Hu Z

References (57)

Title : AChE activity self-breathing control mechanisms regulated by H(2)S(n) and GSH: Persulfidation and glutathionylation on sulfhydryl after disulfide bonds cleavage - Zhu_2024_Int.J.Biol.Macromol_259_129117
Author(s) : Zhu Y , Hu Z , Liu Y , Yan T , Liu L , Wang Y , Bai B
Ref : Int J Biol Macromol , 259 :129117 , 2024
Abstract : Hydrogen sulfide (H(2)S), or dihydrogen sulfane (H(2)S(n)), acts as a signal molecule through the beneficial mechanism of persulfidation, known as the post-translational transformation of cysteine residues to persulfides. We previously reported that Glutathione (GSH) could regulate enzyme activity through S-desulfurization or glutathionylation of residues to generate protein-SG or protein-SSG, releasing H(2)S. However, little is known about the mechanisms by which H(2)S(n) and GSH affect the disulfide bonds. In this study, we provide direct evidences that H(2)S(n) and GSH modify the sulfhydryl group on Cys272, which forms disulfide bonds in acetylcholinesterase (AChE), to generate Cys-SSH and Cys-SSG, respectively. Glutathionylation of disulfide is a two-step reaction based on nucleophilic substitution, in which the first CS bond is broken, then the SS bond is broken to release H(2)S. H(2)S(n) and GSH controlled self-breathing motion in enzyme catalysis by disconnecting specific disulfide bonds and modifying cysteine residues, thereby regulating AChE activity. Here, we elucidated H(2)S(n) and GSH mechanisms on disulfide in the AChE system and proposed a self-breathing control theory induced by H(2)S(n) and GSH. These theoretical findings shed light on the biological functions of H(2)S(n) and GSH on sulfhydryl and disulfide bonds and enrich the theory of enzyme activity regulation.
ESTHER : Zhu_2024_Int.J.Biol.Macromol_259_129117
PubMedSearch : Zhu_2024_Int.J.Biol.Macromol_259_129117
PubMedID: 38211930

Title : Biotransformation of HBCDs by the microbial communities enriched from mangrove sediments - Yu_2024_J.Hazard.Mater_469_134036
Author(s) : Yu F , Zhang B , Liu Y , Luo W , Chen H , Gao J , Ye X , Li J , Xie Q , Peng T , Wang H , Huang T , Hu Z
Ref : J Hazard Mater , 469 :134036 , 2024
Abstract : 1,2,5,6,9,10-Hexabromocyclododecanes (HBCDs) are a sort of persistent organic pollutants (POPs). This research investigated 12 microbial communities enriched from sediments of four mangroves in China to transform HBCDs. Six microbial communities gained high transformation rates (27.5-97.7%) after 12 generations of serial transfer. Bacteria were the main contributors to transform HBCDs rather than fungi. Analyses on the bacterial compositions and binning genomes showed that Alcanivorax (55.246-84.942%) harboring haloalkane dehalogenase genes dadAH and dadBH dominated the microbial communities with high transformation rates. Moreover, expressions of dadAH and dadBH in the microbial communities and Alcanivorax isolate could be induced by HBCDs. Further, it was found that purified proteins DadAH and DadBH showed high conversion rates on HBCDs in 36 h (91.9 +/- 7.4 and 101.0 +/- 1.8%, respectively). The engineered Escherichia coli BL21 strains harbored two genes could convert 5.7 +/- 0.4 and 35.1 +/- 0.1% HBCDs, respectively, lower than their cell-free crude extracts (61.2 +/- 5.2 and 56.5 +/- 8.7%, respectively). The diastereoisomer-specific transforming trend by both microbial communities and enzymes were gamma- > alpha- > beta-HBCD, differed from alpha- > beta- > gamma-HBCD by the Alcanivorax isolate. The identified transformation products indicated that HBCDs were dehalogenated via HBr elimination (dehydrobromination), hydrolytic and reductive debromination pathways in the enriched cultures. Two enzymes converted HBCDs via hydrolytic debromination. The present research provided theoretical bases for the biotransformation of HBCDs by microbial community and the bioremediation of HBCDs contamination in the environment.
ESTHER : Yu_2024_J.Hazard.Mater_469_134036
PubMedSearch : Yu_2024_J.Hazard.Mater_469_134036
PubMedID: 38493623

Title : GehB Inactivates Lipoproteins to Delay the Healing of Acute Wounds Infected with Staphylococcus aureus - Wang_2023_Curr.Microbiol_81_36
Author(s) : Wang K , Cai X , Rao Y , Liu L , Hu Z , Peng H , Wang Y , Yang Y , Rao X , Nie K , Shang W
Ref : Curr Microbiol , 81 :36 , 2023
Abstract : Staphylococcus aureus is one of the most prevalent bacteria found in acute wounds. S. aureus produces many virulence factors and extracellular enzymes that contribute to bacterial survival, dissemination, and pathogenicity. Lipase GehB is a glycerol ester hydrolase that hydrolyzes triglycerides to facilitate the evasion of S. aureus from host immune recognition. However, the role and mechanism of lipase GehB in skin acute wound healing after S. aureus infection remain unclear. In this study, we found that the gehB gene deletion mutant (USA300deltagehB) stimulated significantly higher levels of pro-inflammatory cytokines in RAW264.7 and Toll-like receptor 2 (TLR2)-transfected HEK293 cells than the wild-type USA300 strain did. Recombinant GehB-His treated lipoprotein (Lpp) reduced stimulation of TLR2-dependent TNF-alpha production by RAW264.7 macrophages. GehB delayed the skin acute wound healing in BALB/c mice infected with S. aureus, while wound healing was similar in C57BL/6 TLR2(-/-) mice infected with either wild-type USA300 or USA300deltagehB. In BALB/c mice, we also observed more bacterial survival, less leukocyte recruitment, lower IL-8 production, and adipocyte differentiation in USA300-infected skin acute wound tissues than those in USA300deltagehB-challenged ones. Our data indicated that GehB inactivates lipoproteins to shield S. aureus from innate immune killing, resulting in delayed the healing of skin acute wounds infected with S. aureus.
ESTHER : Wang_2023_Curr.Microbiol_81_36
PubMedSearch : Wang_2023_Curr.Microbiol_81_36
PubMedID: 38063939

Title : Loss-of-Function Homozygous Variant in LPL Causes Type I Hyperlipoproteinemia and Renal Lipidosis - Wu_2023_Kidney.Int.Rep_8_2428
Author(s) : Wu H , Xu H , Lei S , Yang Z , Yang S , Du J , Zhou Y , Liu Y , Yang Y , Hu Z
Ref : Kidney Int Rep , 8 :2428 , 2023
Abstract : INTRODUCTION: Lipoprotein lipase (LPL) is an important enzyme in lipid metabolism, individuals with LPL gene variants could present type I hyperlipoproteinemia, lipemia retinalis, hepatosplenomegaly, and pancreatitis. To date, there are no reports of renal lipidosis induced by type I hyperlipoproteinemia due to LPL mutation. METHODS: Renal biopsy was conducted to confirm the etiological factor of nephrotic syndrome in a 44-year-old Chinese man. Lipoprotein electrophoresis, apoE genotype detection, and whole-exome sequencing were performed to confirm the dyslipidemia type and genetic factor. Analysis of the 3-dimensional protein structure and in vitro functional study were conducted to verify variant pathogenicity. RESULTS: Renal biopsy revealed numerous CD68 positive foam cells infiltrated in the glomeruli; immunoglobulin and complement staining were negative; and electron microscopy revealed numerous lipid droplets and cholesterol clefts in the cytoplasm of foam cells. Lipoprotein electrophoresis revealed that the patient fulfilled the diagnostic criteria of type I hyperlipoproteinemia. The apoE genotype of the patient was the sigma3/sigma3 genotype. Whole-exome sequencing revealed an LPL (c.292G > A, p.A98T) homozygous variant with alpha-helix instability and reduced post-heparin LPL activity but normal lipid uptake capability compared to the wild-type variant. CONCLUSION: LPL (c.292G > A, p.A98T) is a pathogenic variant that causes renal lipidosis associated with type I hyperlipoproteinemia. This study provides adequate evidence of the causal relationship between dyslipidemia and renal lesions. However, further research is needed to better understand the pathogenetic mechanism of LPL variant-related renal lesions.
ESTHER : Wu_2023_Kidney.Int.Rep_8_2428
PubMedSearch : Wu_2023_Kidney.Int.Rep_8_2428
PubMedID: 38025240
Gene_locus related to this paper: human-LPL

Title : Discovery of two ent-atisane diterpenoid lactones with AChE inhibitory activity from the roots of Euphorbia fischeriana - Wei_2023_Org.Biomol.Chem__
Author(s) : Wei J , Li Z , Shan M , Wu F , Li L , Ma Y , Wu J , Li X , Liu Y , Hu Z , Zhang Y , Wu Z
Ref : Org Biomol Chem , : , 2023
Abstract : Euphorlactone A (1), a rare rearranged ent-atisane norditerpenoid with an undescribed 3-nor-2,4-olide-ent-atisane scaffold, and euphorlactone B (2), a new ent-atisane diterpenoid with an unprecedented seven-membered lactone ring C, were isolated from the roots of Euphorbia fischeriana. Their planar structures with absolute configurations were extensively elucidated by analysis of 1D and 2D NMR data, electronic circular dichroism (ECD) calculations, Rh(2)(OCOCF(3))(4)-induced ECD curves, and single-crystal X-ray diffraction. Euphorlactone A (ELA) showed a remarkable AChE (acetylcholinesterase) inhibitory activity (IC(50) = 2.13 +/- 0.06 microM and K(i) = 0.058 microM), which was five times stronger than that of the positive control (rivastigmine, IC(50) = 12.46 +/- 0.82 microM), and further in vitro enzyme inhibition kinetic analysis and molecular docking studies were performed to investigate the AChE inhibitory mechanism.
ESTHER : Wei_2023_Org.Biomol.Chem__
PubMedSearch : Wei_2023_Org.Biomol.Chem__
PubMedID: 37581482

Title : An overview of microbial enzymatic approaches for pectin degradation - Li_2023_Int.J.Biol.Macromol_254_127804
Author(s) : Li J , Peng C , Mao A , Zhong M , Hu Z
Ref : Int J Biol Macromol , 254 :127804 , 2023
Abstract : Pectin, a complex natural macromolecule present in primary cell walls, exhibits high structural diversity. Pectin is composed of a main chain, which contains a high amount of partly methyl-esterified galacturonic acid (GalA), and numerous types of side chains that contain almost 17 different monosaccharides and over 20 different linkages. Due to this peculiar structure, pectin exhibits special physicochemical properties and a variety of bioactivities. For example, pectin exhibits strong bioactivity only in a low molecular weight range. Many different degrading enzymes, including hydrolases, lyases and esterases, are needed to depolymerize pectin due to its structural complexity. Pectin degradation involves polygalacturonases/rhamnogalacturonases and pectate/pectin lyases, which attack the linkages in the backbone via hydrolytic and beta-elimination modes, respectively. Pectin methyl/acetyl esterases involved in the de-esterification of pectin also play crucial roles. Many alpha-L-rhamnohydrolases, unsaturated rhamnogalacturonyl hydrolases, arabinanases and galactanases also contribute to heterogeneous pectin degradation. Although numerous microbial pectin-degrading enzymes have been described, the mechanisms involved in the coordinated degradation of pectin through these enzymes remain unclear. In recent years, the degradation of pectin by Bacteroides has received increasing attention, as Bacteroides species contain a unique genetic structure, polysaccharide utilization loci (PULs). The specific PULs of pectin degradation in Bacteroides species are a new field to study pectin metabolism in gut microbiota. This paper reviews the scientific information available on pectin structural characteristics, pectin-degrading enzymes, and PULs for the specific degradation of pectin.
ESTHER : Li_2023_Int.J.Biol.Macromol_254_127804
PubMedSearch : Li_2023_Int.J.Biol.Macromol_254_127804
PubMedID: 37913880

Title : Abamectin induced brain and liver toxicity in carp: The healing potential of silybin and potential molecular mechanisms - Wu_2023_Fish.Shellfish.Immunol__109152
Author(s) : Wu X , Xin Y , Ma Y , Ping K , Li Q , Sun Y , Hu Z , Dong J
Ref : Fish Shellfish Immunol , :109152 , 2023
Abstract : Abamectin (ABM) abuse contaminated aquatic environment and posed a potential threat to fish health as well as public safety. Silybin (SIL), a flavonoid, has been widely used as a novel feed additive to promote fish health. This research was to explore the potential antagonistic mechanism between ABM and SIL on brain and liver toxicity was investigated in common carp. Sixty carp were divided into four groups at random: the Control group, the SIL group, the ABM group, and ABM + SIL group. This experiment lasted for 30 d. According to behavioral observation, the detection of levels of acetylcholinesterase (AchE), iron, and mRNA expression levels of blood-brain barrier (BBB) related tight junction proteins (ZO-1, Claudin7, Occludin, MMP2, MMP9, and MMP13) in brain tissues, it was found that SIL relieved neurobehavioral disorders caused by ABM-induced BBB destruction in carp. H&E staining showed SIL mitigated nerve injury and liver injury caused by ABM. Oil red O staining and liver-related parameters showed that SIL alleviated hepatotoxicity and lipid metabolism disorder caused by ABM exposure. Furthermore, this work also explored the specific molecular mechanism of SIL in liver protection and neuroprotection. It was shown that SIL lowered ROS levels in liver and brain tissues via the GSK-3beta/TSC2/TOR pathway. Simultaneously, SIL inhibited NF-kappaB signaling pathway and played an anti-inflammatory role. In conclusion, we believed that SIL supplementation has a protective effect on the brain and liver by regulating oxidative stress and inflammation.
ESTHER : Wu_2023_Fish.Shellfish.Immunol__109152
PubMedSearch : Wu_2023_Fish.Shellfish.Immunol__109152
PubMedID: 37821005

Title : UNC-43\/CaMKII-triggered anterograde signals recruit GABA(A)Rs to mediate inhibitory synaptic transmission and plasticity at C. elegans NMJs - Hao_2023_Nat.Commun_14_1436
Author(s) : Hao Y , Liu H , Zeng XT , Wang Y , Zeng WX , Qian KY , Li L , Chi MX , Gao S , Hu Z , Tong XJ
Ref : Nat Commun , 14 :1436 , 2023
Abstract : Disturbed inhibitory synaptic transmission has functional impacts on neurodevelopmental and psychiatric disorders. An essential mechanism for modulating inhibitory synaptic transmission is alteration of the postsynaptic abundance of GABA(A)Rs, which are stabilized by postsynaptic scaffold proteins and recruited by presynaptic signals. However, how GABAergic neurons trigger signals to transsynaptically recruit GABA(A)Rs remains elusive. Here, we show that UNC-43/CaMKII functions at GABAergic neurons to recruit GABA(A)Rs and modulate inhibitory synaptic transmission at C. elegans neuromuscular junctions. We demonstrate that UNC-43 promotes presynaptic MADD-4B/Punctin secretion and NRX-1alpha/Neurexin surface delivery. Together, MADD-4B and NRX-1alpha recruit postsynaptic NLG-1/Neuroligin and stabilize GABA(A)Rs. Further, the excitation of GABAergic neurons potentiates the recruitment of NLG-1-stabilized-GABA(A)Rs, which depends on UNC-43, MADD-4B, and NRX-1. These data all support that UNC-43 triggers MADD-4B and NRX-1alpha, which act as anterograde signals to recruit postsynaptic GABA(A)Rs. Thus, our findings elucidate a mechanism for pre- and postsynaptic communication and inhibitory synaptic transmission and plasticity.
ESTHER : Hao_2023_Nat.Commun_14_1436
PubMedSearch : Hao_2023_Nat.Commun_14_1436
PubMedID: 36918518

Title : Characterization of a New Thermostable and Organic Solution-Tolerant Lipase from Pseudomonas fluorescens and Its Application in the Enrichment of Polyunsaturated Fatty Acids - Hu_2023_Int.J.Mol.Sci_24_8924
Author(s) : Hu Z , Jiao L , Xie X , Xu L , Yan J , Yang M , Yan Y
Ref : Int J Mol Sci , 24 :8924 , 2023
Abstract : The search for and characterization of new lipases with excellent properties has always been urgent and is of great importance to meet industrial needs. In this study, a new lipase, lipB, from Pseudomonas fluorescens SBW25, belonging to the lipase subfamily I.3, was cloned and expressed in Bacillus subtilis WB800N. Enzymatic properties studies of recombinant LipB found that it exhibited the highest activity towards p-nitrophenyl caprylate at 40 degreesC and pH 8.0, retaining 73% of its original activity after incubation at 70 degreesC for 6 h. In addition, Ca(2+), Mg(2+), and Ba(2+) strongly enhanced the activity of LipB, while Cu(2+), Zn(2+), Mn(2+), and CTAB showed an inhibiting effect. The LipB also displayed noticeable tolerance to organic solvents, especially acetonitrile, isopropanol, acetone, and DMSO. Moreover, LipB was applied to the enrichment of polyunsaturated fatty acids from fish oil. After hydrolyzing for 24 h, it could increase the contents of polyunsaturated fatty acids from 43.16% to 72.18%, consisting of 5.75% eicosapentaenoic acid, 19.57% docosapentaenoic acid, and 46.86% docosahexaenoic acid, respectively. The properties of LipB render it great potential in industrial applications, especially in health food production.
ESTHER : Hu_2023_Int.J.Mol.Sci_24_8924
PubMedSearch : Hu_2023_Int.J.Mol.Sci_24_8924
PubMedID: 37240270
Gene_locus related to this paper: psefs-c3kbe9

Title : Design, synthesis and biological evaluation of novel indanones derivatives as potent acetylcholinesterase\/monoamine oxidase B inhibitors - Hu_2023_Future.Med.Chem__
Author(s) : Hu Z , Zhou S , Li J , Li X , Zhou Y , Zhu Z , Xu J , Liu J
Ref : Future Med Chem , : , 2023
Abstract : Aim: Based on a multitarget design strategy, a series of novel indanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Results: These compounds exhibited significant inhibitory activities against acetylcholinesterase (AChE) and moderate inhibitory activities toward monoamine oxidase B (MAO-B). The optimal compound A1 possessed excellent dual AChE/MAO-B inhibition both in terms of potency (AChE: IC(50) = 0.054 +/- 0.004 microM; MAO-B: IC(50) = 3.25 +/- 0.20 microM), moderate inhibitory effects on self-mediated amyloid-beta (Abeta) aggregation and antioxidant activity. In addition, compound A1 exhibited low neurotoxicity. More importantly, compound A1 showed significant cognitive and spatial memory improvements in the scopolamine-induced AD mouse model. Conclusion: All results suggest that compound A1 may become a promising lead of anti-AD drug for further development.
ESTHER : Hu_2023_Future.Med.Chem__
PubMedSearch : Hu_2023_Future.Med.Chem__
PubMedID: 37902028

Title : Design, Synthesis, and Biological Evaluation of Novel Chromanone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease - Li_2022_ACS.Chem.Neurosci__
Author(s) : Li X , Li T , Zhan F , Cheng F , Lu L , Zhang B , Li J , Hu Z , Zhou S , Jia Y , Allen S , White L , Phillips J , Zhu Z , Xu J , Yao H
Ref : ACS Chem Neurosci , : , 2022
Abstract : Based on a multitarget strategy, a series of novel chromanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). The optimal compound C10 possessed excellent dual AChE/MAO-B inhibition both in terms of potency and equilibrium (AChE: IC(50) = 0.58 0.05 M; MAO-B: IC(50) = 0.41 0.04 M). Further molecular modeling and kinetic investigations revealed that compound C10 was a dual-binding inhibitor bound to both the catalytic anionic site and peripheral anionic site of AChE. In addition, compound C10 exhibited low neurotoxicity and potently inhibited AChE enzymatic activity. Furthermore, compound C10 more effectively protected against mitochondrial dysfunction and oxidation than donepezil, strongly inhibited AChE-induced amyloid aggregation, and moderately reduced glutaraldehyde-induced phosphorylation of tau protein in SH-SY5Y cells. Moreover, compound C10 displayed largely enhanced improvements in cognitive behaviors and spatial memory in a scopolamine-induced AD mice model with better efficacy than donepezil. Overall, the multifunctional profiles of compound C10 suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.
ESTHER : Li_2022_ACS.Chem.Neurosci__
PubMedSearch : Li_2022_ACS.Chem.Neurosci__
PubMedID: 36383455

Title : Inducing new bioactive metabolites production from coculture of Pestalotiopsis sp. and Penicillium bialowiezense - Li_2021_Bioorg.Chem_110_104826
Author(s) : Li F , Yan S , Huang Z , Gao W , Zhang S , Mo S , Lin S , Wang J , Hu Z , Zhang Y
Ref : Bioorg Chem , 110 :104826 , 2021
Abstract : Coculturing two or more fungi is a useful strategy to awaken the silent genes to produce structurally diverse and bioactive natural products. Through the coculture of Pestalotiopsis sp. and Penicillium bialowiezense, six new isoprenylated chromane derivatives, including two pairs of enantiomeric ones (1a/1b-2a/2b) and two optical pure ones (3-4), two new isoprenylated phenol glucoside derivatives (6-7), as well as eight known structural analogues (5 and 8-14), were obtained. The structures of these new compounds were characterized by NMR spectroscopy, single-crystal X-ray crystallography, and ECD calculation. The delta(10,11) double bond of pestaloficin D (5) was revised to E-configurated based on the extensive spectroscopic analyses. Compounds 1a/1b and 2a/2b were the first examples of enantiomeric isoprenylated chromane derivatives, which were successfully separated by chiral HPLC. Additionally, all the isolated compounds were evaluated for the in vitro beta-glucuronidase (GUS) and butyrylcholinesterase (BChE) inhibitory activities. Compounds 1a and 1b showed significant beta-glucuronidase inhibitory potency with IC(50) values of 7.6 and 10.3 microM, respectively. Compound 14 exhibited moderate BChE inhibitory activity with an IC(50) value of 21.3 microM. In addition, the structure-enzyme inhibitory activity relationship of compounds 1-14 is discussed.
ESTHER : Li_2021_Bioorg.Chem_110_104826
PubMedSearch : Li_2021_Bioorg.Chem_110_104826
PubMedID: 33780746

Title : Liamocins biosynthesis, its regulation in Aureobasidium spp., and their bioactivities - Kang_2021_Crit.Rev.Biotechnol__1
Author(s) : Kang XX , Jia SL , Wei X , Zhang M , Liu GL , Hu Z , Chi Z , Chi ZM
Ref : Critical Reviews in Biotechnology , :1 , 2021
Abstract : Liamocins synthesized by Aureobasidium spp. are glycolipids composed of a single mannitol or arabitol headgroup linked to either three, four or even six 3,5-dihydroxydecanoic ester tail-groups. The highest titer of liamocin achieved was over 40.0 g/L. The substrates for liamocins synthesis include glucose, sucrose, xylose, mannitol, and others. The Pks1 is responsible for the biosynthesis of the tail-group 3,5-dihydroxydecanoic acid, both mannitol dehydrogenase (MDH) and mannitol 1-phosphate 5-dehydrogenase (MPDH) catalyze the mannitol biosynthesis and the arabitol biosynthesis is controlled by arabitol dehydrogenase (ArDH). The ester bond formation between 3,5-dihydroxydecanoic acid and mannitol or arabitol is catalyzed by the esterase (Est1). Liamocin biosynthesis is regulated by the specific transcriptional activator (Gal1), global transcriptional activator (Msn2), various signaling pathways, acetyl-CoA flux while Pks1 activity is controlled by PPTase activity. The synthesized liamocins have high bioactivity against the pathogenic bacteria Streptococcus spp. and some kinds of cancer cells while Massoia lactone released liamocins which exhibited obvious antifungal and anticancer activities. Therefore, liamocins and Massoia lactone have many applications in various sectors of biotechnology.
ESTHER : Kang_2021_Crit.Rev.Biotechnol__1
PubMedSearch : Kang_2021_Crit.Rev.Biotechnol__1
PubMedID: 34154468

Title : Transcriptome Analysis of Aedes albopictus (Diptera: Culicidae) Larvae Exposed With a Sublethal Dose of Haedoxan A - Hao_2021_J.Med.Entomol__
Author(s) : Hao H , Zuo Y , Fang J , Sun A , Aioub AAA , Hu Z
Ref : Journal of Medical Entomology , : , 2021
Abstract : Aedes albopictus is the vector of arbovirus diseases including yellow fever, dengue, Zika virus, and chikungunya fever, and it poses an enormous threat to human health worldwide. Previous studies have revealed that haedoxan A (HA), which is an insecticidal sesquilignan from Phryma leptostachya L., is a highly effective natural insecticide for managing mosquitoes and houseflies; however, the mechanisms underlying the response of Ae. albopictus after treatment with sublethal concentrations of HA is not clear. Here, high-throughput sequencing was used to analyze the gene expression changes in Ae. albopictus larvae after treatment with the LC30 of HA. In total, 416 differentially expressed genes (DEGs) were identified, including 328 upregulated genes and 88 downregulated genes. Identification and verification of related DEGs were performed by RT-qPCR. The results showed that two P450 unigenes (CYP4C21 and CYP304A1), one carboxylesterase, and one ABC transporter (ABCG1) were induced by HA, which indicated that these detoxifying enzyme genes might play a major role in the metabolic and detoxification processes of HA. Additionally, acetylcholine receptor subunit 2 (AChRalpha2), AChRalpha5, AChRalpha9, and the glutamate receptor ionotropic kainate 2 (GRIK2) were found to be upregulated in HA-treated larvae, suggesting that HA affected the conduction of action potentials and synaptic transmission by disrupting the function of neural receptors. These results provide a foundation for further elucidating the target of HA and the mechanism of detoxification metabolism in Ae. albopictus.
ESTHER : Hao_2021_J.Med.Entomol__
PubMedSearch : Hao_2021_J.Med.Entomol__
PubMedID: 33999150

Title : Polycyclic polyprenylated acylphloroglucinols with acetylcholinesterase inhibitory activities from Hypericum perforatum - Lou_2020_Fitoterapia__104550
Author(s) : Lou H , Yi P , Hu Z , Li Y , Zeng Y , Gu W , Huang L , Yuan C , Hao X
Ref : Fitoterapia , :104550 , 2020
Abstract : Six new polycyclic polyprenylated acylphloroglucinols, hyperfols CH (1-6), along with seven known ones (7-13), were isolated from the aerial parts of Hypericum perforatum. The structures were identified on the basis of comprehensive spectroscopic data analysis including 1D and 2D NMR, and the absolute configurations of the new compounds were determined by quantum chemical electronic circular dichroism (ECD) calculations. In addition, compounds 4 and 12 exhibited moderate acetylcholinesterase (AChE) inhibitory activities, with IC50 values of 20.32 and 27.37muM, respectively.
ESTHER : Lou_2020_Fitoterapia__104550
PubMedSearch : Lou_2020_Fitoterapia__104550
PubMedID: 32173424

Title : Induced fluorescent enhancement of protein-directed synthesized gold nanoclusters for selective and sensitive detection of flame retardants - Liu_2020_Sci.Total.Environ_713_136488
Author(s) : Liu H , Zhu N , Li M , Huang X , Wu P , Hu Z , Shuai J
Ref : Sci Total Environ , 713 :136488 , 2020
Abstract : Organophosphate flame retardants (OPFRs), typical toxic and hazardous pollutants, are called for new detection approaches to avoid laborious synthetic procedures and large and expensive instruments. Hence, a novel fluorescent probe was constructed for quantitative detection of OPFRs via heightening the fluorescence of acetylcholinesterase synthesized gold nanoclusters (AChE-AuNCs). The as-prepared AChE-AuNCs exhibited high fluorescence emission at about 398 nm with the average particle size of about 1.60 nm. When the AChE-AuNCs was applied to the proposed fluorescent detection, excellent sensitivity with wide linear range (50-1000 ng L(-1)) and low detection limit (30 ng L(-1)) for TClPP with the response time less than 1 h were achieved. The fluorescent probe could be extended to detect other three types of OPFRs (TEP, TPHP, and TBOEP) and the target pollutants could be detectable in the presence of halogenated flame retardants. The mechanism might be mainly contributed by the interaction between OPFRs and AChE-AuNCs restricting internal vibration consumption of their capping ligands. The proposed detection approach could be easily operated and was not involved with other intermediate products. Therefore, AChE-AuNCs could be a promising fluorescent probe for rapid, selective and sensitive detection of OPFRs and even in the practical application.
ESTHER : Liu_2020_Sci.Total.Environ_713_136488
PubMedSearch : Liu_2020_Sci.Total.Environ_713_136488
PubMedID: 31955081

Title : Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro -
Author(s) : Wang M , Cao R , Zhang L , Yang X , Liu J , Xu M , Shi Z , Hu Z , Zhong W , Xiao G
Ref : Cell Res , 30 :269 , 2020
PubMedID: 32020029

Title : Synthesis of cocoa butter substitutes from Cinnamomum camphora seed oil and fully hydrogenated palm oil by enzymatic interesterification - Ma_2019_J.Food.Sci.Technol_56_835
Author(s) : Ma X , Hu Z , Mao J , Xu Y , Zhu X , Xiong H
Ref : J Food Sci Technol , 56 :835 , 2019
Abstract : Cinnamomum camphora trees have a vast range of distribution in southern China and the seed oil has unique fatty acid (FA) properties and various bio-activities. In this work, Cinnamomum camphora seed oil (CCSO) was utilized to synthesize value-added cocoa butter substitute (CBS) by enzymatic interesterification. The synthesis was conducted in a solvent-free system by blending CCSO with fully hydrogenated palm oil under the catalysis of Lipozyme RM IM. The reacted products were assessed with physicochemical properties, i.e. FA composition, slip melting point (SMP), triacylglycerol (TAG), crystal polymorphism, microstructure, melting and crystallization properties and solid fat content (SFC). It showed that MCFAs (capric acid plus lauric acid) was the main fatty acid in products, accounting for over 45%. Comparing to physical blends, some novel TAG species such as LaLaLa and LaMLa/LaLaM were observed after enzymatic interesterification whereas SSS TAGs were reduced. IP presented a ball-like, well-distributed and nearly round crystal microstructure and a smaller crystal size. Moreover, it should be mentioned that SFC of IP ranging from 31.85 to 38.47% at 25 degreeC with most beta' crystal forms, was beneficial to improve the spreadability in term of confectionery products and baked goods. The SMP of the interesterified products was 35.75-36.15 degreeC which closed to the commercial CBS. Hence, the products synthesized can be used to as CBS, and the results in this study also showed CCSO have value-added applications.
ESTHER : Ma_2019_J.Food.Sci.Technol_56_835
PubMedSearch : Ma_2019_J.Food.Sci.Technol_56_835
PubMedID: 30906041

Title : mir-234 controls neuropeptide release at the Caenorhabditis elegans neuromuscular junction - Snieckute_2019_Mol.Cell.Neurosci_98_70
Author(s) : Snieckute G , Baltaci O , Liu H , Li L , Hu Z , Pocock R
Ref : Molecular & Cellular Neurosciences , 98 :70 , 2019
Abstract : miR-137 is a highly conserved microRNA (miRNA) that is associated with the control of brain function and the etiology of psychiatric disorders including schizophrenia and bipolar disorder. The Caenorhabditis elegans genome encodes a single miR-137 ortholog called mir-234, the function of which is unknown. Here we show that mir-234 is expressed in a subset of sensory, motor and interneurons in C. elegans. Using a mir-234 deletion strain, we systematically examined the development and function of these neurons in addition to global C. elegans behaviors. We were however unable to detect phenotypes associated with loss of mir-234, possibly due to genetic redundancy. To circumvent this issue, we overexpressed mir-234 in mir-234-expressing neurons to uncover possible phenotypes. We found that mir-234-overexpression endows resistance to the acetylcholinesterase inhibitor aldicarb, suggesting modification of neuromuscular junction (NMJ) function. Further analysis revealed that mir-234 controls neuropeptide levels, therefore positing a cause of NMJ dysfunction. Together, our data suggest that mir-234 functions to control the expression of target genes that are important for neuropeptide maturation and/or transport in C. elegans. SIGNIFICANCE STATEMENT: The miR-137 family of miRNAs is linked to the control of brain function in humans. Defective regulation of miR-137 is associated with psychiatric disorders that include schizophrenia and bipolar disorder. Previous studies have revealed that miR-137 is required for the development of dendrites and for controlling the release of fast-acting neurotransmitters. Here, we analyzed the function a miR-137 family member (called mir-234) in the nematode animal model using anatomical, behavioral, electrophysiological and neuropeptide analysis. We reveal for the first time that mir-234/miR-137 is required for the release of slow-acting neuropeptides, which may also be of relevance for controlling human brain function.
ESTHER : Snieckute_2019_Mol.Cell.Neurosci_98_70
PubMedSearch : Snieckute_2019_Mol.Cell.Neurosci_98_70
PubMedID: 31200102

Title : Plasma exosome levels in non-small-cell lung cancer: Correlation with clinicopathological features and prognostic implications - Liu_2018_Cancer.Biomark_22_267
Author(s) : Liu Q , Xiang Y , Yuan S , Xie W , Li C , Hu Z , Wu N , Wu L , Yu Z , Bai L , Li Y
Ref : Cancer Biomark , 22 :267 , 2018
Abstract : BACKGROUND: Biomarker studies revealed important clinical significance of exosome for cancer patients. However, there is currently no consensus on exosome quantification methods. METHODS: Bicinchoninic acid (BCA) method, acetylcholinesterase (AChE) method and nanoparticle tracking analysis (NTA) were utilized to quantify 20 plasma exosome samples, and interrelations between these three methods were explored. Associations of plasma exosome levels with characteristics and prognosis of 208 non-small-cell lung cancer (NSCLC) patients were investigated. RESULTS: Results of the three methods for exosome quantification were significantly correlated with each other. Correlation coefficient between AChE and NTA (r= 0.79, P< 0.001) was greater than that between BCA and NTA (r= 0.64, P= 0.003). Plasma exosome levels of 208 NSCLC patients were then quantified with AChE method. Exosome level was significantly associated with tumour stage (P< 0.001) and the history of chronic obstructive pulmonary disease (P= 0.023). Cox proportional hazard analysis demonstrated that higher exosome level was independently associated with poorer overall survival (P= 0.033; hazard ratio = 1.72, 95% confidence interval: 1.05-2.83). CONCLUSIONS: Plasma exosome level correlates with tumor stage and the history of chronic obstructive pulmonary disease, and may serve as a prognostic factor for NSCLC.
ESTHER : Liu_2018_Cancer.Biomark_22_267
PubMedSearch : Liu_2018_Cancer.Biomark_22_267
PubMedID: 29660899

Title : Enantioselective synthesis of novel pyrano[3,2-c]chromene derivatives as AChE inhibitors via an organocatalytic domino reaction - Zheng_2018_Org.Biomol.Chem_16_472
Author(s) : Zheng J , He M , Xie B , Yang L , Hu Z , Zhou HB , Dong C
Ref : Org Biomol Chem , 16 :472 , 2018
Abstract : A series of optically active pyrano[3,2-c]chromenes have been synthesized through an asymmetric domino reaction of 4-hydroxy-2H-chromen-2-ones with malononitriles. The targeted molecules were obtained in excellent yields and enantioselectivities (up to 94% yield, 99% ee). The AChE inhibitory activity studies revealed that compounds 4n (IC50 = 21.3 muM) and 4p (IC50 = 19.2 muM) displayed potent acetylcholinesterase inhibition. In most cases, the S-enantiomers were superior to the corresponding R-enantiomers. Moreover, molecular modelling provides a practical method for understanding the enantioselective discrimination of AChE with these kinds of compounds.
ESTHER : Zheng_2018_Org.Biomol.Chem_16_472
PubMedSearch : Zheng_2018_Org.Biomol.Chem_16_472
PubMedID: 29265146

Title : Controlled synthesis of polydopamine: A new strategy for highly sensitive fluorescence turn-on detection of acetylcholinesterase activity - Yang_2018_Mikrochim.Acta_185_132
Author(s) : Yang M , Zhou H , Zhang Y , Hu Z , Niu N , Yu C
Ref : Mikrochim Acta , 185 :132 , 2018
Abstract : A new water soluble fluorescent coronene probe (CTCA) was synthesized and is shown to display strong fluorescence (with excitation/emission maxima at 313/450 nm) in aqueous solution. Dopamine was oxidized under air to form polydopamine (PDA) which quenches the fluorescence of CTCA. The enzyme acetylcholinesterase (AChE) is known catalyze the hydrolysis of acetylthiocholine to produce thiocholine. Thiocholine inhibits the polymerization of DA, and this leads to recovery in CTCA fluorescence. These findings form the basis for a new method for detection of AChE activity. The assay has a detection limit as low as 0.05 mU.mL(-1) of AChE. It is highly selective, and other enzymes do no noticeably interfere. It was applied to the determination of AChE activity in (spiked) human serum, and of AChE inhibitors in (spiked) lake water samples. Graphical abstract Controlled synthesis of polydopamine for the highly sensitive and selective sensing of AChE activity is reported for the first time.
ESTHER : Yang_2018_Mikrochim.Acta_185_132
PubMedSearch : Yang_2018_Mikrochim.Acta_185_132
PubMedID: 29594716

Title : Synergism of antihypertensives and cholinesterase inhibitors in Alzheimer's disease - Hu_2018_Alzheimers.Dement.(N.Y)_4_542
Author(s) : Hu Z , Wang L , Ma S , Kirisci L , Feng Z , Xue Y , Klunk WE , Kamboh MI , Sweet RA , Becker J , Lv Q , Lopez OL , Xie XQ
Ref : Alzheimers Dement (N Y) , 4 :542 , 2018
Abstract : Introduction: We investigated the effect of antihypertensive (aHTN) medications and cholinesterase inhibitors (ChEIs) on the cognitive decline in patients with Alzheimer's disease (AD) and analyzed synergism by chemogenomics systems pharmacology mapping. Methods: We compared the effect of aHTN drugs on Mini-Mental State Examination scores in 617 AD patients with hypertension, and studied the synergistic effects. Results: The combination of diuretics, calcium channel blockers, and renin-angiotensin-aldosterone system blockers showed slower cognitive decline compared with other aHTN groups (Deltabeta = +1.46, P < .0001). aHTN medications slow down cognitive decline in ChEI users (Deltabeta = +0.56, P = .006), but not in non-ChEI users (Deltabeta = -0.31, P = .53). Discussion: aHTN and ChEI drugs showed synergistic effects. A combination of diuretics, renin-angiotensin-aldosterone system blockers, and calcium channel blockers had the slowest cognitive decline. The chemogenomics systems pharmacology-identified molecular targets provide system pharmacology interpretation of the synergism of the drugs in clinics. The results suggest that improving vascular health is essential for AD treatment and provide a novel direction for AD drug development.
ESTHER : Hu_2018_Alzheimers.Dement.(N.Y)_4_542
PubMedSearch : Hu_2018_Alzheimers.Dement.(N.Y)_4_542
PubMedID: 30386819

Title : New 3,5-dimethylorsellinic acid-based meroterpenoids with BACE1 and AchE inhibitory activities from Aspergillus terreus - Qi_2018_Org.Biomol.Chem_16_9046
Author(s) : Qi C , Qiao Y , Gao W , Liu M , Zhou Q , Chen C , Lai Y , Xue Y , Zhang J , Li D , Wang J , Zhu H , Hu Z , Zhou Y , Zhang Y
Ref : Org Biomol Chem , 16 :9046 , 2018
Abstract : Chemical investigation of the extracts of Aspergillus terreus resulted in the identification of terreusterpenes A-D (1-4), four new 3,5-dimethylorsellinic acid-based meroterpenoids. The structures and absolute configurations of 1-4 were elucidated by spectroscopic analyses including HRESIMS and 1D- and 2D-NMR, chemical conversion, and single crystal X-ray diffraction. Terreusterpenes A (1) and B (2) featured 2,3,5-trimethyl-4-oxo-5-carboxy tetrahydrofuran moieties. Terreusterpene D (4) was characterized by a 4-hydroxy-3-methyl gamma lactone fragment that was generated by accident from the rearrangement of 3 in a mixed tetrahydrofuran-H2O-MeOH solvent. All these compounds were evaluated for the beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) and acetylcholinesterase (AchE) inhibitory activities. Among them, compounds 1 and 2 showed potentially significant BACE1 inhibitory activity, with IC50 values of 5.98 and 11.42 muM, respectively. Interestingly, compound 4 exhibited promising BACE1 and AchE inhibitory activities, with IC50 values of 1.91 and 8.86 muM, respectively, while 3 showed no such activity. Taken together, terreusterpenes A and B could be of great importance for the development of new BACE1 inhibitors, while terreusterpene D could serve as the first dual-targeted 3,5-dimethylorsellinic acid-based meroterpenoid for the treatment of Alzheimer's disease.
ESTHER : Qi_2018_Org.Biomol.Chem_16_9046
PubMedSearch : Qi_2018_Org.Biomol.Chem_16_9046
PubMedID: 30430177

Title : The Claudin-like Protein HPO-30 Is Required to Maintain LAChRs at the C. elegans Neuromuscular Junction - Sharma_2018_J.Neurosci_38_7072
Author(s) : Sharma P , Li L , Liu H , Tikiyani V , Hu Z , Babu K
Ref : Journal of Neuroscience , 38 :7072 , 2018
Abstract : Communications across chemical synapses are primarily mediated by neurotransmitters and their postsynaptic receptors. There are diverse molecular systems to localize and regulate the receptors at the synapse. Here, we identify HPO-30, a member of the claudin superfamily of membrane proteins, as a positive regulator for synaptic localization of levamisole-dependent AChRs (LAChRs) at the Caenorhabditis elegans neuromuscular junction (NMJ). The HPO-30 protein localizes at the NMJ and shows genetic and physical association with the LAChR subunits LEV-8, UNC-29, and UNC-38. Using genetic and electrophysiological assays in the hermaphrodite C. elegans, we demonstrate that HPO-30 functions through Neuroligin at the NMJ to maintain postsynaptic LAChR levels at the synapse. Together, this work suggests a novel function for a tight junction protein in maintaining normal receptor levels at the NMJ.SIGNIFICANCE STATEMENT Claudins are a large superfamily of membrane proteins. Their role in maintaining the functional integrity of tight junctions has been widely explored. Our experiments suggest a critical role for the claudin-like protein, HPO-30, in maintaining synaptic levamisole-dependent AChR (LAChR) levels. LAChRs contribute to <20% of the acetylcholine-mediated conductance in adult Caenorhabditis elegans; however, they play a significant functional role in worm locomotion. This study provides a new perspective in the study of LAChR physiology.
ESTHER : Sharma_2018_J.Neurosci_38_7072
PubMedSearch : Sharma_2018_J.Neurosci_38_7072
PubMedID: 29950505

Title : Expression and Activity of the BioH Esterase of Biotin Synthesis is Independent of Genome Context - Cao_2017_Sci.Rep_7_2141
Author(s) : Cao X , Zhu L , Hu Z , Cronan JE
Ref : Sci Rep , 7 :2141 , 2017
Abstract : BioH is an alpha/beta-hydrolase required for synthesis of the pimelate moiety of biotin in diverse bacteria. The bioH gene is found in different genomic contexts. In some cases (e.g., Escherichia coli) the gene is not located within a biotin synthetic operon and its transcription is not coregulated with the other biotin synthesis genes. In other genomes such as Pseudomonas aeruginosa the bioH gene is within a biotin synthesis operon and its transcription is coregulated with the other biotin operon genes. The esterases of pimelate moiety synthesis show remarkable genomic plasticity in that in some biotin operons bioH is replaced by other alpha/ss hydrolases of diverse sequence. The "wild card" nature of these enzymes led us to compare the paradigm "freestanding" E. coli BioH with the operon-encoded P. aeruginosa BioH. We hypothesized that the operon-encoded BioH might differ in its expression level and/or activity from the freestanding BioH gene. We report this is not the case. The two BioH proteins show remarkably similar hydrolase activities and substrate specificity. Moreover, Pseudomonas aeruginosa BioH is more highly expressed than E. coli BioH. Despite the enzymatic similarities of the two BioH proteins, bioinformatics analysis places the freestanding and operon-encoded BioH proteins into distinct clades.
ESTHER : Cao_2017_Sci.Rep_7_2141
PubMedSearch : Cao_2017_Sci.Rep_7_2141
PubMedID: 28526858
Gene_locus related to this paper: fratt-q5nga8 , pseae-PA0502

Title : Not all neuroligin 3 and 4X missense variants lead to significant functional inactivation - Xu_2017_Brain.Behav_7_e00793
Author(s) : Xu X , Hu Z , Zhang L , Liu H , Cheng Y , Xia K , Zhang X
Ref : Brain Behav , 7 :e00793 , 2017
Abstract : INTRODUCTION: Neuroligins are postsynaptic cell adhesion molecules that interact with neurexins to regulate the fine balance between excitation and inhibition of synapses. Recently, accumulating evidence, involving mutation analysis, cellular assays, and mouse models, has suggested that neuroligin (NLGN) mutations affect synapse maturation and function. Previously, four missense variations [p.G426S (NLGN3), p.G84R (NLGN4X), p.Q162K (NLGN4X), and p.A283T (NLGN4X)] in four different unrelated patients have been identified by PCR and direct sequencing.
METHODS: In this study, we analyzed the functional effect of these missense variations by in vitro experiment via the stable HEK293 cells expressing wild-type and mutant neuroligin.
RESULTS: We found that the four mutations did not significantly impair the expression of neuroligin 3 and neuroligin 4X, and also did not measurably inhibit the neurexin 1-neuroligin interaction. These variants might play a modest role in the pathogenesis of autism or might simply be unreported infrequent polymorphisms. CONCLUSION: Our data suggest that these four previously described neuroligin mutations are not primary risk factors for autism.
ESTHER : Xu_2017_Brain.Behav_7_e00793
PubMedSearch : Xu_2017_Brain.Behav_7_e00793
PubMedID: 28948087
Gene_locus related to this paper: human-NLGN4X

Title : De Novo Genome and Transcriptome Assembly of the Canadian Beaver (Castor canadensis) - Lok_2017_G3.(Bethesda)_7_755
Author(s) : Lok S , Paton TA , Wang Z , Kaur G , Walker S , Yuen RK , Sung WW , Whitney J , Buchanan JA , Trost B , Singh N , Apresto B , Chen N , Coole M , Dawson TJ , Ho K , Hu Z , Pullenayegum S , Samler K , Shipstone A , Tsoi F , Wang T , Pereira SL , Rostami P , Ryan CA , Tong AH , Ng K , Sundaravadanam Y , Simpson JT , Lim BK , Engstrom MD , Dutton CJ , Kerr KC , Franke M , Rapley W , Wintle RF , Scherer SW
Ref : G3 (Bethesda) , 7 :755 , 2017
Abstract : The Canadian beaver (Castor canadensis) is the largest indigenous rodent in North America. We report a draft annotated assembly of the beaver genome, the first for a large rodent and the first mammalian genome assembled directly from uncorrected and moderate coverage (< 30 x) long reads generated by single-molecule sequencing. The genome size is 2.7 Gb estimated by k-mer analysis. We assembled the beaver genome using the new Canu assembler optimized for noisy reads. The resulting assembly was refined using Pilon supported by short reads (80 x) and checked for accuracy by congruency against an independent short read assembly. We scaffolded the assembly using the exon-gene models derived from 9805 full-length open reading frames (FL-ORFs) constructed from the beaver leukocyte and muscle transcriptomes. The final assembly comprised 22,515 contigs with an N50 of 278,680 bp and an N50-scaffold of 317,558 bp. Maximum contig and scaffold lengths were 3.3 and 4.2 Mb, respectively, with a combined scaffold length representing 92% of the estimated genome size. The completeness and accuracy of the scaffold assembly was demonstrated by the precise exon placement for 91.1% of the 9805 assembled FL-ORFs and 83.1% of the BUSCO (Benchmarking Universal Single-Copy Orthologs) gene set used to assess the quality of genome assemblies. Well-represented were genes involved in dentition and enamel deposition, defining characteristics of rodents with which the beaver is well-endowed. The study provides insights for genome assembly and an important genomics resource for Castoridae and rodent evolutionary biology.
ESTHER : Lok_2017_G3.(Bethesda)_7_755
PubMedSearch : Lok_2017_G3.(Bethesda)_7_755
PubMedID: 28087693
Gene_locus related to this paper: cascn-a0a250y2s0 , cascn-a0a250y135 , cascn-a0a250y1i6 , cascn-a0a250y2u8 , cascn-a0a250xy53 , ursma-a0a384cw87 , cascn-a0a250y6h8

Title : Retrograde Synaptic Inhibition Is Mediated by alpha-Neurexin Binding to the alpha2delta Subunits of N-Type Calcium Channels - Tong_2017_Neuron_95_326
Author(s) : Tong XJ , Lopez-Soto EJ , Li L , Liu H , Nedelcu D , Lipscombe D , Hu Z , Kaplan JM
Ref : Neuron , 95 :326 , 2017
Abstract : The synaptic adhesion molecules Neurexin and Neuroligin alter the development and function of synapses and are linked to autism in humans. In C. elegans, post-synaptic Neurexin (NRX-1) and pre-synaptic Neuroligin (NLG-1) mediate a retrograde synaptic signal that inhibits acetylcholine (ACh) release at neuromuscular junctions. Here, we show that the retrograde signal decreases ACh release by inhibiting the function of pre-synaptic UNC-2/CaV2 calcium channels. Post-synaptic NRX-1 binds to an auxiliary subunit of pre-synaptic UNC-2/CaV2 channels (UNC-36/alpha2delta), decreasing UNC-36 abundance at pre-synaptic elements. Retrograde inhibition is mediated by a soluble form of NRX-1's ectodomain, which is released from the post-synaptic membrane by the SUP-17/ADAM10 protease. Mammalian Neurexin-1alpha binds alpha2delta-3 and decreases CaV2.2 current in transfected cells, whereas Neurexin-1alpha has no effect on CaV2.2 reconstituted with alpha2delta-1 and alpha2delta-2. Collectively, these results suggest that alpha-Neurexin binding to alpha2delta is a conserved mechanism for regulating synaptic transmission.
ESTHER : Tong_2017_Neuron_95_326
PubMedSearch : Tong_2017_Neuron_95_326
PubMedID: 28669545

Title : Sunitinib, a Clinically Used Anticancer Drug, Is a Potent AChE Inhibitor and Attenuates Cognitive Impairments in Mice - Huang_2016_ACS.Chem.Neurosci_7_1047
Author(s) : Huang L , Lin J , Xiang S , Zhao K , Yu J , Zheng J , Xu D , Mak SH , Hu S , Nirasha S , Wang C , Chen X , Zhang J , Xu S , Wei X , Zhang Z , Zhou D , Zhou W , Cui W , Han YF , Hu Z , Wang Q
Ref : ACS Chem Neurosci , 7 :1047 , 2016
Abstract : Sunitinib, a tyrosine kinase inhibitor, is clinically used for the treatment of cancer. In this study, we found for the first time that sunitinib inhibits acetylcholinesterase (AChE) at submicromolar concentrations in vitro. In addition, sunitinib dramatically decreased the hippocampal and cortical activity of AChE in a time-dependent manner in mice. Molecular docking analysis further demonstrates that sunitinib might interact with both the catalytic anion and peripheral anionic sites within AChE, which is in accordance with enzymatic activity results showing that sunitinib inhibits AChE in a mixed pattern. Most importantly, we evaluated the effects of sunitinib on scopolamine-induced cognitive impairments in mice by using novel object recognition and Morris water maze tests. Surprisingly, sunitinib could attenuate cognitive impairments to a similar extent as donepezil, a marketed AChE inhibitor used for the treatment of Alzheimer's disease. In summary, our results have shown that sunitinib could potently inhibit AChE and attenuate cognitive impairments in mice.
ESTHER : Huang_2016_ACS.Chem.Neurosci_7_1047
PubMedSearch : Huang_2016_ACS.Chem.Neurosci_7_1047
PubMedID: 27046396

Title : A network of autism linked genes stabilizes two pools of synaptic GABA receptors - Tong_2015_Elife_4_
Author(s) : Tong XJ , Hu Z , Liu Y , Anderson D , Kaplan JM
Ref : Elife , 4 : , 2015
Abstract : Changing receptor abundance at synapses is an important mechanism for regulating synaptic strength. Synapses contain two pools of receptors, immobilized and diffusing receptors, both of which are confined to post-synaptic elements. Here we show that immobile and diffusing GABAA receptors are stabilized by distinct synaptic scaffolds at C. elegans neuromuscular junctions. Immobilized GABAA receptors are stabilized by binding to FRM-3/EPB4.1 and LIN-2A/CASK. Diffusing GABAA receptors are stabilized by the synaptic adhesion molecules Neurexin and Neuroligin. Inhibitory post-synaptic currents are eliminated in double mutants lacking both scaffolds. Neurexin, Neuroligin, and CASK mutations are all linked to Autism Spectrum Disorders (ASD). Our results suggest that these mutations may directly alter inhibitory transmission, which could contribute to the developmental and cognitive deficits observed in ASD.
ESTHER : Tong_2015_Elife_4_
PubMedSearch : Tong_2015_Elife_4_
PubMedID: 26575289

Title : In vitro acaricidal activity of 1,8-cineole against Sarcoptes scabiei var. cuniculi and regulating effects on enzyme activity - Hu_2015_Parasitol.Res_114_2959
Author(s) : Hu Z , Chen Z , Yin Z , Jia R , Song X , Li L , Zou Y , Liang X , He C , Yin L , Lv C , Zhao L , Su G , Ye G , Shi F
Ref : Parasitol Res , 114 :2959 , 2015
Abstract : 1,8-Cineole found in many essential oils is a monoterpene and acts as a repellent against Sarcoptes scabiei var. cuniculi. In the present study, the acaricidal activity of 1,8-cineole against S. scabiei var. cuniculi was evaluated and the acaricidal mechanism was also investigated by assaying enzyme activities. The results showed that the lethal concentration of 50 % (LC50) value (95 % confidence limit (CL)) and the lethal time of 50 % (LT50) value (95 % CL) of 1,8-cineole were 2.77 mg/mL and 3.606 h, respectively. The pathological changes under transmission electron microscopy showed that the morphology of the mitochondria was abnormal, the cell nuclear membrane was damaged, and the nuclear chromatin was dissoluted. The activities of superoxide dismutase (SOD), glutathione-s-transferases (GSTs), monoamine oxidase (MAO), nitric oxide synthase (NOS), and acetylcholinesterase (AChE) were significantly changed after treatment with 1,8-cineole for 4, 8, 12, and 24 h. SOD and GSTs are associated with the protection mechanism of scabies mites. And, the activities of SOD and GSTs were increased as compared with the control group. MAO, AChE, and NOS are associated with the nervous system of scabies mites. The activity of MAO was increased whereas the AChE was suppressed. The activity of NOS was suppressed in the high-dose group whereas increased in the middle-dose group and low-dose group. These results indicated that the mechanism of 1,8-cineole mainly attributed to the changes of these enzyme activities related to the nervous system of scabies mites.
ESTHER : Hu_2015_Parasitol.Res_114_2959
PubMedSearch : Hu_2015_Parasitol.Res_114_2959
PubMedID: 25924796

Title : Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients - Xu_2014_Mol.Biol.Rep_41_4133
Author(s) : Xu X , Xiong Z , Zhang L , Liu Y , Lu L , Peng Y , Guo H , Zhao J , Xia K , Hu Z
Ref : Mol Biol Rep , 41 :4133 , 2014
Abstract : Autism is a neurodevelopmental disorder clinically characterized by impairment of social interaction, deficits in verbal communication, as well as stereotypic and repetitive behaviors. Several studies have implicated that abnormal synaptogenesis was involved in the incidence of autism. Neuroligins are postsynaptic cell adhesion molecules and interacted with neurexins to regulate the fine balance between excitation and inhibition of synapses. Recently, mutation analysis, cellular and mice models hinted neuroligin mutations probably affected synapse maturation and function. In this study, four missense variations [p.G426S (NLGN3), p.G84R (NLGN4X), p.Q162 K (NLGN4X) and p.A283T (NLGN4X)] in four different unrelated patients have been identified by PCR and direct sequencing. These four missense variations were absent in the 453 controls and have not been reported in 1000 Genomes Project. Bioinformatic analysis of the four missense variations revealed that p.G84R and p.A283T were "Probably Damaging". The variations may cause abnormal synaptic homeostasis and therefore trigger the patients more predisposed to autism. By case-control analysis, we identified the common SNPs (rs3747333 and rs3747334) in the NLGN4X gene significantly associated with risk for autism [p = 5.09E-005; OR 4.685 (95% CI 2.073-10.592)]. Our data provided a further evidence for the involvement of NLGN3 and NLGN4X gene in the pathogenesis of autism in Chinese population.
ESTHER : Xu_2014_Mol.Biol.Rep_41_4133
PubMedSearch : Xu_2014_Mol.Biol.Rep_41_4133
PubMedID: 24570023

Title : Enhanced production of lipstatin from Streptomyces toxytricini by optimizing fermentation conditions and medium - Zhu_2014_J.Gen.Appl.Microbiol_60_106
Author(s) : Zhu T , Wang L , Wang W , Hu Z , Yu M , Wang K , Cui Z
Ref : J Gen Appl Microbiol , 60 :106 , 2014
Abstract : This paper is concerned with optimization of fermentation conditions for lipstatin production with Streptomyces toxytricini zjut011 by the single factor and orthogonal tests. Five single factors of important effects on lipstatin production were explored. L-Leucine was identified to be the most suitable precursor for lipstatin biosynthesis and for the first time the divalent cations Mg(2+), Co(2+) and Zn(2+) were found to have significant effect on enhancing lipstatin fermentation titer. The effects of the additives on the lipstatin production were in the order of L-leucine Mg(2+) Co(2+) Zn(2+) octanoic acid. The optimized conditions for lipstatin production were determined as 45.72 mmol/L of L-leucine (added on the 4 th day), 31.1985 mmol/L of octanoic acid (added on the 6th day), 12 mmol/L of Mg(2+), 1 mmol/L of Co(2+) and 0.25 mmol/L of Zn(2+). Under these conditions, a maximum lipstatin of 4.208 g/ml was achieved in verification experiments in 500 ml shake flasks.
ESTHER : Zhu_2014_J.Gen.Appl.Microbiol_60_106
PubMedSearch : Zhu_2014_J.Gen.Appl.Microbiol_60_106
PubMedID: 25008166

Title : First report of a sequence type 239 vancomycin-intermediate Staphylococcus aureus isolate in Mainland China - Zhang_2013_Diagn.Microbiol.Infect.Dis_77_64
Author(s) : Zhang X , Hu Q , Yuan W , Shang W , Cheng H , Yuan J , Zhu J , Hu Z , Li S , Chen W , Hu X , Rao X
Ref : Diagn Microbiol Infect Dis , 77 :64 , 2013
Abstract : Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen that causes a wide range of both hospital- and community-acquired infections. The high prevalence of MRSA and the extensive use of vancomycin in Mainland China may lead to the emergence of vancomycin-intermediate S. aureus (VISA) isolates. In this case, we report a VISA isolate from a 34-year-old male patient with steam burn. The isolate was determined to be sequence type 239 staphylococcal cassette chromosome mec type III, the most prevalent MRSA clone in Mainland China.
ESTHER : Zhang_2013_Diagn.Microbiol.Infect.Dis_77_64
PubMedSearch : Zhang_2013_Diagn.Microbiol.Infect.Dis_77_64
PubMedID: 23876353

Title : Testing insecticidal activity of novel chemically synthesized siRNA against Plutella xylostella under laboratory and field conditions - Gong_2013_PLoS.One_8_e62990
Author(s) : Gong L , Chen Y , Hu Z , Hu M
Ref : PLoS ONE , 8 :e62990 , 2013
Abstract : BACKGROUND: Over the last 60 years, synthetic chemical pesticides have served as a main tactic in the field of crop protection, but their availability is now declining as a result of the development of insect resistance. Therefore, alternative pest management agents are needed. However, the demonstration of RNAi gene silencing in insects and its successful usage in disrupting the expression of vital genes opened a door to the development of a variety of novel, environmentally sound approaches for insect pest management. METHODOLOGY/PRINCIPAL FINDINGS: Six small interfering RNAs (siRNAs) were chemically synthesized and modified according to the cDNA sequence of P. xylostella acetylcholine esterase genes AChE1 and AChE2. All of them were formulated and used in insecticide activity screening against P. xylostella. Bioassay data suggested that Si-ace1_003 and Si-ace2_001 at a concentration of 3 microg cm(-2) displayed the best insecticidal activity with 73.7% and 89.0%, mortality, respectively. Additional bioassays were used to obtain the acute lethal concentrations of LC50 and LC90 for Si-ace2_001, which were 53.66 microg/ml and 759.71 microg/ml, respectively. Quantitative Real-time PCR was used to confirm silencing and detected that the transcript levels of P. xylostella AChE2 (PxAChE2) were reduced by 5.7-fold compared to the control group. Consequently, AChE activity was also reduced by 1.7-fold. Finally, effects of the siRNAs on treated plants of Brassica oleracea and Brassica alboglabra were investigated with different siRNA doses. Our results showed that Si-ace2_001 had no negative effects on plant morphology, color and growth of vein under our experimental conditions. CONCLUSIONS: The most important finding of this study is the discovery that chemically synthesized and modified siRNA corresponding to P. xylostella AChE genes cause significant mortality of the insect both under laboratory and field conditions, which provides a novel strategy to control P. xylostella and to develop bio-pesticides based on the RNA interference technology.
ESTHER : Gong_2013_PLoS.One_8_e62990
PubMedSearch : Gong_2013_PLoS.One_8_e62990
PubMedID: 23667556

Title : The role of human carboxylesterases in drug metabolism: have we overlooked their importance? - Laizure_2013_Pharmacotherapy_33_210
Author(s) : Laizure SC , Herring V , Hu Z , Witbrodt K , Parker RB
Ref : Pharmacotherapy , 33 :210 , 2013
Abstract : Carboxylesterases are a multigene family of mammalian enzymes widely distributed throughout the body that catalyze the hydrolysis of esters, amides, thioesters, and carbamates. In humans, two carboxylesterases, hCE1 and hCE2, are important mediators of drug metabolism. Both are expressed in the liver, but hCE1 greatly exceeds hCE2. In the intestine, only hCE2 is present and highly expressed. The most common drug substrates of these enzymes are ester prodrugs specifically designed to enhance oral bioavailability by hydrolysis to the active carboxylic acid after absorption from the gastrointestinal tract. Carboxylesterases also play an important role in the hydrolysis of some drugs to inactive metabolites. It has been widely believed that drugs undergoing hydrolysis by hCE1 and hCE2 are not subject to clinically significant alterations in their disposition, but evidence exists that genetic polymorphisms, drug-drug interactions, drug-disease interactions and other factors are important determinants of the variability in the therapeutic response to carboxylesterase-substrate drugs. The implications for drug therapy are far-reaching, as substrate drugs include numerous examples from widely prescribed therapeutic classes. Representative drugs include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antiplatelet drugs, statins, antivirals, and central nervous system agents. As research interest increases in the carboxylesterases, evidence is accumulating of their important role in drug metabolism and, therefore, the outcomes of pharmacotherapy.
ESTHER : Laizure_2013_Pharmacotherapy_33_210
PubMedSearch : Laizure_2013_Pharmacotherapy_33_210
PubMedID: 23386599

Title : Novel bis-(-)-nor-meptazinol derivatives act as dual binding site AChE inhibitors with metal-complexing property - Zheng_2012_Toxicol.Appl.Pharmacol_264_65
Author(s) : Zheng W , Li J , Qiu Z , Xia Z , Li W , Yu L , Chen H , Chen J , Chen Y , Hu Z , Zhou W , Shao B , Cui Y , Xie Q
Ref : Toxicol Appl Pharmacol , 264 :65 , 2012
Abstract : The strategy of dual binding site acetylcholinesterase (AChE) inhibition along with metal chelation may represent a promising direction for multi-targeted interventions in the pathophysiological processes of Alzheimer's disease (AD). In the present study, two derivatives (ZLA and ZLB) of a potent dual binding site AChE inhibitor bis-(-)-nor-meptazinol (bis-MEP) were designed and synthesized by introducing metal chelating pharmacophores into the middle chain of bis-MEP. They could inhibit human AChE activity with IC(50) values of 9.63uM (for ZLA) and 8.64uM (for ZLB), and prevent AChE-induced amyloid-beta (Abeta) aggregation with IC(50) values of 49.1uM (for ZLA) and 55.3uM (for ZLB). In parallel, molecular docking analysis showed that they are capable of interacting with both the catalytic and peripheral anionic sites of AChE. Furthermore, they exhibited abilities to complex metal ions such as Cu(II) and Zn(II), and inhibit Abeta aggregation triggered by these metals. Collectively, these results suggest that ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency, and may be potential leads of value for further study on disease-modifying treatment of AD.
ESTHER : Zheng_2012_Toxicol.Appl.Pharmacol_264_65
PubMedSearch : Zheng_2012_Toxicol.Appl.Pharmacol_264_65
PubMedID: 22842334

Title : On-line immobilized acetylcholinesterase microreactor for screening of inhibitors from natural extracts by capillary electrophoresis - Min_2012_Anal.Bioanal.Chem_404_2397
Author(s) : Min W , Wang W , Chen J , Wang A , Hu Z
Ref : Anal Bioanal Chem , 404 :2397 , 2012
Abstract : In this study we developed a simple capillary electrophoresis (CE) method with an on-line acetylcholinesterase (AChE) microreactor at the inlet of capillary for inhibitor screening. The fused-silica capillary surface was modified with a polycationic polyethylenimine coating. Solutions of the enzyme and chitosan were then injected to immobilize the enzyme in approximately 2.9 cm of the capillary inlet (total length of capillary 60.2 cm) by electrostatic interaction and the film overlay technique. Separation of enzyme reaction product (thiocholine, ThCh) and unreacted substrate (acetylthiocholine, AThCh) was achieved within 3.0 min. The conditions affecting the efficiency of reaction of the enzyme were optimized by measuring the peak area of ThCh. Under the optimum conditions, using Huperzine-A as model inhibitor, K (i) and IC (50) were 0.551 mumol L(-1) and 1.52 mumol L(-1), respectively, for immobilized AChE. Finally, screening of a small compound library containing two known AChE inhibitors and 30 natural extracts was conducted, and species with inhibition activity were directly identified. Compared with previous publications on screening for AChE inhibitors in natural products based on CE methods, the method developed in this work has the advantages of lower cost per analysis, less leakage, and better bioaffinity for the immobilized enzyme because of the unique properties of sodium alginate and chitosan.
ESTHER : Min_2012_Anal.Bioanal.Chem_404_2397
PubMedSearch : Min_2012_Anal.Bioanal.Chem_404_2397
PubMedID: 22932810

Title : Bioassay-Guided Isolation of Neuroprotective Compounds from Uncaria rhynchophylla against Beta-Amyloid-Induced Neurotoxicity - Xian_2012_Evid.Based.Complement.Alternat.Med_2012_802625
Author(s) : Xian YF , Lin ZX , Mao QQ , Hu Z , Zhao M , Che CT , Ip SP
Ref : Evid Based Complement Alternat Med , 2012 :802625 , 2012
Abstract : Uncaria rhynchophylla is a component herb of many Chinese herbal formulae for the treatment of neurodegenerative diseases. Previous study in our laboratory has demonstrated that an ethanol extract of Uncaria rhynchophylla ameliorated cognitive deficits in a mouse model of Alzheimer's disease induced by D-galactose. However, the active ingredients of Uncaria rhynchophylla responsible for the anti-Alzheimer's disease activity have not been identified. This study aims to identify the active ingredients of Uncaria rhynchophylla by a bioassay-guided fractionation approach and explore the acting mechanism of these active ingredients by using a well-established cellular model of Alzheimer's disease, beta-amyloid- (Abeta-) induced neurotoxicity in PC12 cells. The results showed that six alkaloids, namely, corynoxine, corynoxine B, corynoxeine, isorhynchophylline, isocorynoxeine, and rhynchophylline were isolated from the extract of Uncaria rhynchophylla. Among them, rhynchophylline and isorhynchophylline significantly decreased Abeta-induced cell death, intracellular calcium overloading, and tau protein hyperphosphorylation in PC12 cells. These results suggest that rhynchophylline and isorhynchophylline are the major active ingredients responsible for the protective action of Uncaria rhynchophylla against Abeta-induced neuronal toxicity, and their neuroprotective effect may be mediated, at least in part, by inhibiting intracellular calcium overloading and tau protein hyperphosphorylation.
ESTHER : Xian_2012_Evid.Based.Complement.Alternat.Med_2012_802625
PubMedSearch : Xian_2012_Evid.Based.Complement.Alternat.Med_2012_802625
PubMedID: 22778778

Title : Neurexin and neuroligin mediate retrograde synaptic inhibition in C. elegans - Hu_2012_Science_337_980
Author(s) : Hu Z , Hom S , Kudze T , Tong XJ , Choi S , Aramuni G , Zhang W , Kaplan JM
Ref : Science , 337 :980 , 2012
Abstract : The synaptic adhesion molecules neurexin and neuroligin alter the development and function of synapses and are linked to autism in humans. Here, we found that Caenorhabditis elegans neurexin (NRX-1) and neuroligin (NLG-1) mediated a retrograde synaptic signal that inhibited neurotransmitter release at neuromuscular junctions. Retrograde signaling was induced in mutants lacking a muscle microRNA (miR-1) and was blocked in mutants lacking NLG-1 or NRX-1. Release was rapid and abbreviated when the retrograde signal was on, whereas release was slow and prolonged when retrograde signaling was blocked. The retrograde signal adjusted release kinetics by inhibiting exocytosis of synaptic vesicles (SVs) that are distal to the site of calcium entry. Inhibition of release was mediated by increased presynaptic levels of tomosyn, an inhibitor of SV fusion.
ESTHER : Hu_2012_Science_337_980
PubMedSearch : Hu_2012_Science_337_980
PubMedID: 22859820

Title : The immunoglobulin super family protein RIG-3 prevents synaptic potentiation and regulates Wnt signaling - Babu_2011_Neuron_71_103
Author(s) : Babu K , Hu Z , Chien SC , Garriga G , Kaplan JM
Ref : Neuron , 71 :103 , 2011
Abstract : Cell surface Ig superfamily proteins (IgSF) have been implicated in several aspects of neuron development and function. Here, we describe the function of a Caenorhabditis elegans IgSF protein, RIG-3. Mutants lacking RIG-3 have an exaggerated paralytic response to a cholinesterase inhibitor, aldicarb. Although RIG-3 is expressed in motor neurons, heightened drug responsiveness was caused by an aldicarb-induced increase in muscle ACR-16 acetylcholine receptor (AChR) abundance, and a corresponding potentiation of postsynaptic responses at neuromuscular junctions. Mutants lacking RIG-3 also had defects in the anteroposterior polarity of the ALM mechanosensory neurons. The effects of RIG-3 on synaptic transmission and ALM polarity were both mediated by changes in Wnt signaling, and in particular by inhibiting CAM-1, a Ror-type receptor tyrosine kinase that binds Wnt ligands. These results identify RIG-3 as a regulator of Wnt signaling, and suggest that RIG-3 has an anti-plasticity function that prevents activity-induced changes in postsynaptic receptor fields.
ESTHER : Babu_2011_Neuron_71_103
PubMedSearch : Babu_2011_Neuron_71_103
PubMedID: 21745641

Title : Putative EPHX1 enzyme activity is related with risk of lung and upper aerodigestive tract cancers: a comprehensive meta-analysis - Li_2011_PLoS.One_6_e14749
Author(s) : Li X , Hu Z , Qu X , Zhu J , Li L , Ring BZ , Su L
Ref : PLoS ONE , 6 :e14749 , 2011
Abstract : BACKGROUND: EPHX1 is a key enzyme in metabolizing some exogenous carcinogens such as products of cigarette-smoking. Two functional polymorphisms in the EPHX1 gene, Tyr113His and His139Arg can alter the enzyme activity, suggesting their possible association with carcinogenesis risk, particularly of some tobacco-related cancers. METHODOLOGY/PRINCIPAL FINDINGS: A comprehensive systematic review and meta-analysis was performed of available studies on these two polymorphisms and cancer risk published up to November 2010, consisting of 84 studies (31144 cases and 42439 controls) for Tyr113His and 77 studies (28496 cases and 38506 controls) for His139Arg primarily focused on lung cancer, upper aerodigestive tract (UADT) cancers (including oral, pharynx, larynx and esophagus cancers), colorectal cancer or adenoma, bladder cancer and breast cancer. Results showed that Y113H low activity allele (H) was significantly associated with decreased risk of lung cancer (OR = 0.88, 95%CI = 0.80-0.96) and UADT cancers (OR = 0.86, 95%CI = 0.77-0.97) and H139R high activity allele (R) with increased risk of lung cancer (OR = 1.18, 95%CI = 1.04-1.33) but not of UADT cancers (OR = 1.05, 95%CI = 0.93-1.17). Pooled analysis of lung and UADT cancers revealed that low EPHX1 enzyme activity, predicted by the combination of Y113H and H139R showed decreased risk of these cancers (OR = 0.83, 95%CI = 0.75-0.93) whereas high EPHX1 activity increased risk of the cancers (OR = 1.20, 95%CI = 0.98-1.46). Furthermore, modest difference for the risk of lung and UADT cancers was found between cigarette smokers and nonsmokers both in single SNP analyses (low activity allele H: OR = 0.77/0.85 for smokers/nonsmokers; high activity allele R: OR = 1.20/1.09 for smokers/nonsmokers) and in combined double SNP analyses (putative low activity: OR = 0.73/0.88 for smokers/nonsmokers; putative high activity: OR = 1.02/0.93 for smokers/ nonsmokers). CONCLUSIONS/SIGNIFICANCE: Putative low EPHX1 enzyme activity may have a potential protective effect on tobacco-related carcinogenesis of lung and UADT cancers, whereas putative high EPHX1 activity may have a harmful effect. Moreover, cigarette-smoking status may influence the association of EPHX1 enzyme activity and the related cancer risk.
ESTHER : Li_2011_PLoS.One_6_e14749
PubMedSearch : Li_2011_PLoS.One_6_e14749
PubMedID: 21445251

Title : A neuropeptide-mediated stretch response links muscle contraction to changes in neurotransmitter release - Hu_2011_Neuron_71_92
Author(s) : Hu Z , Pym EC , Babu K , Vashlishan Murray AB , Kaplan JM
Ref : Neuron , 71 :92 , 2011
Abstract : Although Caenorhabditis elegans has been utilized extensively to study synapse formation and function, relatively little is known about synaptic plasticity in C. elegans. We show that a brief treatment with the cholinesterase inhibitor aldicarb induces a form of presynaptic potentiation whereby ACh release at neuromuscular junctions (NMJs) is doubled. Aldicarb-induced potentiation was eliminated by mutations that block processing of proneuropeptides, by mutations inactivating a single proneuropeptide (NLP-12), and by those inactivating an NLP-12 receptor (CKR-2). NLP-12 expression is limited to a single stretch-activated neuron, DVA. Analysis of a YFP-tagged NLP-12 suggests that aldicarb stimulates DVA secretion of NLP-12. Mutations disrupting the DVA mechanoreceptor (TRP-4) decreased aldicarb-induced NLP-12 secretion and blocked aldicarb-induced synaptic potentiation. Mutants lacking NLP-12 or CKR-2 have decreased locomotion rates. Collectively, these results suggest that NLP-12 mediates a mechanosensory feedback loop that couples muscle contraction to changes in presynaptic release, thereby providing a mechanism for proprioceptive control of locomotion.
ESTHER : Hu_2011_Neuron_71_92
PubMedSearch : Hu_2011_Neuron_71_92
PubMedID: 21745640

Title : Accurate determination of the anticancer prodrug simmitecan and its active metabolite chimmitecan in various plasma samples based on immediate deactivation of blood carboxylesterases - Hu_2011_J.Chromatogr.A_1218_6646
Author(s) : Hu Z , Sun Y , Du F , Niu W , Xu F , Huang Y , Li C
Ref : Journal of Chromatography A , 1218 :6646 , 2011
Abstract : Simmitecan (L-P) is an anticancer ester prodrug, which involves activation to chimmitecan (L-2-Z). In the current study, a liquid chromatography/tandem mass spectrometry-based method was developed for simultaneous determination of L-P and L-2-Z in various plasma samples. Because L-P is rapidly converted to L-2-Z by blood carboxylesterase during and after sampling, which hampers accurate determination of L-P and L-2-Z in the biological samples, different carboxylesterase inhibitors were tested. As a result, bis(4-nitrophenyl)phosphate gave the best results with respect to inhibitory capability, hemolysis, and matrix effects and was used to deactivate blood carboxylesterases when sampling. The plasma samples were precipitated with acetonitrile and the resulting supernatants were separated using a pulse gradient method on a C18 column. Irinotecan and camptothecin were used as internal standards for quantification of L-P and L-2-Z, respectively. Protonated L-P, L-2-Z and their internal standards were generated by electrospray ionization and their precursor-product ion pairs (m/z 599-->124, 405-->361, 587-->195, and 349-->305, respectively) were used for measurement. The newly developed bioanalytical assay processed favorable accuracy and precision with lower limits of quantification of 2.1 nM for L-P and 3.4 nM for L-2-Z, and was successfully applied to pharmacokinetic studies in tumor-bearing nude mice, rats, and dogs. There are substantial species differences in the ester activity. The experimental strategies illustrated in our report may be adopted for measurement of other prodrugs (including irinotecan) or drugs subject to ester hydrolysis, as well as their metabolites, in biological matrices.
ESTHER : Hu_2011_J.Chromatogr.A_1218_6646
PubMedSearch : Hu_2011_J.Chromatogr.A_1218_6646
PubMedID: 21839460

Title : The MDGA1 gene confers risk to schizophrenia and bipolar disorder - Li_2011_Schizophr.Res_125_194
Author(s) : Li J , Liu J , Feng G , Li T , Zhao Q , Li Y , Hu Z , Zheng L , Zeng Z , He L , Wang T , Shi Y
Ref : Schizophr Res , 125 :194 , 2011
Abstract : OBJECTIVE: The structural, cytoarchitectural and functional brain abnormalities reported in patients with mental disorders may be due to aberrant neuronal migration influenced by cell adhesion molecules. MDGA1, like Ig-containing cell adhesion molecules, has several cell adhesion molecule-like domains. Moreover, Kahler et al. (2008) reported that the MDGA1 gene was a schizophrenia susceptibility gene in Scandinavian population. To further investigate whether the MDGA1 gene is a shared risk factor of schizophrenia, bipolar disorder and major depressive disorder in Chinese Han population, we conducted this study.
METHODS: We recruited 1135 unrelated schizophrenia patients, 1135 unrelated bipolar disorder patients, 1135 unrelated major depressive disorder patients and 1135 unrelated controls of Chinese Han origin. A total of eleven common SNPs were genotyped using TaqMan(R) technology.
RESULTS: The genotype frequency of rs11759115 differed significantly between schizophrenia patients and controls. The C-C haplotype of rs11759115-rs7769372 was also positively associated with schizophrenia (permutated p=0.046). Rs1883901 was found to be positively associated with bipolar disorder (allele: permutated p=0.0085; genotype: permutated p=0.0009; OR=1.31 [95%CI=1.12-1.52]). The A-G-G haplotype of rs1883901-rs10807187-rs9462343 was also positively associated with bipolar disorder with a global p value of 0.0391 after permutations. No individual SNP or haplotype was associated with major depressive disorder after permutations. CONCLUSION: The MDGA1 gene may confer risk to schizophrenia and bipolar disorder in Chinese Han population.
ESTHER : Li_2011_Schizophr.Res_125_194
PubMedSearch : Li_2011_Schizophr.Res_125_194
PubMedID: 21146959

Title : Genes for the biosynthesis of the fungal polyketides hypothemycin from Hypomyces subiculosus and radicicol from Pochonia chlamydosporia - Reeves_2008_Appl.Environ.Microbiol_74_5121
Author(s) : Reeves CD , Hu Z , Reid R , Kealey JT
Ref : Applied Environmental Microbiology , 74 :5121 , 2008
Abstract : Gene clusters for biosynthesis of the fungal polyketides hypothemycin and radicicol from Hypomyces subiculosus and Pochonia chlamydosporia, respectively, were sequenced. Both clusters encode a reducing polyketide synthase (PKS) and a nonreducing PKS like those in the zearalenone cluster of Gibberella zeae, plus enzymes with putative post-PKS functions. Introduction of an O-methyltransferase (OMT) knockout construct into H. subiculosus resulted in a strain with increased production of 4-O-desmethylhypothemycin, but because transformation of H. subiculosus was very difficult, we opted to characterize hypothemycin biosynthesis using heterologous gene expression. In vitro, the OMT could methylate various substrates lacking a 4-O-methyl group, and the flavin-dependent monooxygenase (FMO) could epoxidate substrates with a 1',2' double bond. The glutathione S-transferase catalyzed cis-trans isomerization of the 7',8' double bond of hypothemycin. Expression of both hypothemycin PKS genes (but neither gene alone) in yeast resulted in production of trans-7',8'-dehydrozearalenol (DHZ). Adding expression of OMT, expression of FMO, and expression of cytochrome P450 to the strain resulted in methylation, 1',2'-epoxidation, and hydroxylation of DHZ, respectively. The radicicol gene cluster encodes halogenase and cytochrome P450 homologues that are presumed to catalyze chlorination and epoxidation, respectively. Schemes for biosynthesis of hypothemycin and radicicol are proposed. The PKSs encoded by the two clusters described above and those encoded by the zearalenone cluster all synthesize different products, yet they have significant sequence identity. These PKSs may provide a useful system for probing the mechanisms of fungal PKS programming.
ESTHER : Reeves_2008_Appl.Environ.Microbiol_74_5121
PubMedSearch : Reeves_2008_Appl.Environ.Microbiol_74_5121
PubMedID: 18567690
Gene_locus related to this paper: hypsb-hpm3 , metcm-rdc1

Title : Novel agents that potentially inhibit irinotecan-induced diarrhea - Yang_2005_Curr.Med.Chem_12_1343
Author(s) : Yang X , Hu Z , Chan SY , Chan E , Goh BC , Duan W , Zhou S
Ref : Curr Med Chem , 12 :1343 , 2005
Abstract : Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea.
ESTHER : Yang_2005_Curr.Med.Chem_12_1343
PubMedSearch : Yang_2005_Curr.Med.Chem_12_1343
PubMedID: 15975002

Title : Insights into the biosynthesis of the benzoquinone ansamycins geldanamycin and herbimycin, obtained by gene sequencing and disruption - Rascher_2005_Appl.Environ.Microbiol_71_4862
Author(s) : Rascher A , Hu Z , Buchanan GO , Reid R , Hutchinson CR
Ref : Applied Environmental Microbiology , 71 :4862 , 2005
Abstract : Geldanamycin and the closely related herbimycins A, B, and C were the first benzoquinone ansamycins to be extensively studied for their antitumor properties as small-molecule inhibitors of the Hsp90 protein chaperone complex. These compounds are produced by two different Streptomyces hygroscopicus strains and have the same modular polyketide synthase (PKS)-derived carbon skeleton but different substitution patterns at C-11, C-15, and C-17. To set the stage for structural modification by genetic engineering, we previously identified the gene cluster responsible for geldanamycin biosynthesis. We have now cloned and sequenced a 115-kb segment of the herbimycin biosynthetic gene cluster from S. hygroscopicus AM 3672, including the genes for the PKS and most of the post-PKS tailoring enzymes. The similarities and differences between the gene clusters and biosynthetic pathways for these closely related ansamycins are interpreted with support from the results of gene inactivation experiments. In addition, the organization and functions of genes involved in the biosynthesis of the 3-amino-5-hydroxybenzoic acid (AHBA) starter unit and the post-PKS modifications of progeldanamycin were assessed by inactivating the subclusters of AHBA biosynthetic genes and two oxygenase genes (gdmM and gdmL) that were proposed to be involved in formation of the geldanamycin benzoquinoid system. A resulting novel geldanamycin analog, KOS-1806, was isolated and characterized.
ESTHER : Rascher_2005_Appl.Environ.Microbiol_71_4862
PubMedSearch : Rascher_2005_Appl.Environ.Microbiol_71_4862
PubMedID: 16085885

Title : Chalcomycin biosynthesis gene cluster from Streptomyces bikiniensis: novel features of an unusual ketolide produced through expression of the chm polyketide synthase in Streptomyces fradiae - Ward_2004_Antimicrob.Agents.Chemother_48_4703
Author(s) : Ward SL , Hu Z , Schirmer A , Reid R , Revill WP , Reeves CD , Petrakovsky OV , Dong SD , Katz L
Ref : Antimicrobial Agents & Chemotherapy , 48 :4703 , 2004
Abstract : Chalcomycin, a 16-membered macrolide antibiotic made by the bacterium Streptomyces bikiniensis, contains a 2,3-trans double bond and the neutral sugar D-chalcose in place of the amino sugar mycaminose found in most other 16-membered macrolides. Degenerate polyketide synthase (PKS)-specific primers were used to amplify DNA fragments from S. bikiniensis with very high identity to a unique ketosynthase domain of the tylosin PKS. The resulting amplimers were used to identify two overlapping cosmids encompassing the chm PKS. Sequencing revealed a contiguous segment of >60 kb carrying 25 putative genes for biosynthesis of the polyketide backbone, the two deoxysugars, and enzymes involved in modification of precursors of chalcomycin or resistance to it. The chm PKS lacks the ketoreductase and dehydratase domains in the seventh module expected to produce the 2,3-double bond in chalcomycin. Expression of PKS in the heterologous host Streptomyces fradiae, from which the tyl genes encoding the PKS had been removed, resulted in production of at least one novel compound, characterized as a 3-keto 16-membered macrolactone in equilibrium with its 3-trans enol tautomer and containing the sugar mycaminose at the C-5 position, in agreement with the structure predicted on the basis of the domain organization of the chm PKS. The production of a 3-keto macrolide from the chm PKS indicates that a discrete set of enzymes is responsible for the introduction of the 2,3-trans double bond in chalcomycin. From comparisons of the open reading frames to sequences in databases, a pathway for the synthesis of nucleoside diphosphate-D-chalcose was proposed.
ESTHER : Ward_2004_Antimicrob.Agents.Chemother_48_4703
PubMedSearch : Ward_2004_Antimicrob.Agents.Chemother_48_4703
PubMedID: 15561847
Gene_locus related to this paper: strbi-q5sfb0 , strbi-q5sfc7 , strbi-q5sfd4

Title : Cloning and characterization of a gene cluster for geldanamycin production in Streptomyces hygroscopicus NRRL 3602 - Rascher_2003_FEMS.Microbiol.Lett_218_223
Author(s) : Rascher A , Hu Z , Viswanathan N , Schirmer A , Reid R , Nierman WC , Lewis M , Hutchinson CR
Ref : FEMS Microbiology Letters , 218 :223 , 2003
Abstract : We illustrate the use of a PCR-based method by which the genomic DNA of a microorganism can be rapidly queried for the presence of type I modular polyketide synthase genes to clone and characterize, by sequence analysis and gene disruption, a major portion of the geldanamycin production gene cluster from Streptomyces hygroscopicus var. geldanus NRRL 3602.
ESTHER : Rascher_2003_FEMS.Microbiol.Lett_218_223
PubMedSearch : Rascher_2003_FEMS.Microbiol.Lett_218_223
PubMedID: 12586396
Gene_locus related to this paper: strhy-Q84G29

Title : A specific role of the Saccharopolyspora erythraea thioesterase II gene in the function of modular polyketide synthases - Hu_2003_Microbiology_149_2213
Author(s) : Hu Z , Pfeifer BA , Chao E , Murli S , Kealey J , Carney JR , Ashley G , Khosla C , Hutchinson CR
Ref : Microbiology , 149 :2213 , 2003
Abstract : Bacterial modular polyketide synthase (PKS) genes are commonly associated with another gene that encodes a thioesterase II (TEII) believed to remove aberrantly loaded substrates from the PKS. Co-expression of the Saccharopolyspora erythraea ery-ORF5 TEII and eryA genes encoding 6-deoxyerythronolide B synthase (DEBS) in Streptomyces hosts eliminated or significantly lowered production of 8,8'-deoxyoleandolide [15-nor-6-deoxyerythronolide B (15-nor-6dEB)], which arises from an acetate instead of a propionate starter unit. Disruption of the TEII gene in an industrial Sac. erythraea strain caused a notable amount of 15-norerythromycins to be produced by utilization of an acetate instead of a propionate starter unit and also resulted in moderately lowered production of erythromycin compared with the amount produced by the parental strain. A similar behaviour of the TEII gene was observed in Escherichia coli strains that produce 6dEB and 15-methyl-6dEB. Direct biochemical analysis showed that the ery-ORF5 TEII enzyme favours hydrolysis of acetyl groups bound to the loading acyl carrier protein domain (ACP(L)) of DEBS. These results point to a clear role of the TEII enzyme, i.e. removal of a specific type of acyl group from the ACP(L) domain of the DEBS1 loading module.
ESTHER : Hu_2003_Microbiology_149_2213
PubMedSearch : Hu_2003_Microbiology_149_2213
PubMedID: 12904561
Gene_locus related to this paper: sacer-Q9JN61

Title : Improving the oral efficacy of CNS drug candidates: discovery of highly orally efficacious piperidinyl piperidine M2 muscarinic receptor antagonists - Wang_2002_J.Med.Chem_45_5415
Author(s) : Wang Y , Chackalamannil S , Hu Z , Greenlee WJ , Clader J , Boyle CD , Kaminski JJ , Billard W , Binch H, 3rd , Crosby G , Ruperto V , Duffy RA , Cohen-Williams M , Coffin VL , Cox KA , Grotz DE , Lachowicz JE
Ref : Journal of Medicinal Chemistry , 45 :5415 , 2002
Abstract : In search of a backup M(2) muscarinic receptor antagonist to the previously reported compound 1, we discovered compound (+)-14, which showed superior oral efficacy in animal models. The improvement of oral efficacy was achieved by modulating both the molecular weight and lipophilicity of the lead compounds.
ESTHER : Wang_2002_J.Med.Chem_45_5415
PubMedSearch : Wang_2002_J.Med.Chem_45_5415
PubMedID: 12459007

Title : Sulfide analogues as potent and selective M(2) muscarinic receptor antagonists - Wang_2002_Bioorg.Med.Chem.Lett_12_1087
Author(s) : Wang Y , Chackalamannil S , Hu Z , McKittrick BA , Greenlee W , Ruperto V , Duffy RA , Lachowicz JE
Ref : Bioorganic & Medicinal Chemistry Lett , 12 :1087 , 2002
Abstract : We have discovered highly potent, selective sulfide M(2) receptor antagonists with low molecular weight and different structural features compared with our phase I clinical candidate Sch 211803. Analogue 30 showed superior M(2) receptor selectivity profile over Sch 211803. More importantly, this study provided new leads for the discovery of M(2) receptor antagonists as potential drug candidates.
ESTHER : Wang_2002_Bioorg.Med.Chem.Lett_12_1087
PubMedSearch : Wang_2002_Bioorg.Med.Chem.Lett_12_1087
PubMedID: 11909724

Title : Biosynthesis of the anti-parasitic agent megalomicin: transformation of erythromycin to megalomicin in Saccharopolyspora erythraea - Volchegursky_2000_Mol.Microbiol_37_752
Author(s) : Volchegursky Y , Hu Z , Katz L , McDaniel R
Ref : Molecular Microbiology , 37 :752 , 2000
Abstract : Megalomicin is a therapeutically diverse compound which possesses antiparasitic, antiviral and antibacterial properties. It is produced by Micromonospora megalomicea and differs from the well-known macrolide antibiotic erythromycin by the addition of a unique deoxyamino sugar, megosamine, to the C-6 hydroxyl. We have cloned and sequenced a 48 kb segment of the megalomicin (meg) biosynthetic gene cluster which contains the modular polyketide synthase (PKS) and the complete pathway for megosamine biosynthesis. The similarities and distinctions between the related megalomicin and erythromycin gene clusters are discussed. Heterologous expression of the megalomicin PKS in Streptomyces lividans led to production of 6-deoxyerythronolide B, the same macrolactone intermediate for erythromycin. A 12 kb fragment harbouring the putative megosamine pathway was expressed in Saccharopolyspora erythraea, resulting in the conversion of erythromycin to megalomicin. Considering the extensive knowledge surrounding the genetic engineering of the erythromycin PKS and the familiarity with genetic manipulation and fermentation of S. erythraea, the ability to produce megalomicin in this strain should allow the engineering of novel megalomicin analogues with potentially improved therapeutic activities.
ESTHER : Volchegursky_2000_Mol.Microbiol_37_752
PubMedSearch : Volchegursky_2000_Mol.Microbiol_37_752
PubMedID: 10972798
Gene_locus related to this paper: micme-MEGAIII , micme-MEGH

Title : Design and synthesis of piperidinyl piperidine analogues as potent and selective M2 muscarinic receptor antagonists - Wang_2000_Bioorg.Med.Chem.Lett_10_2247
Author(s) : Wang Y , Chackalamannil S , Hu Z , Clader JW , Greenlee W , Billard W , Binch H , Crosby G , Ruperto V , Duffy RA , McQuade R , Lachowicz JE
Ref : Bioorganic & Medicinal Chemistry Lett , 10 :2247 , 2000
Abstract : Identification of a number of highly potent M2 receptor antagonists with >100-fold selectivity against the M1 and M3 receptor subtypes is described. In the rat microdialysis assay, this series of compounds showed pronounced enhancement of brain acetylcholine release after oral administration.
ESTHER : Wang_2000_Bioorg.Med.Chem.Lett_10_2247
PubMedSearch : Wang_2000_Bioorg.Med.Chem.Lett_10_2247
PubMedID: 11055330

Title : Engineering lipase at the molecular scale for cleaner biodiesel production - A review - Tan_2023_Mol.Catal_546_113271
Author(s) : Tan Z , Chen G , Chen S , Zhang J , Liu J , Ma X , Liao H , Hu Z , Ge F , Ju F , Shi H , Bilal M
Ref : Molecular Catalysis , 546 :113271
Abstract : Increasing environmental concerns and significant demand for industrial fuels necessitate the development of alternate and sustainable energy sources. Biodiesel is a renewable and environmentally friendly fuel produced by trans-esterifying a variety of feedstocks. Lipases are robust triacylglycerol ester hydrolases that catalyze hydrolysis, esterification, interesterification, transesterification, acylation, acidolysis, alcoholysis, aminolysis, and resolution of racemates. Although the lipase-assisted greener biosynthesis of biodiesel has numerous advantages over the traditional alkali-based process, low catalytic efficiency, marginal stability, and high cost of lipase enzymes limit its widespread industrial processability. Protein engineering methodologies such as directed evolution, semi-rational design, and rational design can effectively tailor or improve the biocatalytic characteristics of lipase enzymes used in biodiesel generation, such as thermostability, solvent tolerance, activity, and substrate specificity. These innovative techniques improved our ability to predict structure-function relationships, engineering qualities, computational tools for designing new biocatalysts, and functional screening to manipulate enzyme traits for application in prevalent industrial bioprocesses. Many recent studies have demonstrated improved lipase performance, such as activity, stability, and specificity via protein engineering. This review spotlights a current overview of lipase engineering at the molecular scale with robust biocatalytic properties for biodiesel synthesis.
ESTHER : Tan_2023_Mol.Catal_546_113271
PubMedSearch : Tan_2023_Mol.Catal_546_113271
PubMedID: