric oxide synthase. In cortical neurons at 12 days in vitro, bis(7)-tacrine concentration-dependently reduced cell death induced by glutamate, beta-amyloid and L-arginine, but not by nitric sodium nitroprusside. N-monomethyl-L-arginine, a nitric oxide synthase inhibitor, also prevented the former three types but not the last type of the cytotoxicity; however, nitric oxide scavengers blocked all of these insults, indicating that nitric oxide mediated these neuronal injuries. Furthermore, with nitric oxide synthase activity assays, it was found that bis(7)-tacrine not only suppressed the activation of nitric oxide synthase caused by glutamate in cortical neurons, but also directly inhibited the activity of nitric oxide synthase in vitro.
ESTHER : Li_2006_Neuroreport_17_471
PubMedSearch : Li_2006_Neuroreport_17_471
PubMedID: 16543809

Title : Novel dimeric acetylcholinesterase inhibitor bis7-tacrine, but not donepezil, prevents glutamate-induced neuronal apoptosis by blocking N-methyl-D-aspartate receptors - Li_2005_J.Biol.Chem_280_18179
Author(s) : Li W , Pi R , Chan HH , Fu H , Lee NT , Tsang HW , Pu Y , Chang DC , Li C , Luo J , Xiong K , Li Z , Xue H , Carlier PR , Pang Y , Tsim KWK , Li M , Han Y
Ref : Journal of Biological Chemistry , 280 :18179 , 2005
Abstract : The neuroprotective properties of bis(7)-tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate-induced excitotoxicity were investigated in primary cultured cerebellar granule neurons (CGNs). Exposure of CGNs to 75 mum glutamate resulted in neuronal apoptosis as demonstrated by Hoechst staining, TUNEL, and DNA fragmentation assays. The bis(7)-tacrine treatment (0.01-1 mum) on CGNs markedly reduced glutamate-induced apoptosis in dose- and time-dependent manners. However, donepezil and other AChE inhibitors, even at concentrations of inhibiting AChE to the similar extents as 1 mum bis(7)-tacrine, failed to prevent glutamate-induced excitotoxicity in CGNs; moreover, both atropine and dihydro-beta-erythroidine, the cholinoreceptor antagonists, did not affect the anti-apoptotic properties of bis(7)-tacrine, suggesting that the neuroprotection of bis(7)-tacrine appears to be independent of inhibiting AChE and cholinergic transmission. In addition, ERK1/2 and p38 pathways, downstream signals of N-methyl-d-aspartate (NMDA) receptors, were rapidly activated after the exposure of glutamate to CGNs. Bis(7)-tacrine inhibited the apoptosis and the activation of these two signals with the same efficacy as the coapplication of PD98059 and SB203580. Furthermore, using fluorescence Ca(2+) imaging, patch clamp, and receptor-ligand binding techniques, bis(7)-tacrine was found effectively to buffer the intracellular Ca(2+) increase triggered by glutamate, to reduce NMDA-activated currents and to compete with [(3)H]MK-801 with an IC(50) value of 0.763 mum in rat cerebellar cortex membranes. These findings strongly suggest that bis(7)-tacrine prevents glutamate-induced neuronal apoptosis through directly blocking NMDA receptors at the MK-801-binding site, which offers a new and clinically significant modality as to how the agent exerts neuroprotective effects.
ESTHER : Li_2005_J.Biol.Chem_280_18179
PubMedSearch : Li_2005_J.Biol.Chem_280_18179
PubMedID: 15710623

Title : [Clinical study on treatment of mild cognitive impairment by modified wuzi yanzong granule] - Wang_2004_Zhongguo.Zhong.Xi.Yi.Jie.He.Za.Zhi_24_392
Author(s) : Wang XM , Fu H , Liu GX
Ref : Zhongguo Zhong Xi Yi Jie He Za Zhi , 24 :392 , 2004
Abstract : OBJECTIVE: To observe the clinical efficacy and safety of modified Wuzi Yanzong Granule (MWYG) in treating mild cognitive impairment (MCI), and to explore its mechanism.
METHODS: Forty-four MCI patients were selected referring to the international recognized Peterson's criteria and randomly divided into two groups, the treated group treated with MWYG and the control group treated with Ginkgo leaf extraction, with the course of 3 months for both groups. Changes of memorial quotient (MQ), superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, mitochondrial DNA (mtDNA) deletion rate and acetylcholinesterase (AchE) before and after treatment were observed.
RESULTS: After treatment, levels of MQ, serum SOD activity increased and serum MDA content, mtDNA deletion rate and AchE decreased in both groups (P < 0.01), but the difference between the two groups was insignificant. No adverse reaction was found in two groups. CONCLUSION: Both MWYG and Ginkgo leaf capsule can effectively improve the memorial function of patients with MCI, the therapeutic mechanism is possibly related with the actions in reducing AchE activity, improving free radical metabolism, and alleviating mitochondrial DNA oxidation damage.
ESTHER : Wang_2004_Zhongguo.Zhong.Xi.Yi.Jie.He.Za.Zhi_24_392
PubMedSearch : Wang_2004_Zhongguo.Zhong.Xi.Yi.Jie.He.Za.Zhi_24_392
PubMedID: 15199619

Title : Molecular cloning of the carboxylesterase gene and biochemical characterization of the encoded protein from Pseudomonas citronellolis ATCC 13674 - Chao_2003_Res.Microbiol_154_521
Author(s) : Chao YP , Fu H , Wang YL , Huang WB , Wang JY
Ref : Res Microbiol , 154 :521 , 2003
Abstract : A genomic library of Pseudomonas citronellolis ATCC 13674 was constructed and screened for esterase activity in Escherichia coli using tributyrin-containing medium. One positive transformant was isolated, and subsequent analyses of the plasmid by restriction mapping revealed a 4.1-kb DNA fragment potentially carrying an esterase gene. The deduced nucleotide sequence of the DNA was found to contain an open reading frame encoding carboxylesterase and designated estA. Amino acid sequence analysis of estA showed the serine conservative motif, GDSAG, located between residues 208 and 212. Together with Ser, residues 310 and 334 corresponding to aspartic acid and histidine, respectively, comprised the catalytic triad. With the aid of immobilized metal ion affinity chromatography, the carboxylesterase fused with poly His at its C-terminus was purified and shown to be strongly inhibited by the tryptophan modifier and mercuric ion, indicating the important role of conservative Trp (189) and cysteine (152 and/or 183) residues in maintaining the structural integrity of the protein. Further analyses showed that the carboxylesterase functioned optimally at 37-40 degrees C with pH ranging between 8 and 9 and displayed a broad substrate spectrum. The protein exhibited greater preference toward short-chain (C2-C4) than medium- and long-chain fatty acids. Higher substrate specificity on para-nitrophenol butyrate was observed in comparison with para-nitrophenol acetate as indicated by the higher kcat/Km value of the former.
ESTHER : Chao_2003_Res.Microbiol_154_521
PubMedSearch : Chao_2003_Res.Microbiol_154_521
PubMedID: 14499938
Gene_locus related to this paper: acilw-ESTA

Title : The highly recombinogenic bz locus lies in an unusually gene-rich region of the maize genome - Fu_2001_Proc.Natl.Acad.Sci.U.S.A_98_8903
Author(s) : Fu H , Park W , Yan X , Zheng Z , Shen B , Dooner HK
Ref : Proceedings of the National Academy of Sciences of the United States of America , 98 :8903 , 2001
Abstract : The bronze (bz) locus exhibits the highest rate of recombination of any gene in higher plants. To investigate the possible basis of this high rate of recombination, we have analyzed the physical organization of the region around the bz locus. Two adjacent bacterial artificial chromosome clones, comprising a 240-kb contig centered around the Bz-McC allele, were isolated, and 60 kb of contiguous DNA spanning the two bacterial artificial chromosome clones was sequenced. We find that the bz locus lies in an unusually gene-rich region of the maize genome. Ten genes, at least eight of which are shown to be transcribed, are contained in a 32-kb stretch of DNA that is uninterrupted by retrotransposons. We have isolated nearly full length cDNAs corresponding to the five proximal genes in the cluster. The average intertranscript distance between them is just 1 kb, revealing a surprisingly compact packaging of adjacent genes in this part of the genome. At least 11 small insertions, including several previously described miniature inverted repeat transposable elements, were detected in the introns and 3' untranslated regions of genes and between genes. The gene-rich region is flanked at the proximal and distal ends by retrotransposon blocks. Thus, the maize genome appears to have scattered regions of high gene density similar to those found in other plants. The unusually high rate of intragenic recombination seen in bz may be related to the very high gene density of the region.
ESTHER : Fu_2001_Proc.Natl.Acad.Sci.U.S.A_98_8903
PubMedSearch : Fu_2001_Proc.Natl.Acad.Sci.U.S.A_98_8903
PubMedID: 11438686

Title : [Activity of cholinesterase of erythrocyte membrane in patients with hot or cold syndrome]. [Chinese] -
Author(s) : Fu H , Peng XZ , Cai TH
Ref : Chung Kuo Chung Hsi I Chieh Ho Tsa Chih , 15 :351 , 1995
PubMedID: 7549386