Hu J

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Full name : Hu Jianxin

First name : Jianxin

Mail : Molecular Signaling Section, Lab. of Bioorganic Chemistry NIDDK-NIH, Bethesda, MD 20892

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Country : USA

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References (100)

Title : Adverse effects of Microcystis aeruginosa exudates on the filtration, digestion, and reproduction organs of benthic bivalve Corbicula fluminea - Hong_2024_Sci.Rep_14_10934
Author(s) : Hong Z , Chen X , Hu J , Chang X , Qian Y
Ref : Sci Rep , 14 :10934 , 2024
Abstract : Cyanobacteria bloom and the secondary metabolites released by the microorganism are extremely harmful to aquatic animals, yet study on their adverse effects in zoobenthos is rare. Corbicula fluminea widely distributed in freshwater environment with algal blooms. It is a typical filter feeding zoobenthos that may be affected by the secondary metabolites of cyanobacteria due to its high filtering rate. In this study, C. fluminea was exposed to Microcystis aeruginosa exudates (MaE) for 96 h, which was obtained from 5x10(5) cells/mL and 2.5x10(6) cells/mL exponential stage M. aeruginosa culture solution that represented cyanobacteria cell density needs environmental risk precaution control and emergent control, respectively. The responses of C. fluminea critical organs to MaE were analyzed and evaluated based on histopathological sections, antitoxicity biomarkers, and organ function biomarkers. The results showed that all the organs underwent structural disorders, cell vacuolization, apoptosis, and necrosis, and the damage levels increased as MaE concentration increased. The detoxification and antioxidant defense systems biomarkers in each organ response to MaE exposure differently and the level of reaction improved when MaE concentration increased. The siphon rate and acetylcholinesterase activity showed that the filtration function decreased significantly as the MaE concentration increased. Increased activity of glutathione S-transferase and amylase in the digestive gland indicate that it is the major detoxification organ of C. fluminea. Increased vitellogenin concentration and enlarged oocytes in the gonad indicate that MaE may have an estrogenic effect on C. fluminea. This study demonstrates that cyanobacteria threat benthic bivalves by inducing oxidative stress, inhibiting filtering feeding system, and disturbing digestion system and reproduction potential of C. fluminea.
ESTHER : Hong_2024_Sci.Rep_14_10934
PubMedSearch : Hong_2024_Sci.Rep_14_10934
PubMedID: 38740841

Title : Role of the soluble epoxide hydrolase in keratinocyte proliferation and sensitivity of skin to inflammatory stimuli - Naeem_2024_Biomed.Pharmacother_171_116127
Author(s) : Naeem Z , Zukunft S , Huard A , Hu J , Hammock BD , Weigert A , Fromel T , Fleming I
Ref : Biomed Pharmacother , 171 :116127 , 2024
Abstract : The lipid content of skin plays a determinant role in its barrier function with a particularly important role attributed to linoleic acid and its derivatives. Here we explored the consequences of interfering with the soluble epoxide hydrolase (sEH) on skin homeostasis. sEH; which converts fatty acid epoxides generated by cytochrome P450 enzymes to their corresponding diols, was largely restricted to the epidermis which was enriched in sEH-generated diols. Global deletion of the sEH increased levels of epoxides, including the linoleic acid-derived epoxide; 12,13-epoxyoctadecenoic acid (12,13-EpOME), and increased basal keratinocyte proliferation. sEH deletion (sEH(-/-) mice) resulted in thicker differentiated spinous and corneocyte layers compared to wild-type mice, a hyperkeratosis phenotype that was reproduced in wild-type mice treated with a sEH inhibitor. sEH deletion made the skin sensitive to inflammation and sEH(-/-) mice developed thicker imiquimod-induced psoriasis plaques than the control group and were more prone to inflammation triggered by mechanical stress with pronounced infiltration and activation of neutrophils as well as vascular leak and increased 12,13-EpOME and leukotriene (LT) B4 levels. Topical treatment of LTB4 antagonist after stripping successfully inhibited inflammation and neutrophil infiltration both in wild type and sEH(-/-) skin. While 12,13-EpoME had no effect on the trans-endothelial migration of neutrophils, like LTB4, it effectively induced neutrophil adhesion and activation. These observations indicate that while the increased accumulation of neutrophils in sEH-deficient skin could be attributed to the increase in LTB4 levels, both 12,13-EpOME and LTB4 contribute to neutrophil activation. Our observations identify a protective role of the sEH in the skin and should be taken into account when designing future clinical trials with sEH inhibitors.
ESTHER : Naeem_2024_Biomed.Pharmacother_171_116127
PubMedSearch : Naeem_2024_Biomed.Pharmacother_171_116127
PubMedID: 38198951

Title : Complete genome sequencing of Hortaea werneckii M-3 for identifying polyester polyurethane degrading enzymes - Ling_2024_Mar.Genomics_75_101111
Author(s) : Ling M , Zhang K , Hu J , Huang X , Fan G , Grossart HP , Luo Z
Ref : Mar Genomics , 75 :101111 , 2024
Abstract : Hortaea werneckii M-3, a black yeast isolated from the marine sediment of the West Pacific, can utilize polyester polyurethane (PU, Impranil DLN) as a sole carbon source. Here, we present the complete genome of Hortaea werneckii M-3 with the focus on PU degradation enzymes. The total genome size is 38,167,921 bp, consisting of 186 contigs with a N50 length of 651,266 bp and a GC content of 53.06%. Genome annotation analysis predicts a total of 13,462 coding genes, which include 99 tRNAs and 105 rRNAs. Some genes encoding PU degrading enzymes including cutinase and urease are identified in this genome. The genome analysis of Hortaea werneckii M-3 will be helpful for further understanding the degradation mechanism of polyester PU by marine yeasts.
ESTHER : Ling_2024_Mar.Genomics_75_101111
PubMedSearch : Ling_2024_Mar.Genomics_75_101111
PubMedID: 38735674

Title : Human umbilical cord mesenchymal stem cells attenuate diet-induced obesity and NASH-related fibrosis in mice - Hu_2024_Heliyon_10_e25460
Author(s) : Hu J , Li S , Zhong X , Wei Y , Sun Q , Zhong L
Ref : Heliyon , 10 :e25460 , 2024
Abstract : Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that may progress to cirrhosis and hepatocellular carcinoma but has no available treatment. Mesenchymal stem cells (MSCs) have become increasingly prominent in cell therapy. Human umbilical cord MSCs (hUC-MSCs) are considered superior to other MSCs due to their strong immunomodulatory ability, ease of collection, low immune rejection, and no tumorigenicity. Though hUC-MSCs have received increasing attention in research, they have been rarely applied in any investigations or treatments of NASH and associated fibrosis. Therefore, this study evaluated the therapeutic efficacy of hUC-MSCs in C57BL/6 mice with diet-induced NASH. At week 32, mice were randomized into two groups: phosphate-buffered saline and MSCs, which were injected into the tail vein. At week 40, glucose metabolism was evaluated using glucose and insulin tolerance tests. NASH-related indicators were examined using various biological methods. hUC-MSC administration alleviated obesity, glucose metabolism, hepatic steatosis, inflammation, and fibrosis. Liver RNA-seq showed that the expression of the acyl-CoA thioesterase (ACOT) family members Acot1, Acot2, and Acot3 involved in fatty acid metabolism were altered. The cytochrome P450 (CYP) members Cyp4a10 and Cyp4a14, which are involved in the peroxisome proliferator-activator receptor (PPAR) signaling pathway, were significantly downregulated after hUC-MSC treatment. In conclusion, hUC-MSCs effectively reduced Western diet-induced obesity, NASH, and fibrosis in mice, partly by regulating lipid metabolism and the PPAR signaling pathway.
ESTHER : Hu_2024_Heliyon_10_e25460
PubMedSearch : Hu_2024_Heliyon_10_e25460
PubMedID: 38356602

Title : Variation in the HSL Gene and Its Association with Carcass and Meat Quality Traits in Yak - Wang_2023_Animals.(Basel)_13_
Author(s) : Wang X , Qi Y , Zhu C , Zhou R , Ruo Z , Zhao Z , Liu X , Li S , Zhao F , Wang J , Hu J , Shi B
Ref : Animals (Basel) , 13 : , 2023
Abstract : Hormone-sensitive lipase (HSL) is involved in the breakdown of triacylglycerols in adipose tissue, which influences muscle tenderness and juiciness by affecting the intramuscular fat content (IMF). This study analyzed the association between different genotypes and haplotypes of the yak HSL gene and carcass and meat quality traits. We used hybridization pool sequencing to detect exon 2, exon 8, and intron 3 variants of the yak HSL gene and genotyped 525 Gannan yaks via KASP to analyze the effects of the HSL gene variants on the carcass and meat quality traits in yaks. According to the results, the HSL gene is highly expressed in yak adipose tissue. Three single nucleotide polymorphisms (SNPs) were identified, with 2 of them located in the coding region and one in the intron region. Variants in the 2 coding regions resulted in amino acid changes. The population had 3 genotypes of GG, AG, and AA, and individuals with the AA genotype had lower WBSF values (p < 0.05). The H3H3 haplotype combinations could improve meat tenderness by reducing the WBSF values and the cooking loss rate (CLR) (p < 0.05). H1H1 haplotype combinations were associated with the increased drip loss rate (DLR) (p < 0.05). The presence of the H1 haplotype was associated the increased CLR in yaks, while that of the H2 haplotype was associated with the decreased DLR in yaks (p < 0.05). These results demonstrated that the HSL gene may influence the meat quality traits in yaks by affecting the IMF content in muscle tissues. Consequently, the HSL gene can possibly be used as a biomarker for improving the meat quality traits in yaks in the future.
ESTHER : Wang_2023_Animals.(Basel)_13_
PubMedSearch : Wang_2023_Animals.(Basel)_13_
PubMedID: 38067071

Title : A promising tool for clinical diagnostics: Dual-emissive carbonized polymer dots based cross-linking enhanced emission for sensitive detection of alkaline phosphatase and butyrylcholinesterase - Li_2023_Biosens.Bioelectron_238_115576
Author(s) : Li T , Wang D , Hu J , Fu X , Ji Y , Li R
Ref : Biosensors & Bioelectronics , 238 :115576 , 2023
Abstract : Compared with single signal readout, dual-signal readout commendably corrects the impact of systematic or background error, achieving more accurate results for the diagnosis of many diseases. This work aimed to design and prepare dual-emissive fluorescent probes for the construction of ratiometric fluorescence biosensors to detect liver disease biomarkers. Sodium alginate (SA) with numerous potential sub-fluorophores and active sites and 4,4',4'',4'''-(porphine-5,10,15,20-tetrayl) tetrakis (benzoic acid) (TCPP) with macrocyclic conjugated structures were introduced to prepare the carbonized polymer dots (CPDs) with red/blue dual emission based on the cross-linking enhanced emission (CEE) effect and the luminescence of macrocyclic conjugated structures. The ratiometric fluorescence sensing systems were constructed by integrating the specific response of CPDs to Cu(2+) and the affinity difference of Cu(2+) to substrates or products of enzymes. The sensing systems, CPDs/Cu(2+)/PPi and CPDs/Cu(2+)/BTCh, were designed to detect liver disease biomarkers, alkaline phosphatase (ALP) and butyrylcholinesterase (BChE), respectively. The limit of detection for ALP and BChE was 0.35 U/L and 0.19 U/L, respectively. The proposed sensors were successfully applied to human serum samples from different health stages with satisfactory recoveries. These results demonstrate the successful design of a novel dual-emissive fluorescent probe and provide a feasible strategy for clinical detection.
ESTHER : Li_2023_Biosens.Bioelectron_238_115576
PubMedSearch : Li_2023_Biosens.Bioelectron_238_115576
PubMedID: 37557027

Title : The roles of serine hydrolases and serum albumin in alisol B 23-acetate hydrolysis in humans - Zhang_2023_Front.Pharmacol_14_1160665
Author(s) : Zhang T , Zhang F , Zhang Y , Li H , Zhu G , Weng T , Huang C , Wang P , He Y , Hu J , Ge G
Ref : Front Pharmacol , 14 :1160665 , 2023
Abstract : Introduction: Alisol B 23-acetate (AB23A), a major bioactive constituent in the Chinese herb Zexie (Rhizoma Alismatis), has been found with multiple pharmacological activities. AB23A can be readily hydrolyzed to alisol B in mammals, but the hydrolytic pathways of AB23A in humans and the key enzymes responsible for AB23A hydrolysis are still unrevealed. This study aims to reveal the metabolic organs and the crucial enzymes responsible for AB23A hydrolysis in human biological systems, as well as to decipher the impact of AB23A hydrolysis on its biological effects. Methods: The hydrolytic pathways of AB23A in human plasma and tissue preparations were carefully investigated by using Q-Exactive quadrupole-Orbitrap mass spectrometer and LC-UV, while the key enzymes responsible for AB23A hydrolysis were studied via performing a set of assays including reaction phenotyping assays, chemical inhibition assays, and enzyme kinetics analyses. Finally, the agonist effects of both AB23A and its hydrolytic metabolite(s) on FXR were tested at the cellular level. Results: AB23A could be readily hydrolyzed to form alisol B in human plasma, intestinal and hepatic preparations, while human butyrylcholinesterase (hBchE) and human carboxylesterases played key roles in AB23A hydrolysis in human plasma and tissue preparations, respectively. It was also found that human serum albumin (hSA) could catalyze AB23A hydrolysis, while multiple lysine residues of hSA were covalently modified by AB23A, suggesting that hSA catalyzed AB23A hydrolysis via its pseudo-esterase activity. Biological tests revealed that both AB23A and alisol B exhibited similar FXR agonist effects, indicating AB23A hydrolysis did not affect its FXR agonist effect. Discussion: This study deciphers the hydrolytic pathways of AB23A in human biological systems, which is very helpful for deep understanding of the metabolic rates of AB23A in humans, and useful for developing novel prodrugs of alisol B with desirable pharmacokinetic behaviors.
ESTHER : Zhang_2023_Front.Pharmacol_14_1160665
PubMedSearch : Zhang_2023_Front.Pharmacol_14_1160665
PubMedID: 37089921

Title : Uncovering the interactions between PME and PMEI at the gene and protein levels: Implications for the design of specific PMEI - Wang_2023_J.Mol.Model_29_286
Author(s) : Wang Y , Zhang D , Huang L , Zhang Z , Shi Q , Hu J , He G , Guo X , Shi H , Liang L
Ref : J Mol Model , 29 :286 , 2023
Abstract : CONTEXT: Pectin methylesterase inhibitor (PMEI) can specifically bind and inhibit the activity of pectin methylesterase (PME), which has been widely used in fruit and vegetable juice processing. However, the limited three-dimensional structure, unclear action mechanism, low thermal stability and biological activity of PMEI severely limited its application. In this work, molecular recognition and conformational changes of PME and PMEI were analyzed by various molecular simulation methods. Then suggestions were proposed for improving thermal stability and affinity maturation of PMEI through semi-rational design. METHODS: Phylogenetic trees of PME and PMEI were established using the Maximum likelihood (ML) method. The results show that PME and PMEI have good sequence and structure conservation in various plants, and the simulated data can be widely adopted. In this work, MD simulations were performed using AMBER20 package and ff14SB force field. Protein interaction analysis indicates that H-bonds, van der Waals forces, and the salt bridge formed of K224 with ID116 are the main driving forces for mutual molecular recognition of PME and PMEI. According to the analyses of free energy landscape (FEL), conformational cluster, and motion, the association with PMEI greatly disrupts PME's dispersed functional motion mode and biological function. By monitoring the changes of residue contact number and binding free energy, (I)G35M/ (I)G35R: (I)T93F and (I)T113W/ (I)T113W: (I)D116W mutations contribute to thermal stability and affinity maturation of the PME-PMEI complex system, respectively. This work reveals the interaction between PME and PMEI at the gene and protein levels and provides options for modifying specific PMEI.
ESTHER : Wang_2023_J.Mol.Model_29_286
PubMedSearch : Wang_2023_J.Mol.Model_29_286
PubMedID: 37610510

Title : Gut microbiota-based pharmacokinetic-pharmacodynamic study and molecular mechanism of specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase - Yu_2023_J.Pharm.Anal_13_1024
Author(s) : Yu H , Xu H , Yang X , Zhang Z , Hu J , Lu J , Fu J , Bu M , Zhang H , Zhai Z , Wang J , Jiang J , Wang Y
Ref : J Pharm Anal , 13 :1024 , 2023
Abstract : Specnuezhenide (SNZ) is among the main components of Fructus Ligustri Lucidi, which has anti-inflammation, anti-oxidation, and anti-tumor effect. The low bioavailability makes it difficult to explain the mechanism of pharmacological effect of SNZ. In this study, the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were explored. SNZ can be rapidly metabolized by the gut microbiome, and two intestinal bacterial metabolites of SNZ, salidroside and tyrosol, were discovered. In addition, carboxylesterase may be the main intestinal bacterial enzyme that mediates its metabolism. At the same time, no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate, indicating that the gut microbiota is the main part involved in the metabolism of SNZ. In addition, pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut microbiota. Interestingly, tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ, which indicated that SNZ exhibited potential to inhibit tumor growth, and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor tissues. At the same time, SNZ modulated the structure of gut microbiota and fungal group, which may be the mechanism governing the antitumoral activity of SNZ. Furthermore, SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in vivo. In the future, targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs.
ESTHER : Yu_2023_J.Pharm.Anal_13_1024
PubMedSearch : Yu_2023_J.Pharm.Anal_13_1024
PubMedID: 37842660

Title : Enzymatic synthesis of novel pyrrole esters and their thermal stability - Hu_2023_BMC.Chem_17_123
Author(s) : Hu J , Zhou M , Zhang Y , Zhang X , Ji X , Zhao M , Lai M
Ref : BMC Chem , 17 :123 , 2023
Abstract : In the present work a simple enzymatic approach (Novozym 435) for transesterification to synthesize pyrrole esters was reported. To generate the best reaction conditions, which resulted in the optimum yield of 92%, the effects of lipase type, solvent, lipase load, molecular sieves, substrate molar ratio of esters to alcohol, reaction temperature, reaction duration, and speed of agitation were evaluated. The range of alcohols was assessed under optimal circumstances. The spectrum observations conclusively demonstrated that the compounds could be generated with high yield under the circumstances utilized for synthesis. The odor characteristics of the pyrrolyl esters obtained were examined by gas chromatography-mass spectrometry-olfactometry (GC-MS-O). Among them, compounds of benzhydryl 1H-pyrrole-2-carboxylate (3j), butyl 1H-pyrrole-2-carboxylate (3k) and pentyl 1H-pyrrole-2-carboxylate (3l) present sweet and acid aroma. In addition, the thermal degradation process was further studied using the Py-GC/MS (pyrolysis-gas chromatography/mass spectrometry), TG (thermogravimetry), and DSC (differential scanning calorimeter) techniques. The outcomes of the Py-GC/MS, TG, and DSC techniques show that they have excellent thermal stability.
ESTHER : Hu_2023_BMC.Chem_17_123
PubMedSearch : Hu_2023_BMC.Chem_17_123
PubMedID: 37742035

Title : New Hydrolase from Aeromicrobium sp. HA for the Biodegradation of Zearalenone: Identification, Mechanism, and Application - Hu_2023_J.Agric.Food.Chem_71_2411
Author(s) : Hu J , Wang G , Hou M , Du S , Han J , Yu Y , Gao H , He D , Shi J , Lee YW , Mohamed SR , Dawood DH , Hong Q , Liu X , Xu J
Ref : Journal of Agricultural and Food Chemistry , 71 :2411 , 2023
Abstract : Zearalenone (ZEN) is an estrogenic mycotoxin most frequently found in cereals that can cause reproductive disorders in livestock and pose a severe threat to animal husbandry. In this study, we isolated a ZEN-degrading Aeromicrobium strain from soil and found that ZenH, a hydrolase, is responsible for the hydrolysis of ZEN through comparative proteomics and biochemical studies. ZenH exhibited the highest similarity with lactone hydrolase ZHD607 from Phialophora americana at 21.52%. ZenH displayed maximal enzymatic activity at pH 7.0 and 55 degreesC with a Michaelis constant of 12.64 microM. The catalytic triad of ZenH was identified as S117-D142-H292 by molecular docking and site-directed mutagenesis. ZenH catalyzed the hydrolysis of ZEN to a novel metabolite, (S,E)-4-hydroxy-2-(10-hydroxy-6-oxoundec-1-en-1-yl)-7-oxabicyclo[4.2.0]octa-1,3,5-trien-8-one, which exhibited significantly lower estrogenic toxicity than ZEN. This study illustrates a novel ZEN-degrading enzyme and reveals a new degradation product. Furthermore, the enzyme showed good potential for detoxifying ZEN during food processing.
ESTHER : Hu_2023_J.Agric.Food.Chem_71_2411
PubMedSearch : Hu_2023_J.Agric.Food.Chem_71_2411
PubMedID: 36701132

Title : Lipid mediators generated by the cytochrome P450-Epoxide hydrolase pathway - Fromel_2023_Adv.Pharmacol_97_327
Author(s) : Fromel T , Hu J , Fleming I
Ref : Advances in Pharmacology , 97 :327 , 2023
Abstract : The cytochrome P450 (CYP) soluble epoxide hydrolase (sEH) pathway generates a large number of biologically active epoxides and diols from a range of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs). While epoxides of arachidonic acid or epoxyeicosatrienoic acids are probably the best studied of these mediators, epoxides of linoleic acid as well as the fish oils; docosahexaenoic acid and eicosapentaenoic acid have also been attributed signaling actions. Cell and tissue levels of the PUFA epoxides are largely determined by the sEH and in many cases inflammation and chronic diseases, e.g., cardiovascular disease, diabetes and Alzheimer's disease, have been associated with increased sEH expression and the accelerated conversion of PUFA epoxides to their corresponding diols. In low concentrations, the diols act to influence stem and progenitor cells as well as brown adipose tissue but in high concentrations, they tend to have pro-inflammatory and cytotoxic effects that promote disease progression. This review outlines some of the actions to the PUFA epoxides and diols in physiology and pathophysiology as well as the beneficial effects associates with sEH inhibition.
ESTHER : Fromel_2023_Adv.Pharmacol_97_327
PubMedSearch : Fromel_2023_Adv.Pharmacol_97_327
PubMedID: 37236763

Title : Novel donepezil-chalcone-rivastigmine hybrids as potential multifunctional anti-Alzheimer's agents: Design, synthesis, in vitro biological evaluation, in vivo and in silico studies - Sang_2022_Bioorg.Chem_127_106007
Author(s) : Sang Z , Bai P , Ban Y , Wang K , Wu A , Mi J , Hu J , Xu R , Zhu G , Wang J , Zhang J , Wang C , Tan Z , Tang L
Ref : Bioorg Chem , 127 :106007 , 2022
Abstract : Alzheimer's disease (AD) is a chronic, progressive brain neurodegenerative disorder. Up to now, there is no effective drug to halt or reverse the progress of AD. Given the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy is considered as the promising therapy. Herein, a series of novel donepezil-chalone-rivastigmine hybrids was rationally designed and synthesized by fusing donepezil, chalone and rivastigmine. The in vitro bioactivity results displayed that compound 10c was a reversible huAChE (IC(50) = 0.87 microM) and huBuChE (IC(50) = 3.3 microM) inhibitor. It also presented significant anti-inflammation effects by suppressing the level of IL-6 and TNF-alpha production, and significantly inhibited self-mediated Abeta(1-42) aggregation (60.6%) and huAChE-mediated induced Abeta(1-40) aggregation (46.2%). In addition, 10c showed significant neuroprotective effect on Abeta(1-42)-induced PC12 cell injury and activated UPS pathway in HT22 cells to degrade tau and amyloid precursor protein (APP). Furthermore, compound 10c presented good stabilty in artificial gastrointestinal fluids and liver microsomes in vitro. The pharmacokinetic study showed that compound 10c was rapidly absorbed in rats and distributed in rat brain after intragastric administration. The PET-CT imaging demonstrated that [(11)C]10c could quickly enter the brain and washed out gradually in vivo. Further, compound 10c at a dose of 5 mg/kg improved scopolamine-induced memory impairment, deserving further investigations.
ESTHER : Sang_2022_Bioorg.Chem_127_106007
PubMedSearch : Sang_2022_Bioorg.Chem_127_106007
PubMedID: 35849893

Title : Activation of GPR55 attenuates cognitive impairment, oxidative stress, neuroinflammation, and synaptic dysfunction in a streptozotocin-induced Alzheimer's mouse model - Xiang_2022_Pharmacol.Biochem.Behav__173340
Author(s) : Xiang X , Wang X , Wu Y , Hu J , Li Y , Jin S , Wu X
Ref : Pharmacol Biochem Behav , :173340 , 2022
Abstract : Alzheimer's disease (AD) is a neurodegenerative disease characterized by cascading changes in cognition and behavior. G-protein-coupled receptor 55 (GPR55) has been used as a promising target for the treatment of diabetes, but its function in AD is unclear. The objective of this study was to investigate the neuroprotective effects of O-1602, a GPR55 agonist, on the streptozotocin (STZ)-induced AD mouse model. A single intracerebroventricular (i.c.v.) injection of STZ into the brains of mice significantly induced cognitive impairment. In contrast, O-1602 (2.0 or 4.0 microg/mouse, i.c.v.) can improve the cognitive dysfunction caused by STZ in the Morris water maze (MWM) and novel object recognition (NOR) tests. Importantly, O-1602 treatment reversed STZ-induced GPR55 down-regulation, reduced the activity of beta-secretase 1 (BACE1) and the level of Abeta(1-42), and abolished the up-regulation of acetylcholinesterase (AChE) activity in the hippocampus and frontal cortex. Besides, O-1602 markedly suppressed STZ-induced oxidative stress, characterized by decreased malondialdehyde (MDA) level, and increased the levels of glutathione (GSH), superoxide dismutases (SOD), and catalase (CAT), as well as attenuated neuroinflammation as indicated by decreased series of pro-inflammatory cytokines and microglia activation. O-1602 treatment also ameliorated synaptic dysfunction by promoting the up-regulation of PSD-95 protein in the STZ-treated mice. Our results suggest that O-1602 has potent neuroprotective effects against STZ-induced neurotoxicity. Meanwhile, these findings suggest that GPR55 might be a novel and promising target for the treatment of AD.
ESTHER : Xiang_2022_Pharmacol.Biochem.Behav__173340
PubMedSearch : Xiang_2022_Pharmacol.Biochem.Behav__173340
PubMedID: 35090841

Title : LC-MS\/MS assay of fluoropezil and its two major metabolites in human plasma: an application to pharmacokinetic studies - Guo_2022_Bioanalysis_14_817
Author(s) : Guo R , Hu J , Jing J , Liu Y , Li J , Zhou Y , Liu H , Zhou L , Chen X
Ref : Bioanalysis , 14 :817 , 2022
Abstract : Background: LC-MS/MS methods were developed for pharmacokinetic analysis and verified to measure fluoropezil, a new AchE inhibitor for Alzheimer's disease treatment, and its two primary metabolites (N-debenzyl fluoride fluoropezil [M1] and N-oxidized fluoropezil [M11]) in human plasma. Methods & results: Analytes were extracted from 50 microl plasma using protein precipitation and separated by HPLC using a bridged ethyl hybrid column and gradient elution procedure. Analytical detection was performed with a triple quadrupole mass spectrometer and electrospray ionization source in multiple reaction monitoring mode. The LC-MS/MS method was fully validated. The quantification linear ranges were 0.100-50.0 ng/ml (fluoropezil), 0.0500-25.0 ng/ml (M1) and 0.0500-25.0 ng/ml (M11). Conclusion: A sensitive, reliable LC-MS/MS method was established and used successfully to explore the pharmacokinetics of fluoropezil.
ESTHER : Guo_2022_Bioanalysis_14_817
PubMedSearch : Guo_2022_Bioanalysis_14_817
PubMedID: 35735138

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

Title : Cholinesterase is a Potential Biomarker with High Accuracy for the Nephrotic Syndrome Diagnosis in Minors - Zhu_2022_J.Multidiscip.Healthc_15_2375
Author(s) : Zhu X , Hu J
Ref : J Multidiscip Healthc , 15 :2375 , 2022
Abstract : BACKGROUND: Serum Cholinesterase (CHE) levels have been found to be elevated in individuals with nephrotic syndrome (NS); nevertheless, it is unknown whether CHE can serve as a biomarker for NS diagnosis and what its diagnostic relevance is for NS in minors. METHODS: In this study, 138 minors aged 1-17 years with NS were enrolled, including 101 patients with the first episode of NS and 37 patients with relapsing NS. One hundred and four minors suffering from nephritis and 109 healthy minors were included as control groups. The clinical information and laboratory data of all NS patients and the control group were obtained. Logistic regression, correlation analyses and receiver operator characteristic curve were used to examine the value of CHE for NS patients. RESULTS: Compared to patients diagnosed with nephritis and healthy minors in the control group, the serum CHE levels of total/first episode/relapsing NS patients were substantially higher (P < 0.05). The CHE was an independent risk predictor of total (adjusted odds ratio [OR] = 2.23, 95% confidence interval [CI]: 1.57-3.18)/first episode (adjusted OR = 4.02, 95% CI: 1.47-11.08)/relapsing (adjusted OR = 2.04, 95% CI: 1.42-2.93) NS, and was positively correlated with total cholesterol in total/first episode/relapsing NS patients, respectively. The optimal cutoff for total/first episode/relapsing NS all was 11 KU/L, but the diagnostic accuracy in first episode NS (area under the curve [AUC] = 0.96, 95% CI: 0.94-0.98) was higher than the total NS (AUC = 0.93, 95% CI: 0.91-0.96) and relapsing NS (AUC = 0.85, 95% CI: 0.78-0.92). CONCLUSION: CHE is a possible biomarker for NS and has good diagnostic accuracy for NS in minors, particularly for the first episode of NS in minors.
ESTHER : Zhu_2022_J.Multidiscip.Healthc_15_2375
PubMedSearch : Zhu_2022_J.Multidiscip.Healthc_15_2375
PubMedID: 36277118

Title : MicroRNA-199a-3p regulates proliferation and milk fat synthesis of ovine mammary epithelial cells by targeting VLDLR - Wang_2022_Front.Vet.Sci_9_948873
Author(s) : Wang J , Hao Z , Hu L , Qiao L , Luo Y , Hu J , Liu X , Li S , Zhao F , Shen J , Li M , Zhao Z
Ref : Front Vet Sci , 9 :948873 , 2022
Abstract : In our previous study, microRNA (miR)-199a-3p was found to be the most upregulated miRNA in mammary gland tissue during the non-lactation period compared with the peak-lactation period. However, there have been no reports describing the function of miR-199a-3p in ovine mammary epithelial cells (OMECs) and the biological mechanisms by which the miRNA affects cell proliferation and milk fat synthesis in sheep. In this study, the effect of miR-199a-3p on viability, proliferation, and milk fat synthesis of OMECs was investigated, and the target relationship of the miRNA with very low-density lipoprotein receptor (VLDLR) was also verified. Transfection with a miR-199a-3p mimic increased the viability of OMECs and the number of Edu-labeled positive OMECs. In contrast, a miR-199-3p inhibitor had the opposite effect with the miR-199a-3p mimic. The expression levels of three marker genes were also regulated by both the miR-199a-3p mimic and miR-199-3p inhibitor in OMECs. Together, these results suggest that miR-199a-3p promotes the viability and proliferation of OMECs. A dual luciferase assay confirmed that miR-199a-3p can target VLDLR by binding to the 3'-untranslated regions (3'UTR) of the gene. Further studies found a negative correlation in the expression of miR-199a-3p with VLDLR. The miR-199a-3p mimic decreased the content of triglycerides, as well as the expression levels of six milk fat synthesis marker genes in OMECs, namely, lipoprotein lipase gene (LPL), acetyl-CoA carboxylase alpha gene (ACACA), fatty acid binding protein 3 gene (FABP3), CD36, stearoyl-CoA desaturase gene (SCD), and fatty acid synthase gene (FASN). The inhibition of miR-199a-3p increased the level of triglycerides and the expression of LPL, ACACA, FABP3, SCD, and FASN in OMECs. These findings suggest that miR-199a-3p inhibited milk fat synthesis of OMECs. This is the first study to reveal the molecular mechanisms by which miR-199a-3p regulates the proliferation and milk fat synthesis of OMECs in sheep.
ESTHER : Wang_2022_Front.Vet.Sci_9_948873
PubMedSearch : Wang_2022_Front.Vet.Sci_9_948873
PubMedID: 35990270

Title : Effects of Flavonoid Supplementation on Nanomaterial-Induced Toxicity: A Meta-Analysis of Preclinical Animal Studies - Xie_2022_Front.Nutr_9_929343
Author(s) : Xie D , Hu J , Wu T , Xu W , Meng Q , Cao K , Luo X
Ref : Front Nutr , 9 :929343 , 2022
Abstract : BACKGROUND: Nanomaterials, widely applied in various fields, are reported to have toxic effects on human beings; thus, preventive or therapeutic measures are urgently needed. Given the anti-inflammatory and antioxidant activities, supplementation with flavonoids that are abundant in the human diet has been suggested as a potential strategy to protect against nanomaterial-induced toxicities. However, the beneficial effects of flavonoids remain inconclusive. In the present study, we performed a meta-analysis to comprehensively explore the roles and mechanisms of flavonoids for animals intoxicated with nanomaterials. METHODS: A systematic literature search in PubMed, EMBASE, and Cochrane Library databases was performed up to April 2022. STATA 15.0 software was used for meta-analyses. RESULTS: A total of 26 studies were identified. The results showed that flavonoid supplementation could significantly increase the levels of antioxidative enzymes (superoxide dismutase, catalase, glutathione, glutathione peroxidase, and glutathione-S-transferase), reduce the production of oxidative agents (malonaldehyde) and pro-inflammatory mediators (tumor necrosis factor-alpha, interleukin-6, IL-1beta, C-reactive protein, immunoglobulin G, nitric oxide, vascular endothelial growth factor, and myeloperoxidase), and alleviate cell apoptosis (manifested by decreases in the mRNA expression levels of pro-apoptotic factors, such as caspase-3, Fas cell surface death receptor, and Bax, and increases in the mRNA expression levels of Bcl2), DNA damage (reductions in tail length and tail DNA%), and nanomaterial-induced injuries of the liver (reduced alanine aminotransferase and aspartate aminotransferase activities), kidney (reduced urea, blood urea nitrogen, creatinine, and uric acid concentration), testis (increased testosterone, sperm motility, 17beta-hydroxysteroid dehydrogenase type, and reduced sperm abnormalities), and brain (enhanced acetylcholinesterase activities). Most of the results were not changed by subgroup analyses. CONCLUSION: Our findings suggest that appropriate supplementation of flavonoids may be effective to prevent the occupational detriments resulting from nanomaterial exposure.
ESTHER : Xie_2022_Front.Nutr_9_929343
PubMedSearch : Xie_2022_Front.Nutr_9_929343
PubMedID: 35774549

Title : Design, synthesis, and evaluation of novel O-alkyl ferulamide derivatives as multifunctional ligands for treating Alzheimer's disease - Zhu_2022_J.Enzyme.Inhib.Med.Chem_37_1375
Author(s) : Zhu G , Bai P , Wang K , Mi J , Yang J , Hu J , Ban Y , Xu R , Chen R , Wang C , Tang L , Sang Z
Ref : J Enzyme Inhib Med Chem , 37 :1375 , 2022
Abstract : Herein, a series of novel O-alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities in vitro showed that compounds 5a, 5d, 5e, 5f, and 5h indicated significantly selective MAO-B inhibitory potency (IC(50) = 0.32, 0.56, 0.54, 0.73, and 0.86 microM, respectively) and moderate antioxidant activity. Moreover, compounds 5a, 5d, 5e, 5f, and 5h showed potent anti-inflammatory properties, remarkable effects on self-induced Abeta(1-42) aggregation, and potent neuroprotective effect on Abeta(1-42)-induced PC12 cell injury. Furthermore, compounds 5a, 5d, 5e, 5f, and 5h presented good blood-brain barrier permeation in vitro and drug-like properties. More interesting, the PET/CT images with [(11)C]5f demonstrated that [(11)C]5f could penetrate the BBB with a high brain uptake and exhibited good brain clearance kinetic property. Therefore, compound 5f would be a promising multi-functional agent for the treatment of AD.
ESTHER : Zhu_2022_J.Enzyme.Inhib.Med.Chem_37_1375
PubMedSearch : Zhu_2022_J.Enzyme.Inhib.Med.Chem_37_1375
PubMedID: 35549612

Title : Biodegradation of polyester polyurethane by the marine fungus Cladosporium halotolerans 6UPA1 - Zhang_2022_J.Hazard.Mater_437_129406
Author(s) : Zhang K , Hu J , Yang S , Xu W , Wang Z , Zhuang P , Grossart HP , Luo Z
Ref : J Hazard Mater , 437 :129406 , 2022
Abstract : Lack of degradability and the accumulation of polymeric wastes increase the risk for the health of the environment. Recently, recycling of polymeric waste materials becomes increasingly important as raw materials for polymer synthesis are in short supply due to the rise in price and supply chain disruptions. As an important polymer, polyurethane (PU) is widely used in modern life, therefore, PU biodegradation is desirable to avoid its accumulation in the environment. In this study, we isolated a fungal strain Cladosporium halotolerans from the deep sea which can grow in mineral medium with a polyester PU (Impranil DLN) as a sole carbon source. Further, we demonstrate that it can degrade up to 80% of Impranil PU after 3 days of incubation at 28 degC by breaking the carbonyl groups (1732 cm(-1)) and C-N-H bonds (1532 cm(-1) and 1247 cm(-1)) as confirmed by Fourier-transform infrared (FTIR) spectroscopy analysis. Gas chromatography-mass spectrometry (GC-MS) analysis revealed polyols and alkanes as PU degradation intermediates, indicating the hydrolysis of ester and urethane bonds. Esterase and urease activities were detected in 7 days-old cultures with PU as a carbon source. Transcriptome analysis showed a number of extracellular protein genes coding for enzymes such as cutinase, lipase, peroxidase and hydrophobic surface binding proteins A (HsbA) were expressed when cultivated on Impranil PU. The yeast two-hybrid assay revealed that the hydrophobic surface binding protein ChHsbA1 directly interacts with inducible esterases, ChLip1 (lipase) and ChCut1 (cutinase). Further, the KEGG pathway for "fatty acid degradation" was significantly enriched in Impranil PU inducible genes, indicating that the fungus may use the degradation intermediates to generate energy via this pathway. Taken together, our data indicates secretion of both esterase and hydrophobic surface binding proteins by C. halotolerans plays an important role in Impranil PU absorption and subsequent degradation. Our study provides a mechanistic insight into Impranil PU biodegradation by deep sea fungi and provides the basis for future development of biotechnological PU recycling.
ESTHER : Zhang_2022_J.Hazard.Mater_437_129406
PubMedSearch : Zhang_2022_J.Hazard.Mater_437_129406
PubMedID: 35753302

Title : Abnormal exocrine-endocrine cell cross-talk promotes beta-cell dysfunction and loss in MODY8 - Kahraman_2022_Nat.Metab_4_76
Author(s) : Kahraman S , Dirice E , Basile G , Diegisser D , Alam J , Johansson BB , Gupta MK , Hu J , Huang L , Soh CL , Huangfu D , Muthuswamy SK , Raeder H , Molven A , Kulkarni RN
Ref : Nat Metab , 4 :76 , 2022
Abstract : MODY8 (maturity-onset diabetes of the young, type 8) is a dominantly inherited monogenic form of diabetes associated with mutations in the carboxyl ester lipase (CEL) gene expressed by pancreatic acinar cells. MODY8 patients develop childhood-onset exocrine pancreas dysfunction followed by diabetes during adulthood. However, it is unclear how CEL mutations cause diabetes. In the present study, we report the transfer of CEL proteins from acinar cells to beta-cells as a form of cross-talk between exocrine and endocrine cells. Human beta-cells show a relatively higher propensity for internalizing the mutant versus the wild-type CEL protein. After internalization, the mutant protein forms stable intracellular aggregates leading to beta-cell secretory dysfunction. Analysis of pancreas sections from a MODY8 patient reveals the presence of CEL protein in the few extant beta-cells. The present study provides compelling evidence for the mechanism by which a mutant gene expressed specifically in acinar cells promotes dysfunction and loss of beta-cells to cause diabetes.
ESTHER : Kahraman_2022_Nat.Metab_4_76
PubMedSearch : Kahraman_2022_Nat.Metab_4_76
PubMedID: 35058633
Gene_locus related to this paper: human-CEL

Title : The Enhancement Effect of Acetylcholine and Pyridostigmine on Bone-Tendon Interface Healing in a Murine Rotator Cuff Model - Wang_2021_Am.J.Sports.Med__363546520988680
Author(s) : Wang Z , Chen Y , Xiao H , Li S , Zhang T , Hu J , Lu H , Xie H
Ref : Am J Sports Med , :363546520988680 , 2021
Abstract : BACKGROUND: How to improve rotator cuff healing remains a challenge. Little is known about the effect of the parasympathetic transmitter acetylcholine (ACh) and the acetylcholinesterase inhibitor pyridostigmine (PYR), both of which have anti-inflammatory properties, in the healing process of rotator cuff injury. HYPOTHESIS: ACh and PYR could enhance bone-tendon interface healing in a murine model of rotator cuff repair. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 160 C57BL/6 mice underwent unilateral rotator cuff repair surgery. Fibrin gel (FG) was used as a drug carrier. The mice were randomly assigned to 4 groups with 40 mice per group: FG group (received FG alone), 10(-5) M ACh group (received FG containing 10(-5) M ACh), 10(-6) M ACh group (received FG containing 10(-6) M ACh), and PYR group (received FG containing 25 microg of PYR). Ten mice in each group were euthanized at 2, 4, 8, and 12 weeks postoperatively. Histologic, immunohistochemical, and biomechanical evaluations were performed for analysis. RESULTS: Histologically, fibrocartilage-like tissue was shown at the repaired site. The proteoglycan content of the 10(-5) M ACh group was significantly increased compared with the FG group at 4 weeks. M2 macrophages were identified at the repaired site for all groups at 2 and 4 weeks. At 8 weeks, M2 macrophages withdrew back to the tendon in the FG group, but a number of M2 macrophages were retained at the repaired sites in the ACh and PYR groups. Biomechanically, failure load and stiffness of the ACh and PYR groups were significantly higher than those of the FG group at 4 weeks. The stiffness of the ACh and PYR groups was significantly increased compared with the FG group at 8 weeks (P < .001 for all). At 12 weeks, most of the healing properties of the ACh and PYR groups were not significantly different compared with the FG group. CONCLUSION: ACh and PYR enhanced the early stage of bone-tendon insertion healing after rotator cuff repair. CLINICAL RELEVANCE: These findings imply that ACh and PYR could serve as potential therapeutic strategies for rotator cuff healing.
ESTHER : Wang_2021_Am.J.Sports.Med__363546520988680
PubMedSearch : Wang_2021_Am.J.Sports.Med__363546520988680
PubMedID: 33592162

Title : Inhibitory Effect of Lactococcus lactis subsp. lactis HFY14 on Diphenoxylate-Induced Constipation in Mice by Regulating the VIP-cAMP-PKA-AQP3 Signaling Pathway - Tan_2021_Drug.Des.Devel.Ther_15_1971
Author(s) : Tan Q , Hu J , Zhou Y , Wan Y , Zhang C , Liu X , Long X , Tan F , Zhao X
Ref : Drug Des Devel Ther , 15 :1971 , 2021
Abstract : AIM: The naturally fermented yak yogurt of pastoralists in the Tibetan Plateau, China, because of its unique geographical environment and the unique lifestyle of Tibetan pastoralists, is very different from other kinds of sour milk, and the microorganisms it contains are special. Lactococcus lactis subsp. lactis HFY14 (LLSL-HFY14) is a new lactic acid bacterium isolated from naturally fermented yak yogurt. The purpose of this study was to study the inhibitory effect of the bacterium on constipation. METHODS: Constipation was induced in ICR mice with diphenoxylate, and the constipated mice were treated with LLSL-HFY14. The weight and feces of the mice were visually detected. Colonic tissues were observed on hematoxylin and eosin-stained sections. Serum indices were detected with kits. mRNA expression in the colon was determined by quantitative polymerase chain reaction assay. RESULTS: Constipation caused weight loss, the number of defecation granules, defecation weight, fecal water content decreased, and the first black stool excretion time increased. LLSL-HFY14 alleviated these symptoms, and the effects were similar to those of lactulose (drug). The pathological examination revealed that constipation caused pathological changes in the colon, and LLSL-HFY14 effectively alleviated the disease. LLSL-HFY14 increased serum levels of motilin, gastrin, endothelin, substance P, acetylcholinesterase, and vasoactive intestinal peptide (VIP) and decreased serum levels of somatostatin in constipated mice. In addition, LLSL-HFY14 upregulated VIP, cAMP, protein kinase A, and aquaporin 3 expression in colonic tissues of constipated mice in a dose-dependent manner. CONCLUSION: LLSL-HFY14 inhibited constipation, similar to lactulose, and has the potential to become a biological agent.
ESTHER : Tan_2021_Drug.Des.Devel.Ther_15_1971
PubMedSearch : Tan_2021_Drug.Des.Devel.Ther_15_1971
PubMedID: 34007157

Title : Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1 - Zhou_2021_Clin.Transl.Med_11_e449
Author(s) : Zhou L , Zhang C , Yang X , Liu L , Hu J , Hou Y , Tao H , Sugimura H , Chen Z , Wang L , Chen K
Ref : Clin Transl Med , 11 :e449 , 2021
Abstract : BACKGROUND: Androgen deprivation therapy (ADT) is the main clinical treatment for patients with advanced prostate cancer (PCa). However, PCa eventually progresses to castration-resistant prostate cancer (CRPC), largely because of androgen receptor variation and increased intratumoral androgen synthesis. Several studies have reported that one abnormal lipid accumulation is significantly related to the development of PCa. Melatonin (MLT) is a functionally pleiotropic indoleamine molecule and a key regulator of energy metabolism. The aim of our study is finding the links between CRPC and MLT and providing the basis for MLT treatment for CRPC. METHODS: We used animal CRPC models with a circadian rhythm disorder, and PCa cell lines to assess the role of melatonin in PCa. RESULTS: We demonstrated that MLT treatment inhibited tumor growth and reversed enzalutamide resistance in animal CRPC models with a circadian rhythm disorder. A systematic review and meta-analysis demonstrated that MLT is positively associated with an increased risk of developing advanced PCa. Restoration of carboxylesterase 1 (CES1) expression by MLT treatment significantly reduced lipid droplet (LD) accumulation, thereby inducing apoptosis by increasing endoplasmic reticulum stress, reducing de novo intratumoral androgen synthesis, repressing CRPC progression and reversing the resistance to new endocrine therapy. Mechanistic investigations demonstrated that MLT regulates the epigenetic modification of CES1. Ces1-knockout (Ces(-/-) ) mice verified the important role of endogenous Ces1 in PCa. CONCLUSIONS: Our findings provide novel preclinical and clinical information about the role of melatonin in advanced PCa and characterize the importance of enzalutamide combined with MLT administration as a therapy for advanced PCa.
ESTHER : Zhou_2021_Clin.Transl.Med_11_e449
PubMedSearch : Zhou_2021_Clin.Transl.Med_11_e449
PubMedID: 34185414
Gene_locus related to this paper: human-CES1

Title : Changes of embryonic development, locomotor activity, and metabolomics in zebrafish co-exposed to chlorpyrifos and deltamethrin - Hu_2021_J.Appl.Toxicol_41_1345
Author(s) : Hu Y , Hu J , Li W , Gao Y , Tian Y
Ref : J Appl Toxicol , 41 :1345 , 2021
Abstract : Organophosphates (OPs) and pyrethroids (PYRs) are extensively used pesticides and often occur in the form of mixture, whereas little was known about their joint toxicities. We aim to investigate the individual and joint effects of OPs and PYRs exposure on zebrafish embryo by employing chlorpyrifos (CPF) and deltamethrin (DM) as representatives. Zebrafish embryos at 2 hours post fertilization (hpf) were exposed to CPF (4.80, 39.06, and 78.13 microg/L), DM exposure (0.06, 1.60, and 3.19 microg/L), and CPF + DM (4.80 + 0.06, 39.06 + 1.60, and 78.13 + 3.19 microg/L) until 144 hpf. Embryonic development, locomotor activity, and metabolomic changes were recorded and examined. Results displayed that individual exposure to CPF and DM significantly increased the mortality and malformation rate of zebrafish embryos, but decreased hatching rate was only found in CPF + DM co-exposure groups (p < .05). Meanwhile, individual CPF exposure had no detrimental effect on locomotor activity, high dose of individual CPF exposure decreased the swimming speed but had adaptability to the conversion from dark to light, whereas high dose of CPF + DM co-exposure exhibited not only significant decline in swimming speed but also no adaptability to the repeated stimulations, suggesting deficit in learning and memory function. In metabolomic analysis, individual CPF exposure mainly influenced the metabolism of glycerophospholipids and amino acids, individual DM exposure mainly influenced glycerophospholipids, and CPF + DM co-exposure mainly influenced glycerophospholipids and amino acids. Taken together, our findings suggested the embryonic toxicities and neurobehavioral changes caused by CPF and/or DM exposure. The disorder metabolomics of glycerophospholipids and amino acids might be involved in the underlying mechanism of those toxicities.
ESTHER : Hu_2021_J.Appl.Toxicol_41_1345
PubMedSearch : Hu_2021_J.Appl.Toxicol_41_1345
PubMedID: 33247449

Title : Crosstalk of cholinergic pathway on thyroid disrupting effects of the insecticide chlorpyrifos in zebrafish (Danio rerio) - Qiao_2020_Sci.Total.Environ__143769
Author(s) : Qiao K , Hu T , Jiang Y , Huang J , Hu J , Gui W , Ye Q , Li S , Zhu G
Ref : Sci Total Environ , :143769 , 2020
Abstract : Chlorpyrifos is a widely used organophosphate insecticide and ubiquitously detected in the environment. However, little attention has been paid to its endocrine disrupting effect to non-target organisms. In the present study, zebrafish was exposed to 13 and 65 g/L of chlorpyrifos for 7 and 10 days to determine the induced neurotoxicity and the alteration of thyroid metabolism. The 120 h LC(50) and LC(10) of chlorpyrifos was estimated as 1.35 mg/L and 0.62 mg/L based on the acute embryo toxicity assay, respectively. The acetylcholinesterase (AChE) inhibitory was detected by 13 g/L chlorpyrifos and could be reversed by the co-exposure of 100 and 1000 g/L anticholinergic agent atropine. For thyroid hormone level, 13 and 65 g/L of chlorpyrifos induced increased free T(3) levels in 10 dpf (days post-fertilization). The expression of thyroid related genes in 7 and 10 dpf exposed zebrafish were measured by the quantitative Real-Time PCR (qRT-PCR) assay. The mRNA expression of tshba, thrb, crhb, ttr, tpo, ugt1ab and slc5a5 had significant change. However, the alterations of thyroid hormone and mRNA expression could be partly rescued by the addition of atropine. The molecular docking of chlorpyrifos and T(3) to the thyroid receptor beta in zebrafish using homology modelling and CDOCKER procedures shown weaker binding ability of chlorpyrifos compared to T(3). Therefore, we concluded that the disturbance of thyroid signaling in zebrafish might arise from the developmental neurotoxicity induced by chlorpyrifos.
ESTHER : Qiao_2020_Sci.Total.Environ__143769
PubMedSearch : Qiao_2020_Sci.Total.Environ__143769
PubMedID: 33221011
Gene_locus related to this paper: danre-ACHE

Title : Protective effect of Soluble Epoxide Hydrolase Inhibition in Retinal Vasculopathy associated with Polycystic Kidney Disease - Lin_2020_Theranostics_10_7857
Author(s) : Lin J , Hu J , Schlotterer A , Wang J , Kolibabka M , Awwad K , Dietrich N , Breitschopf K , Wohlfart P , Kannt A , Lorenz K , Feng Y , Popp R , Hoffmann S , Fleming I , Hammes HP
Ref : Theranostics , 10 :7857 , 2020
Abstract : Rationale: Vasoregression secondary to glial activation develops in various retinal diseases, including retinal degeneration and diabetic retinopathy. Photoreceptor degeneration and subsequent retinal vasoregression, characterized by pericyte loss and acellular capillary formation in the absence diabetes, are also seen in transgenic rats expressing the polycystic kidney disease (PKD) gene. Activated Muller glia contributes to retinal vasodegeneration, at least in part via the expression of the soluble epoxide hydrolase (sEH). Given that an increase in sEH expression triggered vascular destabilization in diabetes, and that vasoregression is similar in diabetic mice and PKD rats, the aim of the present study was to determine whether sEH inhibition could prevent retinal vasoregression in the PKD rat. Methods: One-month old male homozygous transgenic PKD rats were randomly allocated to receive vehicle or a sEH inhibitor (sEH-I; Sar5399, 30 mg/kg) for four weeks. Wild-type Sprague-Dawley (SD) littermates received vehicle as controls. Retinal sEH expression and activity were measured by Western blotting and LC-MS, and vasoregression was quantified in retinal digestion preparations. Microglial activation and immune response cytokines were assessed by immunofluorescence and quantitative PCR, respectively. 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP) mediated Notch signaling, microglial activation and migration were assessed in vivo and in vitro. Results: This study demonstrates that sEH expression and activity were increased in PKD retinae, which led to elevated production of 19,20-DHDP and the depression of Notch signaling. The latter changes elicited pericyte loss and the recruitment of CD11b(+)/CD74(+) microglia to the perivascular region. Microglial activation increased the expression of immune-response cytokines, and reduced levels of Notch3 and delta-like ligand 4 (Dll4). Treatment with Sar5399 decreased 19,20-DHDP generation and increased Notch3 expression. Sar5399 also prevented vasoregression by reducing pericyte loss and suppressed microglial activation as well as the expression of immune-response cytokines. Mechanistically, the activation of Notch signaling by Dll4 maintained a quiescent microglial cell phenotype, i.e. reduced both the surface presentation of CD74 and microglial migration. In contrast, in retinal explants, 19,20-DHDP and Notch inhibition both promoted CD74 expression and reversed the Dll4-induced decrease in migration. Conclusions: Our data indicate that 19,20-DHDP-induced alterations in Notch-signaling result in microglia activation and pericyte loss and contribute to retinal vasoregression in polycystic kidney disease. Moreover, sEH inhibition can ameliorate vasoregression through reduced activity of inflammatory microglia. sEH inhibition is thus an attractive new therapeutic approach to prevent retinal vasoregression.
ESTHER : Lin_2020_Theranostics_10_7857
PubMedSearch : Lin_2020_Theranostics_10_7857
PubMedID: 32685025

Title : Chemical composition and larvicidal activity against Aedes mosquitoes of essential oils from Arisaema fargesii - Huang_2020_Pest.Manag.Sci_76_534
Author(s) : Huang Y , Lin M , Jia M , Hu J , Zhu L
Ref : Pest Manag Sci , 76 :534 , 2020
Abstract : BACKGROUND: Dengue fever is caused by the spread of dengue virus by Aedes mosquito vectors. Currently, the most effective way to control dengue is by preventing mosquitoes from spreading the disease. Arisaema fargesii is a Chinese herbal medicine commonly used to repel mosquitoes. In our laboratory, anti-mosquito chemical components were extracted from A. fargesii, and the effects of these substances on mosquito larvae were examined. RESULTS: In total, 48 compounds corresponding to 98.79% of the total oil were identified and the major compounds identified were linalool (12.38%), carvacrol (8.27%), eugenol (5.21%), and beta-selinene (5.36%). Essential oil had larvicidal activity against Ae. aegypti and Ae. albopictus with LC50 values of 40.49 mg/L, 47.01 mg/L, respectively. The LC50 values of carvacrol, eugenol, linalool and beta-selinene were 32.78, 56.34, 70.56, 136.03 mg/L against Ae. aegypti larvae, and 39.08, 52.07, 82.34, 151.74 mg/L, respectively, against Ae. albopictus larvae. Biochemical assays of Aedes larvae showed that the activities of acetylcholinesterase (AChE), monooxygenases (MO), glutathione-S-transferase (GST), p-Nitrophenyl acetate (p-NPA) esterase, alpha-esterase and beta-esterase were significantly affected by carvacrol. Essential oil induced the detoxification mechanism for the action of GST and MO. CONCLUSION: The result indicates that essential oil of A. fargesii and its isolated constituent have good inhibitory effects on the defense enzymes of Aedes mosquito larvae. A. fargesii essential oil can be used to control Aedes mosquito larvae to prevent the spread of dengue fever. (c) 2019 Society of Chemical Industry.
ESTHER : Huang_2020_Pest.Manag.Sci_76_534
PubMedSearch : Huang_2020_Pest.Manag.Sci_76_534
PubMedID: 31270930

Title : Soluble epoxide hydrolase inhibitors improve angiogenic function of endothelial progenitor cells via ERK\/p38-mediated miR-126 upregulation in myocardial infarction mice after exercise - Gui_2020_Exp.Cell.Res__112360
Author(s) : Gui Y , Chen J , Hu J , Liao C , Ouyang M , Deng L , Yang J , Xu D
Ref : Experimental Cell Research , :112360 , 2020
Abstract : It is well established that exercise could protect against myocardial infarction (MI). Previously, we found that epoxyeicosatrienoic acids (EETs) could be induced by exercise and has been found to protect against MI via promoting angiogenic function of endothelial progenitor cells (EPCs). However, the underling mechanism of EETs in promoting EPC functions is unclear. C57BL/6 mice were fed with a novel soluble epoxide hydrolase inhibitor (sEHi), TPPU, to increase EET levels, for 1 week before undergoing MI surgery. Mice were then subjected to exercise training for 4 weeks. Bone marrow-derived EPCs were isolated and cultured in vitro. Exercise upregulated miR-126 expression but downregulated the protein levels of its target gene, Spred1, in EPCs from MI mice. TPPU further enhanced the effects of exercise on EPCs. Spred1 overexpression abolished the protective effects of TPPU on EPC functions. Downregulation of miR-126 by antagomiR-126 impaired the inhibitor effects of TPPU on Spred1 mRNA and protein expression. Additionally, TPPU upregulated miR-126 is partially mediated through ERK/p38 MAPK pathway. This study showed that sEHi promoted miR-126 expression, which might be related to the beneficial effect of sEHi on EPC functions in MI mice under exercise conditions, by increasing ERK and p38 MAPK phosphorylation and inhibiting Spred1.
ESTHER : Gui_2020_Exp.Cell.Res__112360
PubMedSearch : Gui_2020_Exp.Cell.Res__112360
PubMedID: 33188851

Title : Improving the production of AHL lactonase AiiO-AIO6 from Ochrobactrum sp. M231 in intracellular protease-deficient Bacillus subtilis - Xia_2020_AMB.Express_10_138
Author(s) : Xia R , Yang Y , Pan X , Gao C , Yao Y , Liu X , Teame T , Zhang F , Hu J , Ran C , Zhang Z , Liu-Clarke J , Zhou Z
Ref : AMB Express , 10 :138 , 2020
Abstract : Quorum quenching (QQ) blocks bacterial cell-to-cell communication (i.e., quorum sensing), and is a promising antipathogenic strategy to control bacterial infection via inhibition of virulence factor expression and biofilm formation. QQ enzyme AiiO-AIO6 from Ochrobactrum sp. M231 has several excellent properties and shows biotherapeutic potential against important bacterial pathogens of aquatic species. AiiO-AIO6 can be secretory expressed in Bacillus subtilis via a non-classical secretion pathway. To improve AiiO-AIO6 production, four intracellular protease-deletion mutants of B. subtilis 1A751 were constructed by individually knocking out the intracellular protease-encoding genes (tepA, ymfH, yrrN and ywpE). The AiiO-AIO6 expression plasmid pWB-AIO6BS was transformed into the B. subtilis 1A751 and its four intracellular protease-deletion derivatives. Results showed that all recombinant intracellular protease-deletion derivatives (BStepA, BSymfH, BSyrrN and BSywpE) had a positive impact on AiiO-AIO6 production. The highest amount of AiiO-AIO6 extracellular production of BSywpE in shake flask reached 1416.47 U/mL/OD(600), which was about 121% higher than that of the wild-type strain. Furthermore, LC-MS/MS analysis of the degrading products of 3-oxo-C8-HSL by purification of AiiO-AIO6 indicated that AiiO-AIO6 was an AHL-lactonase which hydrolyzes the lactone ring of AHLs. Phylogenetic analysis showed that AiiO-AIO6 was classified as a member of the alpha/beta hydrolase family with a conserved "nucleophile-acid-histidine" catalytic triad. In summary, this study showed that intracellular proteases were responsible for the reduced yields of heterologous proteins and provided an efficient strategy to enhance the extracellular production of AHL lactonase AiiO-AIO6.
ESTHER : Xia_2020_AMB.Express_10_138
PubMedSearch : Xia_2020_AMB.Express_10_138
PubMedID: 32757095
Gene_locus related to this paper: ocha4-a6wx49

Title : The immunotoxicity and neurobehavioral toxicity of zebrafish induced by famoxadone-cymoxanil - Cheng_2020_Chemosphere_247_125870
Author(s) : Cheng B , Zhang H , Hu J , Peng Y , Yang J , Liao X , Liu F , Guo J , Hu C , Lu H
Ref : Chemosphere , 247 :125870 , 2020
Abstract : As a new protective and therapeutic fungicide, studies on famoxadone-cymoxanil are rare, and its toxicity to aquatic organisms has not been reported. In the present study, zabrafish embryos were exposed to several concentrations of famoxadone-cymoxanil at 10 hpf. Then, the changes of their shape, heart rate, development and function of innate and adaptive immune cells, oxidative stress, apoptosis, the expression of apoptosis-related genes and immune-related genes, the locomotor behavior were observed and detected in acute toxicity of famoxadone-cymoxanil. Our studies showed that, after exposure to famoxadone-cymoxanil, zebrafish embryos had decreased heart rate, shortened body length, swollen yolk sac. Secondly, the number of innate and adaptive immune cells was significantly reduced; and neutrophil migration and retention at the injury area were inhibited, indicating the developmental toxicity and immunotoxicity of famoxadone-cymoxanil on the zebrafish. We also found that the oxidative stress related indicators of embryos were changed significantly, and apoptosis were substantially increased. Further investigation of changes of some key genes in TLR signaling including TLR4, MYD88 and NF-kappaB p65 revealed that the mRNA expression of these genes was up-regulated. Meanwhile, the mRNA expression of some proinflammatory cytokines such as TNF-alpha, IFN-gamma, IL6 and IL-1beta was also up-regulated. In addition, the activity, the total distance, time and average speed were decreased along with the increase of exposure concentration. The absolute turn angle, sinuosity and the enzymatic activity of acetylcholinesterase (AChE) were also increased. These results suggested that famoxadone-cymoxanil can induce developmental toxicity, immunotoxicity and neurobehavioral toxicity in zebrafish larvae.
ESTHER : Cheng_2020_Chemosphere_247_125870
PubMedSearch : Cheng_2020_Chemosphere_247_125870
PubMedID: 31931321

Title : Cytotoxic lycodine alkaloids from the aerial parts of Lycopodiastrum casuarinoides - Zhang_2020_J.Asian.Nat.Prod.Res_22_217
Author(s) : Zhang HB , Hu J , Li JX , Hao SH
Ref : J Asian Nat Prod Res , 22 :217 , 2020
Abstract : A phytochemical investigation on the 75% EtOH extract of the aerial parts of Lycopodiastrum casuarinoides resulted in the isolation of three new lycodine alkaloids, 16-hydroxy-9-oxo-lycocasuarinine D (1), 6alpha-hydroxy-16-dehydroxy-lycocasuarinine A (2), and 6alpha,16-dihydroxy-lycocasuarinine B (3). Structural elucidation of all the compounds was performed by spectral methods such as 1D- and 2D-NMR, infrared, ultraviolet, and HR-ESI-MS. The isolated alkaloids were tested in vitro for cytotoxic potential against six lung cancer cell lines. Consequently, alkaloid 1 exhibited cytotoxicity against all the tested tumor cell lines with IC(50) values less than 20 microM.[Formula: see text].
ESTHER : Zhang_2020_J.Asian.Nat.Prod.Res_22_217
PubMedSearch : Zhang_2020_J.Asian.Nat.Prod.Res_22_217
PubMedID: 30740993

Title : Genomics-Driven Discovery of Phytotoxic Cytochalasans Involved in the Virulence of the Wheat Pathogen Parastagonospora nodorum - Li_2020_ACS.Chem.Biol_15_226
Author(s) : Li H , Wei H , Hu J , Lacey E , Sobolev AN , Stubbs KA , Solomon PS , Chooi YH
Ref : ACS Chemical Biology , 15 :226 , 2020
Abstract : The etiology of fungal pathogenesis of grains is critical to global food security. The large number of orphan biosynthetic gene clusters uncovered in fungal plant pathogen genome sequencing projects suggests that we have a significant knowledge gap about the secondary metabolite repertoires of these pathogens and their roles in plant pathogenesis. Cytochalasans are a family of natural products of significant interest due to their ability to bind to actin and interfere with cellular processes that involved actin polymerization; however, our understanding of their biosynthesis and biological roles remains incomplete. Here, we identified a putative polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) gene cluster (phm) that was upregulated in the pathogen Parastagonospora nodorum during its infection on wheat. Overexpression of the transcription factor gene phmR encoded in the phm gene cluster resulted in the production of two leucine-derived cytochalasans, phomacins D and E (1 and 2, respectively), and an acetonyl adduct phomacin F. Heterologous expression of the PKS-NRPS gene phmA and the trans-enoyl reductase (ER) gene phmE in Aspergillus nidulans resulted in the production of a novel 2-pyrrolidone precursor prephomacin. Reverse genetics and wheat seedling infection assays showed that deltaphmA mutants exhibited significantly reduced virulence compared to the wild type. We further demonstrated that both 1 and 2 showed potent actin polymerization-inhibitory activities and exhibited potentially monocot-specific antigerminative activities. The findings from this study have advanced our knowledge based on the biosynthesis and biological roles of cytochalasans, the latter of which could have significant implications for our understanding of the molecular mechanisms of fungus-plant interactions.
ESTHER : Li_2020_ACS.Chem.Biol_15_226
PubMedSearch : Li_2020_ACS.Chem.Biol_15_226
PubMedID: 31815421
Gene_locus related to this paper: phano-phmG

Title : Correlation analysis between CARMEN variants and alcohol-induced osteonecrosis of the femoral head in the Chinese population - Guo_2020_BMC.Musculoskelet.Disord_21_547
Author(s) : Guo Y , Cao Y , Gong S , Zhang S , Hou F , Zhang X , Hu J , Yang Z , Yi J , Luo D , Chen X , Song J
Ref : BMC Musculoskelet Disord , 21 :547 , 2020
Abstract : BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a complicated disease associated with trauma, hormone abuse and excessive alcohol consumption. Polymorphisms of long non-coding RNAs have been also linked with the development of ONFH. Our research aimed to explore the relationship between CARMEN (Cardiac Mesoderm Enhancer-Associated Non-Coding RNA) variants and ONFH risk. METHODS: Our study used Agena MassARRAY Assay to genotype 6 selected single nucleotide polymorphisms (SNPs) in 731 participants (308 alcohol-induced ONFH patients and 423 controls). We used odds ratios (ORs) and 95% confidence intervals (CIs) to calculate the effect of gene polymorphisms on the occurrence of alcohol-induced ONFH by logistic regression analysis and haplotype analysis. RESULTS: Our overall analysis illustrated that rs13177623 and rs12654195 had an association with a reduced risk of ONFH after adjustment for age and gender. We also found that rs13177623, rs12654195 and rs11168100 were associated with a decreased susceptibility to alcohol-induced ONFH in people <=45 years. In addition, the necrotic sites stratification analysis showed that rs12654195 was only found to be related to alcohol-induced ONFH risk in the recessive model. In patients with different clinical stages, rs353300 was observed to be associated with a higher incidence of ONFH. Individuals with different genotypes of rs13177623, rs12654195 and rs11168100 had significantly different clinical parameters (cholinesterase, globulin, percentage of neutrophils and the absolute value of lymphocytes). CONCLUSIONS: Our data provided new light on the association between CARMEN polymorphisms and alcohol-induced ONFH risk in the Chinese Han population.
ESTHER : Guo_2020_BMC.Musculoskelet.Disord_21_547
PubMedSearch : Guo_2020_BMC.Musculoskelet.Disord_21_547
PubMedID: 32799824

Title : The botanical origin and antioxidant, anti-BACE1 and antiproliferative properties of bee pollen from different regions of South Korea - Zou_2020_BMC.Complement.Med.Ther_20_236
Author(s) : Zou Y , Hu J , Huang W , Zhu L , Shao M , Dordoe C , Ahn YJ , Wang D , Zhao Y , Xiong Y , Wang X
Ref : BMC Complement Med Ther , 20 :236 , 2020
Abstract : BACKGROUND: Bee pollen (BP) has been used as a traditional medicine and food diet additive due to its nutritional and biological properties. The potential biological properties of bee pollen vary greatly with the botanical and geographical origin of the pollen grains. This study was conducted to characterize the botanical origin and assess the antioxidant effects of ethanol extracts of 18 different bee pollen (EBP) samples from 16 locations in South Korea and their inhibitory activities on human beta-amyloid precursor cleavage enzyme (BACE1), acetylcholinesterase (AChE), human intestinal bacteria, and 5 cancer cell lines. METHODS: The botanical origin and classification of each BP sample was evaluated using palynological analysis by observing microscope slides. We measured the biological properties, including antioxidant capacity, inhibitory activities against human BACE1, and AChE, and antiproliferative activities toward five cancer cell lines, of the 18 EBPs. In addition, the growth inhibitory activities on four harmful intestinal bacteria, six lactic acid-producing bacteria, two nonpathogenic bacteria, and an acidulating bacterium were also assessed. RESULTS: Four samples (BP3, BP4, BP13 and BP15) were found to be monofloral and presented four dominant pollen types: Quercus palustris, Actinidia arguta, Robinia pseudoacacia, and Amygdalus persica. One sample (BP12) was found to be bifloral, and the remaining samples were considered to be heterofloral. Sixteen samples showed potent antioxidant activities with EC(50) from 292.0 to 673.9 microg/mL. Fourteen samples presented potent inhibitory activity against human BACE1 with EC(50) from 236.0 to 881.1 microg/mL. All samples showed antiproliferative activity toward the cancer cell lines PC-3, MCF-7, A549, NCI-H727 and AGS with IC(50) from 2.7 to 14.4mG/Ml, 0.9 to 12.7mG/Ml, 5.0 to > 25mG/Ml, 2.7 to 17.7mG/Ml, and 2.4 to 8.7mG/Ml, respectively. In addition, total phenol and flavonoid contents had no direct correlation with antioxidant, anti-human BACE1, or antiproliferative activities. CONCLUSION: Fundamentally, Korean bee pollen-derived preparations could be considered a nutritional addition to food to prevent various diseases related to free radicals, neurodegenerative problems, and cancers. The botanical and geographical origins of pollen grains could help to establish quality control standards for bee pollen consumption and industrial production.
ESTHER : Zou_2020_BMC.Complement.Med.Ther_20_236
PubMedSearch : Zou_2020_BMC.Complement.Med.Ther_20_236
PubMedID: 32711521

Title : Karrikin Signaling Acts Parallel to and Additively with Strigolactone Signaling to Regulate Rice Mesocotyl Elongation in Darkness - Zheng_2020_Plant.Cell_32_2780
Author(s) : Zheng J , Hong K , Zeng L , Wang L , Kang S , Qu M , Dai J , Zou L , Zhu L , Tang Z , Meng X , Wang B , Hu J , Zeng D , Zhao Y , Cui P , Wang Q , Qian Q , Wang Y , Li J , Xiong G
Ref : Plant Cell , 32 :2780 , 2020
Abstract : Seedling emergence in monocots depends mainly on mesocotyl elongation, requiring coordination between developmental signals and environmental stimuli. Strigolactones (SLs) and karrikins are butenolide compounds that regulate various developmental processes; both are able to negatively regulate rice (Oryza sativa) mesocotyl elongation in the dark. Here, we report that a karrikin signaling complex, DWARF14-LIKE (D14L)-DWARF3 (D3)-O. sativa SUPPRESSOR OF MAX2 1 (OsSMAX1) mediates the regulation of rice mesocotyl elongation in the dark. We demonstrate that D14L recognizes the karrikin signal and recruits the SCF(D3) ubiquitin ligase for the ubiquitination and degradation of OsSMAX1, mirroring the SL-induced and D14- and D3-dependent ubiquitination and degradation of D53. Overexpression of OsSMAX1 promoted mesocotyl elongation in the dark, whereas knockout of OsSMAX1 suppressed the elongated-mesocotyl phenotypes of d14l and d3 OsSMAX1 localizes to the nucleus and interacts with TOPLESS-RELATED PROTEINs, regulating downstream gene expression. Moreover, we showed that the GR24 enantiomers GR24(5DS) and GR24 (ent-5DS) specifically inhibit mesocotyl elongation and regulate downstream gene expression in a D14- and D14L-dependent manner, respectively. Our work revealed that karrikin and SL signaling play parallel and additive roles in modulating downstream gene expression and negatively regulating mesocotyl elongation in the dark.
ESTHER : Zheng_2020_Plant.Cell_32_2780
PubMedSearch : Zheng_2020_Plant.Cell_32_2780
PubMedID: 32665307

Title : Thiol-suppressed I(2)-etching of AuNRs: acetylcholinesterase-mediated colorimetric detection of organophosphorus pesticides - Qing_2020_Mikrochim.Acta_187_497
Author(s) : Qing Z , Li Y , Luo G , Hu J , Zou Z , Lei Y , Liu J , Yang R
Ref : Mikrochim Acta , 187 :497 , 2020
Abstract : For the first time it is demonstrated that sulfhydryl compounds can suppress longitudinal etching of gold nanorods via consuming oxidizers, which provides a new signaling mechanism for colorimetric sensing. As a proof of concept, a colorimetric assay is developed for detecting organophosphorus pesticides, which are most widely used in modern agriculture to improve food production but with high toxicity to animals and the ecological environment. Triazophos was selected as a model organophosphorus pesticide. In the absence of triazophos, the active acetylcholinesterase can catalyze the conversion of acetylthiocholine iodide to thiocholine whose thiol group can suppress the I(2)-induced etching of gold nanorods. When triazophos is present, the activity of AchE is inhibited, and I(2)-induced etching of gold nanorods results in triazophos concentration-dependent color change from brown to blue, pink, and red. The aspect ratio of gold nanorods reduced with gradually blue-shifted longitudinal absorption. There was a linear detection range from 0 to 117 nM (R(2) = 0.9908), the detection limit was 4.69 nM, and a good application potential was demonstrated by the assay of real water samples. This method will not only contribute to public monitoring of organophosphorus pesticides but also has verified a new signaling mechanism which will open up a new path to develop colorimetric detection methods. It has been first found that sulfhydryl compounds can suppress longitudinal etching of gold nanorods (AuNRs) via consuming oxidizers, which provides a new signaling mechanism for colorimetric sensing. As a proof of concept, a colorimetric assay is developed for sensitively detecting organophosphorus pesticides (OPs). It will not only contribute to public monitoring of OPs but also has verified a new signaling mechanism which will open up a new path to develop multicolor colorimetric methods.
ESTHER : Qing_2020_Mikrochim.Acta_187_497
PubMedSearch : Qing_2020_Mikrochim.Acta_187_497
PubMedID: 32803418

Title : Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6\/JAK2\/STAT3 signaling in glioma - Zhou_2020_Cell.Oncol.(Dordr)_43_461
Author(s) : Zhou J , Jiang Y , Zhao J , Zhang H , Fu J , Luo P , Ma Y , Zou D , Gao H , Hu J , Zhang Y , Jing Z
Ref : Cell Oncol (Dordr) , 43 :461 , 2020
Abstract : PURPOSE: The iron-chelating agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) has been found to inhibit cell growth and to induce apoptosis in several human cancers. However, its effects and mechanism of action in glioma are unknown. METHODS: Human glioma cell line LN229 and patient-derived glioma stem cells GSC-42 were applied for both in vitro and in vivo xenograft nude mouse experiments. The anti-tumor effects of Dp44mT were assessed using MTS, EdU, TUNEL, Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation and immunohistochemical assays. RESULTS: We found that Dp44mT can upregulate the expression of the anti-oncogene N-myc downstream-regulated gene (NDRG)2 by directly binding to and activating the RAR-related orphan receptor (ROR)A. In addition, we found that NDRG2 overexpression suppressed inflammation via activation of interleukin (IL)-6/Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling. CONCLUSIONS: Our data indicate that Dp44mT may serve as an effective drug for the treatment of glioma by targeting RORA and enhancing NDRG2-mediated IL-6/JAK2/STAT3 signaling.
ESTHER : Zhou_2020_Cell.Oncol.(Dordr)_43_461
PubMedSearch : Zhou_2020_Cell.Oncol.(Dordr)_43_461
PubMedID: 32207044
Gene_locus related to this paper: human-NDRG2

Title : An efficient LSPR method to quantitatively detect dimethoate: Development, characterization and evaluation - Li_2020_PLoS.One_15_e0239632
Author(s) : Li D , Zhang Y , Guo Q , Sun X , Zhang H , Wang S , Birech Z , Hu J
Ref : PLoS ONE , 15 :e0239632 , 2020
Abstract : In recent years, there has been growing concern among consumers about pesticide contamination in fruits. Therefore, rapid, reliable, and consistent detection methods for OPPs, especially dimethoate, are crucially needed. The existing quantitative methods for detecting dimethoate are not suitable for rapid measuring system such as the dimethoate samples from two channels. Hence this paper examines the utilization of a dual-channel system for utilize the absorption variations of the Localized Surface Plasmon Resonance (LSPR) bands of gold nanoparticles (AuNPs) were investigate for detection of dimethoate. Under optimized conditions, the relationship between concentrations of dimethoate and absorbance ratios (A(520)/A(640)) was linearly found in the concentration range of 10-100 nM. Result from the experiment shows that both channels exhibit a linear correlation coefficient as high as 0.97 and a limit of detection (LOD) as low as 5.5 nM. This LSPR detection system was characterized by testing the dimethoate in apple samples and the recovery rates were found to be in the range of 85.90% to 107.37%. The proposed dual-channel LSPR system for detecting dimethoate creating a new approach for detecting organophosphate insecticide in agricultural fields. It could lay the foundation for designing a high-throughput analysis of the insecticides using a wavelength division multiplexing switch (WDMS).
ESTHER : Li_2020_PLoS.One_15_e0239632
PubMedSearch : Li_2020_PLoS.One_15_e0239632
PubMedID: 32970749

Title : Mori Ramulus (Chin.Ph.)-the Dried Twigs of Morus alba L.\/Part 1: Discovery of Two Novel Coumarin Glycosides from the Anti-Hyperuricemic Ethanol Extract - Yao_2019_Molecules_24_
Author(s) : Yao J , He H , Xue J , Wang J , Jin H , Wu J , Hu J , Wang R , Kuchta K
Ref : Molecules , 24 : , 2019
Abstract : In Traditional Chinese Medicine (TCM), Mori ramulus (Chin.Ph.)-the dried twigs of Morus alba L.-is extensively used as an antirheumatic agent and also finds additional use in asthma therapy. As a pathological high xanthine oxidase (XO, EC 1.1.3.22) activity is strongly correlated to hyperuricemy and gout, standard anti-hyperuremic therapy typically involves XO inhibitors like allopurinol, which often cause adverse effects by inhibiting other enzymes involved in purine metabolism. Mori ramulus may therefore be a promissing source for the development of new antirheumatic therapeutics with less side effects. Coumarins, one of the dominant groups of bioactive constituents of M. alba, have been demonstrated to possess anti-inflammatory, antiplatelet aggregation, antitumor, and acetylcholinesterase (AChE) inhibitory activities. The combination of HPLC (DAD) and Q-TOF technique could give excellent separating and good structural characterization abilities which make it suitable to analyze complex multi-herbal extracts in TCM. The aim of this study was to develop a HPLC (DAD)/ESI-Q-TOF-MS/MS method for the identification and profiling of pharmacologically active coumarin glycosides in Mori ramulus refined extracts for used in TCM. This HPLC (DAD)/ESI-Q-TOF-MS/MS method provided a rapid and accurate method for identification of coumarin glycosides-including new natural products described here for the first time-in the crude extract of M. alba L. In the course of this project, two novel natural products moriramulosid A (umbelliferone-6-beta-d-apiofuranosyl-(1-->6)-beta-d-glucopyranoside) and moriramulosid B (6-[[6-O-(6-deoxy-alpha-l-mannopyranosyl)-beta-d-glucopyranosyl]oxy]-2H-1-benzopy ran-1-one) were newly discovered and the known natural product Scopolin was identified in M. alba L. for the first time.
ESTHER : Yao_2019_Molecules_24_
PubMedSearch : Yao_2019_Molecules_24_
PubMedID: 30754654

Title : Dual functional cholinesterase and PDE4D inhibitors for the treatment of Alzheimer's disease: Design, synthesis and evaluation of tacrine-pyrazolo[3,4-b]pyridine hybrids - Pan_2019_Bioorg.Med.Chem.Lett_29_2150
Author(s) : Pan T , Xie S , Zhou Y , Hu J , Luo H , Li X , Huang L
Ref : Bioorganic & Medicinal Chemistry Lett , 29 :2150 , 2019
Abstract : A series of tacrine-pyrazolo[3,4-b]pyridine hybrids were synthesised and evaluated as dual cholinesterase (ChE) and phosphodiesterase 4D (PDE4D) inhibitors for the treatment of Alzheimer's disease (AD). Compound 10j, which is tacrine linked with pyrazolo[3,4-b]pyridine moiety by a six-carbon spacer, was the most potent acetylcholinesterase (AChE) with IC50 value of 0.125muM. Moreover, compound 10j provided a desired balance of AChE and butylcholinesterase (BuChE) and PDE4D inhibition activities, with IC50 value of 0.449 and 0.271muM, respectively. The above results indicated that this hybrid was a promising dual functional agent for the treatment of AD.
ESTHER : Pan_2019_Bioorg.Med.Chem.Lett_29_2150
PubMedSearch : Pan_2019_Bioorg.Med.Chem.Lett_29_2150
PubMedID: 31281020

Title : Heterologous biosynthesis of elsinochrome A sheds light on the formation of the photosensitive perylenequinone system - Hu_2019_Chem.Sci_10_1457
Author(s) : Hu J , Sarrami F , Li H , Zhang G , Stubbs KA , Lacey E , Stewart SG , Karton A , Piggott AM , Chooi YH
Ref : Chem Sci , 10 :1457 , 2019
Abstract : Perylenequinones are a class of aromatic polyketides characterised by a highly conjugated pentacyclic core, which confers them with potent light-induced bioactivities and unique photophysical properties. Despite the biosynthetic gene clusters for the perylenequinones elsinochrome A (1), cercosporin (4) and hypocrellin A (6) being recently identified, key biosynthetic aspects remain elusive. Here, we first expressed the intact elc gene cluster encoding 1 from the wheat pathogen Parastagonospora nodorum heterologously in Aspergillus nidulans on a yeast-fungal artificial chromosome (YFAC). This led to the identification of a novel flavin-dependent monooxygenase, ElcH, responsible for oxidative enolate coupling of a perylenequinone intermediate to the hexacyclic dihydrobenzo(ghi)perylenequinone in 1. In the absence of ElcH, the perylenequione intermediate formed a hexacyclic cyclohepta(ghi)perylenequinone system via an intramolecular aldol reaction resulting in 6 and a novel hypocrellin 12 with opposite helicity to 1. Theoretical calculations supported that 6 and 12 resulted from atropisomerisation upon formation of the 7-membered ring. Using a bottom-up pathway reconstruction approach on a tripartite YFAC system developed in this study, we uncovered that both a berberine bridge enzyme-like oxidase ElcE and a laccase-like multicopper oxidase ElcG are involved in the double coupling of two naphthol intermediates to form the perylenequinone core. Gene swapping with the homologs from the biosynthetic pathway of 4 showed that cognate pairing of the two classes of oxidases is required for the formation of the perylenequinone core, suggesting the involvement of protein-protein interactions.
ESTHER : Hu_2019_Chem.Sci_10_1457
PubMedSearch : Hu_2019_Chem.Sci_10_1457
PubMedID: 30809363
Gene_locus related to this paper: phano-elca

Title : Soluble epoxide hydrolase promotes astrocyte survival in retinopathy of prematurity - Hu_2019_J.Clin.Invest_129_5204
Author(s) : Hu J , Bibli SI , Wittig J , Zukunft S , Lin J , Hammes HP , Popp R , Fleming I
Ref : J Clinical Investigation , 129 :5204 , 2019
Abstract : Polyunsaturated fatty acids such as docosahexaenoic acid (DHA) positively affect the outcome of retinopathy of prematurity (ROP). Given that DHA metabolism by cytochrome P450 and soluble epoxide hydrolase (sEH) enzymes affects retinal angiogenesis and vascular stability, we investigated the role of sEH in a mouse model of ROP. In WT mice, hyperoxia elicited tyrosine nitration and inhibition of sEH and decreased generation of the DHA-derived diol 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP). Correspondingly, in a murine model of ROP, sEH-/- mice developed a larger central avascular zone and peripheral pathological vascular tuft formation than did their WT littermates. Astrocytes were the cells most affected by sEH deletion, and hyperoxia increased astrocyte apoptosis. In rescue experiments, 19,20-DHDP prevented astrocyte loss by targeting the mitochondrial membrane to prevent the hyperoxia-induced dissociation of presenilin-1 and presenilin-1-associated protein to attenuate poly ADP-ribose polymerase activation and mitochondrial DNA damage. Therapeutic intravitreal administration of 19,20-DHDP not only suppressed astrocyte loss, but also reduced pathological vascular tuft formation in sEH-/- mice. Our data indicate that sEH activity is required for mitochondrial integrity and retinal astrocyte survival in ROP. Moreover, 19,20-DHDP may be more effective than DHA as a nutritional supplement for preventing retinopathy in preterm infants.
ESTHER : Hu_2019_J.Clin.Invest_129_5204
PubMedSearch : Hu_2019_J.Clin.Invest_129_5204
PubMedID: 31479425

Title : The genome of broomcorn millet - Zou_2019_Nat.Commun_10_436
Author(s) : Zou C , Li L , Miki D , Li D , Tang Q , Xiao L , Rajput S , Deng P , Peng L , Jia W , Huang R , Zhang M , Sun Y , Hu J , Fu X , Schnable PS , Chang Y , Li F , Zhang H , Feng B , Zhu X , Liu R , Schnable JC , Zhu JK
Ref : Nat Commun , 10 :436 , 2019
Abstract : Broomcorn millet (Panicum miliaceum L.) is the most water-efficient cereal and one of the earliest domesticated plants. Here we report its high-quality, chromosome-scale genome assembly using a combination of short-read sequencing, single-molecule real-time sequencing, Hi-C, and a high-density genetic map. Phylogenetic analyses reveal two sets of homologous chromosomes that may have merged ~5.6 million years ago, both of which exhibit strong synteny with other grass species. Broomcorn millet contains 55,930 protein-coding genes and 339 microRNA genes. We find Paniceae-specific expansion in several subfamilies of the BTB (broad complex/tramtrack/bric-a-brac) subunit of ubiquitin E3 ligases, suggesting enhanced regulation of protein dynamics may have contributed to the evolution of broomcorn millet. In addition, we identify the coexistence of all three C4 subtypes of carbon fixation candidate genes. The genome sequence is a valuable resource for breeders and will provide the foundation for studying the exceptional stress tolerance as well as C4 biology.
ESTHER : Zou_2019_Nat.Commun_10_436
PubMedSearch : Zou_2019_Nat.Commun_10_436
PubMedID: 30683860
Gene_locus related to this paper: panmi-a0a3l6qvl9 , 9poal-a0a2s3hbt0 , panmi-a0a3l6sxg5 , 9poal-a0a2t7cdl4 , panmi-a0a3l6ta96 , panmi-a0a3l6qv47 , panmi-a0a3l6s688 , panmi-a0a3l6tph0

Title : Fungal Dirigent Protein Controls the Stereoselectivity of Multicopper Oxidase-Catalyzed Phenol Coupling in Viriditoxin Biosynthesis - Hu_2019_J.Am.Chem.Soc_141_8068
Author(s) : Hu J , Li H , Chooi YH
Ref : Journal of the American Chemical Society , 141 :8068 , 2019
Abstract : Paecilomyces variotii produces the antibacterial and cytotoxic ( M)-viriditoxin (1) together with a trace amount of its atropisomer ( P)-viriditoxin 1'. Elucidation of the biosynthesis by heterologous pathway reconstruction in Aspergillus nidulans identified the multicopper oxidase (MCO) VdtB responsible for the regioselective 6,6'-coupling of semiviriditoxin (10), which yielded 1 and 1' at a ratio of 1:2. We further uncovered that VdtD, an alpha/beta hydrolase-like protein lacking the catalytic serine, directs the axial chirality of the products. Using recombinant VdtB and VdtD as cell-free extracts from A. nidulans, we demonstrated that VdtD acts like a dirigent protein to control the stereoselectivity of the coupling catalyzed by VdtB to yield 1 and 1' at a ratio of 20:1. Furthermore, we uncovered a unique Baeyer-Villiger monooxygenase (BVMO) VdtE that could transform the alkyl methylketone side chain to methyl ester against the migratory aptitude.
ESTHER : Hu_2019_J.Am.Chem.Soc_141_8068
PubMedSearch : Hu_2019_J.Am.Chem.Soc_141_8068
PubMedID: 31045362
Gene_locus related to this paper: byssn-VdtD , byssp-vdta1

Title : Design, Synthesis, and Biological Evaluation of Dual-Target Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 9A (PDE9A) for the Treatment of Alzheimer's Disease - Hu_2019_ACS.Chem.Neurosci_10_537
Author(s) : Hu J , Huang YD , Pan T , Zhang T , Su T , Li X , Luo HB , Huang L
Ref : ACS Chem Neurosci , 10 :537 , 2019
Abstract : A series of dual-target AChE/PDE9A inhibitor compounds were designed, synthesized, and evaluated as anti-Alzheimer's Disease (AD) agents. Among these target compounds, 11a (AChE: IC50 = 0.048 muM; PDE9A: IC50 = 0.530 muM) and 11b (AChE: IC50 = 0.223 muM; PDE9A: IC50 = 0.285 muM) exhibited excellent and balanced dual-target AChE/PDE9A inhibitory activities. Meanwhile, those two compounds possess good blood-brain barrier (BBB) penetrability and low neurotoxicity. Especially, 11a and 11b could ameliorate learning deficits induced by scopolamine (Scop). Moreover, 11a could also improve cognitive and spatial memory in Abeta25-35-induced cognitive deficit mice in the Morris water-maze test. In summary, our research developed a series of potential dual-target AChE/PDE9A inhibitors, and the data indicated that 11a was a promising candidate drug for the treatment of AD.
ESTHER : Hu_2019_ACS.Chem.Neurosci_10_537
PubMedSearch : Hu_2019_ACS.Chem.Neurosci_10_537
PubMedID: 30252439

Title : Genome-wide association studies reveal genetic loci associated with plasma cholinesterase activity in ducks - Xu_2019_Anim.Genet_50_287
Author(s) : Xu Y , Liu H , Jiang Y , Fan W , Hu J , Zhang Y , Guo Z , Xie M , Huang W , Liu X , Zhou Z , Hou S
Ref : Anim Genet , 50 :287 , 2019
Abstract : Plasma cholinesterase (PCHE) activity is an important auxiliary test in human clinical medicine. It can distinguish liver diseases from non-liver diseases and help detect organophosphorus poisoning. Animal experiments have confirmed that PCHE activity is associated with obesity and hypertension and changes with physiological changes in an animal's body. The objective of this study was to locate the genetic loci responsible for PCHE activity variation in ducks. PCHE activity of Pekin duck x mallard F2 ducks at 3 and 8 weeks of age were analyzed, and genome-wide association studies were conducted. A region of about 1.5 Mb (21.8-23.3 Mb) on duck chromosome 9 was found to be associated with PCHE activity at both 3 and 8 weeks of age. The top SNP, g.22643979C>T in the butyrylcholinesterase (BCHE) gene, was most highly associated with PCHE activity at 3 weeks (-logP = 21.45) and 8 weeks (-logP = 27.60) of age. For the top SNP, the strong associations of CC and CT genotypes with low PCHE activity and the TT genotype with high PCHE activity indicates the dominant inheritance of low PCHE activity. Problems with block inheritance or linkage exist in this region. This study supports that BCHE is a functional gene for determining PCHE levels in ducks and that the genetic variations around this gene can cause phenotypic variations of PCHE activity.
ESTHER : Xu_2019_Anim.Genet_50_287
PubMedSearch : Xu_2019_Anim.Genet_50_287
PubMedID: 30994195
Gene_locus related to this paper: anapl-BCHE

Title : Current anti-Alzheimer's disease effect of natural products and their principal targets - Zhu_2019_J.Integr.Neurosci_18_327
Author(s) : Zhu Y , Peng L , Hu J , Chen Y , Chen F
Ref : J Integr Neurosci , 18 :327 , 2019
Abstract : Various bioactive substances isolated from natural products play a pivotal role in the prevention and cure of neurodegenerative diseases, such as Alzheimer's disease. Currently, there are many theories about the pathogenesis of this disease. In this review we discuss among them, the cholinergic hypotheses, the Abeta toxicity hypothesis, and the tau dysfunction hypothesis. Multiple potential targets are a focus for the development of anti-AD drugs. There is an urgent need to develop more effective therapies to treat and delay the onset of the disease and to find safe and effective drugs. In this review, the recent progress of anti-AD effects and their principal targets are updated.
ESTHER : Zhu_2019_J.Integr.Neurosci_18_327
PubMedSearch : Zhu_2019_J.Integr.Neurosci_18_327
PubMedID: 31601083

Title : The fungal gene cluster for biosynthesis of the antibacterial agent viriditoxin - Urquhart_2019_Fungal.Biol.Biotechnol_6_2
Author(s) : Urquhart AS , Hu J , Chooi YH , Idnurm A
Ref : Fungal Biol Biotechnol , 6 :2 , 2019
Abstract : BACKGROUND: Viriditoxin is one of the 'classical' secondary metabolites produced by fungi and that has antibacterial and other activities; however, the mechanism of its biosynthesis has remained unknown. RESULTS: Here, a gene cluster (vdt) responsible for viriditoxin synthesis was identified, via a bioinformatics analysis of the genomes of Paecilomyces variotii and Aspergillus viridinutans that both are viriditoxin producers. The function of the eight-membered gene cluster of P. variotii was characterized by targeted gene disruptions, revealing the roles of each gene in the synthesis of this molecule and establishing its biosynthetic pathway, which includes a Baeyer-Villiger monooxygenase catalyzed reaction. Additionally, a predicted catalytically-inactive hydrolase was identified as being required for the stereoselective biosynthesis of (M)-viriditoxin. The subcellular localizations of two proteins (VdtA and VdtG) were determined by fusing these proteins to green fluorescent protein, to establish that at least two intracellular structures are involved in the compartmentalization of the synthesis steps of this metabolite. CONCLUSIONS: The predicted pathway for the synthesis of viriditoxin was established by a combination of genomics, bioinformatics, gene disruption and chemical analysis processes. Hence, this work reveals the basis for the synthesis of an understudied class of fungal secondary metabolites and provides a new model species for understanding the synthesis of biaryl compounds with a chiral axis.
ESTHER : Urquhart_2019_Fungal.Biol.Biotechnol_6_2
PubMedSearch : Urquhart_2019_Fungal.Biol.Biotechnol_6_2
PubMedID: 31304040
Gene_locus related to this paper: byssp-vdta1

Title : Urinary biomarkers for assessment of human exposure to monomeric aryl phosphate flame retardants - Zhao_2019_Environ.Int_124_259
Author(s) : Zhao F , Kang Q , Zhang X , Liu J , Hu J
Ref : Environ Int , 124 :259 , 2019
Abstract : While monomeric aryl organophosphate flame retardants (m-aryl-OPFRs) are used worldwide in a variety of consumer products, specific biomarkers for epidemiologic studies are lacking. To explore the potential of urinary hydroxylated metabolites of m-aryl-OPFRs as the biomarkers, we detected triphenyl phosphate (TPHP), 2-ethylhexyl diphenyl phosphate (EHDPP), and tricresyl phosphate (TCrP) in 259 whole blood samples and their 5 hydroxylated and 2 diester metabolites in the paired urine samples from the general population. 2-Ethyl-5-hydroxyhexyl diphenyl phosphate (5-OH-EHDPP), 4-hydroxyphenyl diphenyl phosphate (4-OH-TPHP), and 3-hydroxy-4-methylphenyl di-p-tolyl phosphate (3-OH-MDTP) were detected in >80% of urine samples after enzymatic hydrolysis of conjugates, and their concentrations showed significant positive correlations with the blood concentrations of their corresponding parent compounds, respectively. To characterize the temporal reliability, the m-aryl-OPFRs metabolites were also determined in urine samples repeated nine times from six volunteers over 3 months. Urinary 5-OH-EHDPP showed strong temporal reliability (creatinine-corrected intraclass correlation coefficients (ICCs), 0.77; 95% confidence interval [CI], 0.58 to 0.90), and urinary 3-OH-MDTP (creatinine-corrected ICC, 0.52; 95% CI, 0.37 to 0.87) and 4-OH-TPHP (0.56; 95% CI, 0.32 to 0.80) showed moderate-to-strong temporal reliability, while relatively weak temporal reliability was found for urinary DPHP (creatinine-corrected ICC, 0.37; 95% CI, 0.12 to 0.62). This study confirmed specific, reliable, and frequently detected biomarkers for TPHP and EHDPP and developed new biomarker of TCrP for future epidemiological research on health effects of m-aryl-OPFRs.
ESTHER : Zhao_2019_Environ.Int_124_259
PubMedSearch : Zhao_2019_Environ.Int_124_259
PubMedID: 30660026

Title : (-)Epigallocatechin-3-gallate attenuates anesthesiainduced memory deficit in young mice via modulation of nitric oxide expression - Ding_2018_Mol.Med.Rep_18_4813
Author(s) : Ding L , Gao X , Hu J , Yu S
Ref : Mol Med Rep , 18 :4813 , 2018
Abstract : (-)Epigallocatechin-3gallate- (EGCG) is a type of polyphenol monomer and is the predominant component of catechin compounds extractable from green tea. Previous studies have demonstrated that EGCG exhibits numerous bioactivities both in vitro and in vivo, including antitumor, antioxidant and antiinflammatory activities, as well as lowering blood lipid levels and protecting against radiation. The present study aimed to investigate whether administration of EGCG may attenuate anesthesiainduced memory deficit in young mice and to reveal the associated underlying mechanisms. The present study revealed that EGCG administration significantly attenuated memory deficit, oxidative stress and cell apoptosis exhibited by anesthesiainduced mice, as determined by Morris water maze testing and ELISA analysis. Furthermore, the results of ELISA and western blot analysis demonstrated that EGCG administration restored acetylcholinesterase activity and modulated the expression levels of neuronal nitric oxide synthase (nNOS), betaamyloid and amyloid precursor protein in anesthesiainduced mice. The present study also employed Larginine as an nNOS substrate and 7nitroindazole as an nNOS inhibitor, which were demonstrated to inhibit or potentiate the effects of EGCG, respectively, on anesthesiainduced memory deficit in mice. Therefore, the present study demonstrated that the administration of EGCG attenuated anesthesiainduced memory deficit in young mice, potentially via the modulation of nitric oxide expression and oxidative stress.
ESTHER : Ding_2018_Mol.Med.Rep_18_4813
PubMedSearch : Ding_2018_Mol.Med.Rep_18_4813
PubMedID: 30320383

Title : Biodegradation of pyraclostrobin by two microbial communities from Hawaiian soils and metabolic mechanism - Chen_2018_J.Hazard.Mater_354_225
Author(s) : Chen X , He S , Liang Z , Li QX , Yan H , Hu J , Liu X
Ref : J Hazard Mater , 354 :225 , 2018
Abstract : Pyraclostrobin has been widely and long-termly applicated to agricultural fields. The removal of pyraclostrobin from ecological environment has received wide attention. In this study, using sequential enrichments with pyraclostrobin as a sole carbon source, two microbial communities (HI2 and HI6) capable of catabolizing pyraclostrobin were obtained from Hawaiian soils. The microfloras analysis indicated that only Proteobacteria and Bacteroides could survive in HI2-soil after acclimatization, whereas the number of Proteobacteria in HI6-soil accounted for more than 99%. The percentages of Pseudomonas in the HI2 and HI6 microfloras were 69.3% and 59.3%, respectively. More than 99% of pyraclostrobin (C0=100mgL(-1)) was degraded by the HI2 and HI6 microorganisms within five days. A unique metabolite was identified by high performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS/MS). A metabolic pathway involving carbamate hydrolysis was proposed. The tertiary amine group of pyraclostrobin was hydrolyzed to primary amine group with the decarboxylation, which facilitated pyraclostrobin detoxification because carboxylester was an important functional group. The metabolic mechanism suggested that Pseudomonas expressing carboxylesterase might be able to degrade carbamate chemicals. Therefore, Pseudomonas might be an ideal candidate for expression and cloning of carbamate-degrading gene in genomics studies. The current study would have important implications in detoxification and bioremediation of carbamates through the CN bond cleavage of methyl carbamate.
ESTHER : Chen_2018_J.Hazard.Mater_354_225
PubMedSearch : Chen_2018_J.Hazard.Mater_354_225
PubMedID: 29753191

Title : Comparative genomic analysis of the Lipase3 gene family in five plant species reveals distinct evolutionary origins - Wang_2018_Genetica_146_179
Author(s) : Wang D , Zhang L , Hu J , Gao D , Liu X , Sha Y
Ref : Genetica , 146 :179 , 2018
Abstract : Lipases are physiologically important and ubiquitous enzymes that share a conserved domain and are classified into eight different families based on their amino acid sequences and fundamental biological properties. The Lipase3 family of lipases was reported to possess a canonical fold typical of alpha/beta hydrolases and a typical catalytic triad, suggesting a distinct evolutionary origin for this family. Genes in the Lipase3 family do not have the same functions, but maintain the conserved Lipase3 domain. There have been extensive studies of Lipase3 structures and functions, but little is known about their evolutionary histories. In this study, all lipases within five plant species were identified, and their phylogenetic relationships and genetic properties were analyzed and used to group them into distinct evolutionary families. Each identified lipase family contained at least one dicot and monocot Lipase3 protein, indicating that the gene family was established before the split of dicots and monocots. Similar intron/exon numbers and predicted protein sequence lengths were found within individual groups. Twenty-four tandem Lipase3 gene duplications were identified, implying that the distinctive function of Lipase3 genes appears to be a consequence of translocation and neofunctionalization after gene duplication. The functional genes EDS1, PAD4, and SAG101 that are reportedly involved in pathogen response were all located in the same group. The nucleotide diversity (Dxy) and the ratio of nonsynonymous to synonymous nucleotide substitutions rates (Ka/Ks) of the three genes were significantly greater than the average across the genomes. We further observed evidence for selection maintaining diversity on three genes in the Toll-Interleukin-1 receptor type of nucleotide binding/leucine-rich repeat immune receptor (TIR-NBS LRR) immunity-response signaling pathway, indicating that they could be vulnerable to pathogen effectors.
ESTHER : Wang_2018_Genetica_146_179
PubMedSearch : Wang_2018_Genetica_146_179
PubMedID: 29468429

Title : Soluble epoxide hydrolase inhibitors, t-AUCB, downregulated miR-133 in a mouse model of myocardial infarction - Gui_2018_Lipids.Health.Dis_17_129
Author(s) : Gui Y , Li D , Chen J , Wang Y , Hu J , Liao C , Deng L , Xiang Q , Yang T , Du X , Zhang S , Xu D
Ref : Lipids Health Dis , 17 :129 , 2018
Abstract : BACKGROUND: It has been demonstrated that soluble epoxide hydrolase inhibitors (sEHIs) are protective against ischemia-induced lethal arrhythmias, but the mechanisms involved are unknown. Previously, we showed that sEHIs might reduce the incidence of ischemic arrhythmias by suppressing microRNA-1 (miR-1) in the myocardium. As miR-1 and miR-133 have the same proarrhythmic effects in the heart, we assumed that the beneficial effects of sEHIs might also relate to the regulation of miR-133. METHODS: A mouse model of myocardial infarction (MI) was established by ligating the coronary artery. The sEHI t-AUCB (trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid) was administered daily for 7 days before MI. Myocardial infarct size and cardiac function was assessed at 24 h post-MI. The miRNA expression profiles of sham and MI mice treated with or without t-AUCB were determined by microarray and verified by real-time PCR. The incidence of arrhythmias was assessed by in vivo electrophysiologic studies. The mRNA levels of miR-133, its target genes (KCNQ1 [potassium voltage-gated channel subfamily Q member 1] and KCNH2 [potassium voltage-gated channel subfamily H member 2]), and serum response factor (SRF) were measured by real-time PCR; KCNQ1, KCNH2, and SRF protein levels were assessed by western blotting. RESULTS: We demonstrated that the treatment with sEHIs could reduce infarct size, improve cardia function, and prevent the development of cardiac arrhythmias in MI mice. The expression levels of 14 miRNAs differed between the sham and MI groups. t-AUCB treatment altered the expression of eight miRNAs: two were upregulated and six were downregulated. Of these, the muscle-specific miR-133 was downregulated in the ischemic myocardium. In line with this, up-regulation of miR-133 and down-regulation of KCNQ1 and KCNH2 mRNA/protein were observed in ischemic myocaridum, whereas administration of sEHIs produced an opposite effect. In addition, miR-133 overexpression inhibited expression of the target mRNA, whereas t-AUCB reversed the effects. Furthermore, SRF might participate in the negative regulation of miR-133 by t-AUCB. CONCLUSIONS: In MI mice, sEHI t-AUCB can repress miR-133, consequently stimulating KCNQ1 and KCNH2 mRNA and protein expression, suggesting a possible mechanism for its potential therapeutic application in ischemic arrhythmias.
ESTHER : Gui_2018_Lipids.Health.Dis_17_129
PubMedSearch : Gui_2018_Lipids.Health.Dis_17_129
PubMedID: 29843720

Title : Responses of Antioxidant Defense and Immune Gene Expression in Early Life Stages of Large Yellow Croaker (Pseudosciaena crocea) Under Methyl Mercury Exposure - Wu_2018_Front.Physiol_9_1436
Author(s) : Wu F , Huang W , Liu Q , Xu X , Zeng J , Cao L , Hu J , Gao Y , Jia S
Ref : Front Physiol , 9 :1436 , 2018
Abstract : Early life stages of marine organisms are the most sensitive stages to environment stressors including pollutants. In order to understand the toxicological effects induced by MeHg exposure on juveniles of large yellow croaker (Pseudosciaena crocea), a toxicity test was performed wherein fish were exposed to sub-lethal concentrations of MeHg under laboratory conditions (18 +/- 1 degrees C; 26 +/- 1 in salinity). After 30 days of 0-4.0 mug L(-1) MeHg exposure, SOD activity was significantly decreased in the 0.25, 1.0, and 4.0 mug L(-1) treatments; while CAT activity was significantly increased in the 4.0 mug L(-1) treatments; GSH level, GPx activity were significantly elevated in the 4.0 mug L(-1) treatments, respectively. Meanwhile, malondialdehyde content was also significantly increased in the 1.0 and 4.0 mug L(-1) treatments with respect to the control. Acetylcholinesterase activity was significantly decreased by 18.3, 25.2, and 21.7% in the 0.25, 1.0, and 4.0 mug L(-1) treatments, respectively. The expression of TCTP, GST3, Hsp70, Hsp27 mRNA were all up-regulated in juveniles with a dose-dependent manner exposed to MeHg. These results suggest that large yellow croaker juveniles have the potential to regulate the levels of antioxidant enzymes and initiate immune response in order to protect fish to some extent from oxidative stress induced by MeHg.
ESTHER : Wu_2018_Front.Physiol_9_1436
PubMedSearch : Wu_2018_Front.Physiol_9_1436
PubMedID: 30364149

Title : Activation of Peroxisome Proliferator-Activated Receptor Gamma and Disruption of Progesterone Synthesis of 2-Ethylhexyl Diphenyl Phosphate in Human Placental Choriocarcinoma Cells: Comparison with Triphenyl Phosphate - Hu_2017_Environ.Sci.Technol_51_4061
Author(s) : Hu W , Gao F , Zhang H , Hiromori Y , Arakawa S , Nagase H , Nakanishi T , Hu J
Ref : Environ Sci Technol , 51 :4061 , 2017
Abstract : 2-Ethylhexyl diphenyl phosphate (EHDPP), an organophosphate flame retardant (OPFR), is frequently detected in human blood. In this study, the sensitive dual-luciferase reporter gene assay and molecular docking were used to investigate the activation of EHDPP to human peroxisome proliferator-activated receptor gamma (PPARG). Results show that EHDPP exhibited stronger PPARG activation (EC(20): 2.04 microM) than triphenyl phosphate (TPhP) (EC(20): 2.78 microM). EHDPP upregulated the gene expression of 3beta-hydroxysteroid dehydrogenase type 1 (3beta-HSD1) in human placental choriocarcinoma cells in a dose-dependent manner, and the lowest observable effective concentration was 10 microM, lower than that of TPhP (20 microM). EHDPP significantly altered progesterone secretion at a lower concentration (10 microM) than that of TPhP (20 microM), and both EHDPP and TPhP significantly promoted human chorionic gonadotropin (hCG) production at 20 microM. Furthermore, inactivation of PPARG by either a pharmacological inhibitor (GW9662) or small interfering RNA (siRNA) abolished the change in progesterone secretion and gene expression in the cells exposed to EHDPP, suggesting that the PPARG signaling pathway plays a role in the upregulation of progesterone by the two OPFRs. This is the first report to show that OPFRs can alter the biosynthesis of progesterone in the placenta, which could affect female reproduction and fetal development.
ESTHER : Hu_2017_Environ.Sci.Technol_51_4061
PubMedSearch : Hu_2017_Environ.Sci.Technol_51_4061
PubMedID: 28282128

Title : Functional genomics-guided discovery of a light-activated phytotoxin in the wheat pathogen Parastagonospora nodorum via pathway activation - Chooi_2017_Environ.Microbiol_19_1975
Author(s) : Chooi YH , Zhang G , Hu J , Muria-Gonzalez MJ , Tran PN , Pettitt A , Maier AG , Barrow RA , Solomon PS
Ref : Environ Microbiol , 19 :1975 , 2017
Abstract : Parastagonospora nodorum is an important pathogen of wheat. The contribution of secondary metabolites to this pathosystem is poorly understood. A biosynthetic gene cluster (SNOG_08608-08616) has been shown to be upregulated during the late stage of P. nodorum wheat leaf infection. The gene cluster shares several homologues with the Cercospora nicotianae CTB gene cluster encoding the biosynthesis of cercosporin. Activation of the gene cluster by overexpression (OE) of the transcription factor gene (SNOG_08609) in P. nodorum resulted in the production of elsinochrome C, a perelyenequinone phytotoxin structurally similar to cercosporin. Heterologous expression of the polyketide synthase gene elcA from the gene cluster in Aspergillus nidulans resulted in the production of the polyketide precursor nortoralactone common to the cercosporin pathway. Elsinochrome C could be detected on wheat leaves infected with P. nodorum, but not in the elcA disruption mutant. The compound was shown to exhibit necrotic activity on wheat leaves in a light-dependent manner. Wheat seedling infection assays showed that deltaelcA exhibited reduced virulence compared with wild type, while infection by an OE strain overproducing elsinochrome C resulted in larger lesions on leaves. These data provided evidence that elsinochrome C contributes to the virulence of P. nodorum against wheat.
ESTHER : Chooi_2017_Environ.Microbiol_19_1975
PubMedSearch : Chooi_2017_Environ.Microbiol_19_1975
PubMedID: 28251756
Gene_locus related to this paper: phano-elca

Title : Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy - Hu_2017_Nature_552_248
Author(s) : Hu J , Dziumbla S , Lin J , Bibli SI , Zukunft S , de Mos J , Awwad K , Fromel T , Jungmann A , Devraj K , Cheng Z , Wang L , Fauser S , Eberhart CG , Sodhi A , Hammock BD , Liebner S , Muller OJ , Glaubitz C , Hammes HP , Popp R , Fleming I
Ref : Nature , 552 :248 , 2017
Abstract : Diabetic retinopathy is an important cause of blindness in adults, and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema. Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization. Here we identify soluble epoxide hydrolase (sEH) as a key enzyme that initiates pericyte loss and breakdown of endothelial barrier function by generating the diol 19,20-dihydroxydocosapentaenoic acid, derived from docosahexaenoic acid. The expression of sEH and the accumulation of 19,20-dihydroxydocosapentaenoic acid were increased in diabetic mouse retinas and in the retinas and vitreous humour of patients with diabetes. Mechanistically, the diol targeted the cell membrane to alter the localization of cholesterol-binding proteins, and prevented the association of presenilin 1 with N-cadherin and VE-cadherin, thereby compromising pericyte-endothelial cell interactions and inter-endothelial cell junctions. Treating diabetic mice with a specific sEH inhibitor prevented the pericyte loss and vascular permeability that are characteristic of non-proliferative diabetic retinopathy. Conversely, overexpression of sEH in the retinal Muller glial cells of non-diabetic mice resulted in similar vessel abnormalities to those seen in diabetic mice with retinopathy. Thus, increased expression of sEH is a key determinant in the pathogenesis of diabetic retinopathy, and inhibition of sEH can prevent progression of the disease.
ESTHER : Hu_2017_Nature_552_248
PubMedSearch : Hu_2017_Nature_552_248
PubMedID: 29211719

Title : Unexpected extrapyramidal symptoms and pulmonary aspergillosis in exertional heatstroke with fulminant liver failure: a case report - Jiao_2017_J.Med.Case.Rep_11_37
Author(s) : Jiao J , Zhou F , Kang H , Liu C , Yang M , Hu J
Ref : J Med Case Rep , 11 :37 , 2017
Abstract : BACKGROUND: Exertional heatstroke is a life-threatening condition with high mortality because of the rapid progress of multiple organ dysfunction syndrome even if aggressive treatments are initiated rapidly. Mild to moderate hepatic injury is common in exertional heatstroke, while fulminant liver failure is rare. Extrapyramidal symptoms and pulmonary aspergillosis secondary to liver failure induced by exertional heatstroke have never been reported in prior cases. CASE PRESENTATION: A 25-year-old Han Chinese man presented with exertional heatstroke with fulminant liver failure, subsequent pulmonary aspergillosis, and extrapyramidal symptoms. Moreover, he also presented with coma, rhabdomyolysis, acute kidney injury, and disseminated intravascular coagulation. He recovered under conservative treatment including therapeutic plasma exchange plus continuous veno-venous hemofiltration, fluid resuscitation, antibiotics, and other support therapy.
CONCLUSIONS: Therapeutic plasma exchange plus continuous veno-venous hemofiltration could be effective for patients with heatstroke who suffer liver failure and other organ failure. Patients with liver failure are at high risk for pulmonary aspergillosis. Movement disorder in these patients might be extrapyramidal symptoms induced by consistent low level of cholinesterase resulted from hepatic injury besides brain injury.
ESTHER : Jiao_2017_J.Med.Case.Rep_11_37
PubMedSearch : Jiao_2017_J.Med.Case.Rep_11_37
PubMedID: 28183359

Title : Mono-2-ethylhexyl phthalate inhibits human extravillous trophoblast invasion via the PPARgamma pathway - Gao_2017_Toxicol.Appl.Pharmacol_327_23
Author(s) : Gao F , Hu W , Li Y , Shen H , Hu J
Ref : Toxicol Appl Pharmacol , 327 :23 , 2017
Abstract : Concerns over the adverse reproductive outcomes in human have been raised, more evidence including the underlying mechanism are required. Since extravillous trophoblast (EVT) invasion is an important physiological step during early development, the effects of mono-2-ethylhexyl phthalate (MEHP), the bioactive metabolite of DEHP, on EVT invasion were investigated using Matrigel-coated transwell chambers and cell line HTR-8/SVneo. In the transwell-based invasive assay, MEHP exposure inhibited EVT invasion as judged by decreased invasion index. Further analysis showed that MEHP exposure significantly inhibited the activity of matrix metalloproteinase-9 (MMP-9), which is an important positive regulator of EVT invasion. Meanwhile, the protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), one key negative regulator of EVT invasion, were upregulated by MEHP treatment. Finally, inactivation of PPARgamma pathway by either PPARgamma inhibitors or PPARgamma shRNA knockdown rescued the MEHP-induced inhibited invasion of HTR-8/SVneo cells, which is accompanied by the recovery of inhibited MMP-9 expression. The present study provides the evidence that MEHP exposure inhibits trophoblast invasion via PPARgamma at concentrations comparable to those found in humans, which provides an insight in understanding the mechanisms of DEHP-associated early pregnancy loss.
ESTHER : Gao_2017_Toxicol.Appl.Pharmacol_327_23
PubMedSearch : Gao_2017_Toxicol.Appl.Pharmacol_327_23
PubMedID: 28416457

Title : Design, synthesis, and evaluation of multitarget-directed ligands against Alzheimer's disease based on the fusion of donepezil and curcumin - Yan_2017_Bioorg.Med.Chem_25_2946
Author(s) : Yan J , Hu J , Liu A , He L , Li X , Wei H
Ref : Bioorganic & Medicinal Chemistry , 25 :2946 , 2017
Abstract : By fusing donepezil and curcumin, a novel series of compounds were obtained as multitarget-directed ligands against Alzheimer's disease. Among them, compound 11b displayed potent acetylcholinesterase (AChE) inhibition (IC50=187nM) and the highest BuChE/AChE selectivity (66.3). Compound 11b also inhibited 45.3% Abeta1-42 self-aggregation at 20muM and displayed remarkable antioxidant effects. The metal-chelating property of compound 11b was elucidated by determining the 1:1 stoichiometry for the 11b-Cu(II) complex. The excellent blood-brain barrier permeability of 11b also indicated the potential for the compound to penetrate the central nervous system.
ESTHER : Yan_2017_Bioorg.Med.Chem_25_2946
PubMedSearch : Yan_2017_Bioorg.Med.Chem_25_2946
PubMedID: 28454848

Title : Evogliptin: a new dipeptidyl peptidase inhibitor for the treatment of type 2 diabetes - Tan_2016_Expert.Opin.Pharmacother_17_1285
Author(s) : Tan X , Hu J
Ref : Expert Opin Pharmacother , 17 :1285 , 2016
Abstract : INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel, potent oral antihyperglycemic agents that reduce degradation of endogenous glucagon-like peptide 1 (GLP-1) to increase insulin secretion and satiety and decrease glucagon. DPP-4 inhibitors enhance insulin secretion in a glucose-dependent manner, which potentially reduces hypoglycemia risks during monotherapy or combination therapy with other antidiabetic agents. Evogliptin (Suganon(TM)) is a new oral DPP-4 inhibitor developed for the treatment of patients with type 2 diabetes inadequately controlled by diet and exercise. AREAS COVERED: This review summarizes the collected data concerning mechanism of action, clinical efficacy, and safety of evogliptin in improving glycemic control in patients with type 2 diabetes. Additional non-glycemic benefits and safety profiles of evogliptin are also discussed. EXPERT OPINION: Evogliptin is effective in improving glycosylated hemoglobin (HbA1c) and fasting plasma glucose without inducing hypoglycemia events, which potentially can improve adherence and prevent complications. It is also found that evogliptin has benefits on insulin secretory and beta-cell functions. Based on the current clinical data, evogliptin has a neutral effect on body weight. These attributes contribute to the clinical practice in monotherapy or in combination with other antidiabetic agents.
ESTHER : Tan_2016_Expert.Opin.Pharmacother_17_1285
PubMedSearch : Tan_2016_Expert.Opin.Pharmacother_17_1285
PubMedID: 27156529

Title : Genome-wide identification, classification and expression analysis in fungal-plant interactions of cutinase gene family and functional analysis of a putative ClCUT7 in Curvularia lunata - Liu_2016_Mol.Genet.Genomics_291_1105
Author(s) : Liu T , Hou J , Wang Y , Jin Y , Borth W , Zhao F , Liu Z , Hu J , Zuo Y
Ref : Mol Genet Genomics , 291 :1105 , 2016
Abstract : Cutinase is described as playing various roles in fungal-plant pathogen interactions, such as eliciting host-derived signals, fungal spore attachment and carbon acquisition during saprophytic growth. However, the characteristics of the cutinase genes, their expression in compatible interactions and their roles in pathogenesis have not been reported in Curvularia lunata, an important leaf spot pathogen of maize in China. Therefore, a cutinase gene family analysis could have profound significance. In this study, we identified 13 cutinase genes (ClCUT1 to ClCUT13) in the C. lunata genome. Multiple sequence alignment showed that most fungal cutinase proteins had one highly conserved GYSQG motif and a similar DxVCxG[ST]-[LIVMF](3)-x(3)H motif. Gene structure analyses of the cutinases revealed a complex intron-exon pattern with differences in the position and number of introns and exons. Based on phylogenetic relationship analysis, C. lunata cutinases and 78 known cutinase proteins from other fungi were classified into four groups with subgroups, but the C. lunata cutinases clustered in only three of the four groups. Motif analyses showed that each group of cutinases from C. lunata had a common motif. Real-time PCR indicated that transcript levels of the cutinase genes in a compatible interaction between pathogen and host had varied expression patterns. Interestingly, the transcript levels of ClCUT7 gradually increased during early pathogenesis with the most significant up-regulation at 3 h post-inoculation. When ClCUT7 was deleted, pathogenicity of the mutant decreased on unwounded maize (Zea mays) leaves. On wounded maize leaves, however, the mutant caused symptoms similar to the wild-type strain. Moreover, the ClCUT7 mutant had an approximately 10 % reduction in growth rate when cutin was the sole carbon source. In conclusion, we identified and characterized the cutinase family genes of C. lunata, analyzed their expression patterns in a compatible host-pathogen interaction, and explored the role of ClCUT7 in pathogenicity. This work will increase our understanding of cutinase genes in other fungal-plant pathogens.
ESTHER : Liu_2016_Mol.Genet.Genomics_291_1105
PubMedSearch : Liu_2016_Mol.Genet.Genomics_291_1105
PubMedID: 26767524

Title : Construction of an immobilised acetylcholinesterase column and its application in screening insecticidal constituents from Magnolia officinalis - Ye_2015_Pest.Manag.Sci_71_607
Author(s) : Ye YH , Li C , Yang J , Ma L , Xiao Y , Hu J , Rajput NA , Gao CF , Zhang YY , Wang MH
Ref : Pest Manag Sci , 71 :607 , 2015
Abstract : BACKGROUND: Application of a matrix-immobilised target enzyme for screening inhibitors is widely used in drug development, but there are few studies in insecticide discovery. In this paper, an economical and effective immobilised acetylcholinesterase (AChE) column was prepared using the sol-gel embedment method, which was further combined with high-performance liquid chromatography for screening the AChE inhibitors and insecticidal compounds from complex natural products.
RESULTS: AChE inhibitory constituents magnolol and honokiol were isolated from the ethanol extract of Magnolia officinalis, with IC50 values of 0.069 and 0.057 mM respectively. In an in vivo bioassay, magnolol and honokiol showed insecticidal activity against Nilaparvata lugens, with LC50 values of 0.324 and 0.137 mM, which are comparable with that of commonly used insecticide chlorpyrifos (0.233 mM). Moreover, molecular docking was carried out against a homology model of N. lugens AChE. The complexes showed that magnolol and honokiol placed themselves nicely into the active site of the enzyme and exhibited an interaction energy that was in accordance with our activity profile data. CONCLUSION: These results demonstrate that magnolol and honokiol have great applied potential to be developed as natural insecticides, and an immobilised AChE column is very useful as a rapid screening tool for target enzymes towards potent inhibitors. (c) 2014 Society of Chemical Industry.
ESTHER : Ye_2015_Pest.Manag.Sci_71_607
PubMedSearch : Ye_2015_Pest.Manag.Sci_71_607
PubMedID: 25228142

Title : Neuroprotective activity of (1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (4R) in vitro and in vivo in rodent models of brain ischemia - Martins_2015_Neurosci_291_250
Author(s) : Martins AH , Hu J , Xu Z , Mu C , Alvarez P , Ford BD , El Sayed KA , Eterovic VA , Ferchmin PA , Hao J
Ref : Neuroscience , 291 :250 , 2015
Abstract : (1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (4R) is a precursor to key flavor ingredients in leaves of Nicotiana species. The present study shows 4R decreased brain damage in rodent ischemic stroke models. The 4R-pretreated mice had lower infarct volumes (26.2+/-9.7 mm3) than those in control groups (untreated: 63.4+/-4.2 mm3, DMSO: 60.2+/-14.2 mm3). The 4R-posttreated rats also had less infarct volumes (120+/-65 mm3) than those in the rats of the DMSO group (291+/-95 mm3). The results from in vitro experiments indicate that 4R decreased neuro2a cell (neuroblastoma cells) apoptosis induced by oxygen-glucose deprivation (OGD), and improved the population spikes' (PSs) recovery in rat acute hippocampal slices under OGD; a phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin, abolished the effect of 4R on PSs recovery. Furthermore, 4R also inhibited monocyte adhesion to murine brain-derived endothelial (bEND5) cells and upregulation of intercellular adhesion molecule-1(ICAM-1) induced by OGD/reoxygenation (OGD/R), and restored the p-Akt level to pre-OGD/R values in bEND5 cells. In conclusion, the present study indicates that 4R has a protective effect in rodent ischemic stroke models. Inhibition of ICAM-1 expression and restoration of Akt phosphorylation are the possible mechanisms involved in cellular protection by 4R.
ESTHER : Martins_2015_Neurosci_291_250
PubMedSearch : Martins_2015_Neurosci_291_250
PubMedID: 25677097

Title : Pigment epithelium-derived factor regulates microvascular permeability through adipose triglyceride lipase in sepsis - He_2015_Clin.Sci.(Lond)_129_49
Author(s) : He T , Hu J , Yan G , Li L , Zhang D , Zhang Q , Chen B , Huang Y
Ref : Clinical Science (Lond) , 129 :49 , 2015
Abstract : The integrity of the vascular barrier, which is essential to blood vessel homoeostasis, can be disrupted by a variety of soluble permeability factors during sepsis. Pigment epithelium-derived factor (PEDF), a potent endogenous anti-angiogenic molecule, is significantly increased in sepsis, but its role in endothelial dysfunction has not been defined. To assess the role of PEDF in the vasculature, we evaluated the effects of exogenous PEDF in vivo using a mouse model of cecal ligation and puncture (CLP)-induced sepsis and in vitro using human dermal microvascular endothelial cells (HDMECs). In addition, PEDF was inhibited using a PEDF-monoclonal antibody (PEDF-mAb) or recombinant lentivirus vectors targeting PEDF receptors, including adipose triglyceride lipase (ATGL) and laminin receptor (LR). Our results showed that exogenous PEDF induced vascular hyperpermeability, as measured by extravasation of Evan's Blue (EB), dextran and microspheres in the skin, blood, trachea and cremaster muscle, both in a normal state and under conditions of sepsis. In control and LR-shRNA-treated HDMECs, PEDF alone or in combination with inflammatory mediators resulted in activation of RhoA, which was accompanied by actin rearrangement and disassembly of intercellular junctions, impairing endothelial barrier function. But in ATGL-shRNA-treated HDMECs, PEDF failed to induce the aforementioned alterations, suggesting that PEDF-induced hyperpermeability was mediated through the ATGL receptor. These results reveal a novel role for PEDF as a potential vasoactive substance in septic vascular hyperpermeability. Furthermore, our results suggest that PEDF and ATGL may serve as therapeutic targets for managing vascular hyperpermeability in sepsis.
ESTHER : He_2015_Clin.Sci.(Lond)_129_49
PubMedSearch : He_2015_Clin.Sci.(Lond)_129_49
PubMedID: 25700221

Title : Lysophosphatidylcholine synthesis by lipase-catalyzed ethanolysis - Yang_2015_J.Oleo.Sci_64_443
Author(s) : Yang G , Yang R , Hu J
Ref : J Oleo Sci , 64 :443 , 2015
Abstract : Lysophosphatidylcholine (LPC) is amphiphilic substance, and possesses excellent physiological functions. In this study, LPC was prepared through ethanolysis of phosphatidylcholine (PC) in n-hexane or solvent free media catalyzed by Novozym 435 (from Candida antarctica), Lipozyme TLIM (from Thermomcyces lanuginosus) and Lipozyme RMIM (from Rhizomucor miehei). The results showed that three immobilized lipases from Candida Antarctica, Thermomcyces lanuginosus and Rhizomucor miehei could catalyze ethanolysis of PC efficiently. In n-hexane, the LPC conversions of ethanolysis of PC catalyzed by Novozyme 435, Lipozyme TLIM and Lipozyme RMIM could reach to 98.5 +/- 1.6%, 94.6 +/- 1.4% and 93.7 +/- 1.8%, respectively. In solvent free media, the highest LPC conversions of ethanolysis of PC catalyzed by Novozyme 435, Lipozyme TL IM and Lipozyme RM IM were 97.7 +/- 1.7%, 93.5 +/- 1.2% and 93.8 +/- 1.9%, respectively. The catalytic efficiencies of the three lipases were in the order of Novozyme 435 > Lipozyme TLIM > Lipozyme RMIM. Furthermore, their catalytic efficiencies in n-hexane were better than those in solvent free media.
ESTHER : Yang_2015_J.Oleo.Sci_64_443
PubMedSearch : Yang_2015_J.Oleo.Sci_64_443
PubMedID: 25766935

Title : Decreased carboxylesterases expression and hydrolytic activity in type 2 diabetic mice through Akt\/mTOR\/HIF-1alpha\/Stra13 pathway - Chen_2015_Xenobiotica_45_782
Author(s) : Chen R , Wang Y , Ning R , Hu J , Liu W , Xiong J , Wu L , Liu J , Hu G , Yang J
Ref : Xenobiotica , 45 :782 , 2015
Abstract : 1. This study investigated the alteration of carboxylesterases in type 2 diabetes. We found that the carboxylesterase 1d (Ces1d) and carboxylesterase 1e (Ces1e) expression and the capacity of hydrolytic activity of liver and intestine decreased, whereas the Akt/mTOR/HIF-1alpha/ Stra13 (DEC1) signaling was activated in T2D mice. Consistently, high insulin could give rise to the same results in the high-glucose DMEM condition, which mimicked T2D, in primary mouse hepatocytes. 2. Perifosine or rapamycin almost abolished the decrease of the Ces1d and Ces1e expression and the hydrolytic activity induced by the insulin in the primary mouse hepatocytes. 3. The responsiveness of human hepatoma (HepG2) cells to high insulin in high-glucose condition was similar to that of primary mouse hepatocytes in terms of the altered expression of carboxylesterases. 4. The knockdown of HIF-1alpha or DEC1 with shRNA construct abrogated the decrease of the CES1 and CES2 expression induced by the insulin in high glucose condition in HepG2 cells. 5. Taken together, the decreased carboxylesterases expression and hydrolytic activity in T2D mice are through the Akt/mTOR/HIF-1alpha/Stra13 (DEC1) pathway.
ESTHER : Chen_2015_Xenobiotica_45_782
PubMedSearch : Chen_2015_Xenobiotica_45_782
PubMedID: 25801056

Title : Proteomic analysis of ubiquitinated proteins from deltamethrin-resistant and susceptible strains of the diamondback moth, Plutella Xylostella L - Cheng_2015_Arch.Insect.Biochem.Physiol_90_70
Author(s) : Cheng L , Du Y , Hu J , Jiao D , Li J , Zhou Z , Xu Q , Li F
Ref : Archives of Insect Biochemistry & Physiology , 90 :70 , 2015
Abstract : Ubiquitin, a small protein consisting of 76 amino acids, acts in protein degradation, DNA repair, signal transduction, transcriptional regulation, and receptor control through endocytosis. Using proteomics, we compared the differentially ubiquitinated proteins between a deltamethrin-resistant (DR) strain and a deltamethrin-sensitive (DS) strain in third-instar larvae of the diamondback moth. We used polyubiquitin affinity beads to enrich ubiquitinated proteins and then performed one-dimensional SDS-PAGE separation and mass spectrometric identification. In the DR strain, We found 17 proteins that were upregulated (relative to the DS strain), including carbonic anhydrase family members, ADP ribosylation factor 102F CG11027-PA, protein kinase 61C, phospholipase A2 , dihydrolipoamide dehydrogenase, tyrosine hydroxylase, and heat shock proteins, and five proteins that were downregulated in the DS strain, including carboxylesterase and DNA cytosine-5 methyltransferase. These results were also verified by qPCR. The differentially ubiquitinated proteins/enzymes were mainly responsible for protein binding, catalytic activity, and molecular transducer activity. These results improve our understanding of the relationship between protein ubiquitination and the deltamethrin stress response.
ESTHER : Cheng_2015_Arch.Insect.Biochem.Physiol_90_70
PubMedSearch : Cheng_2015_Arch.Insect.Biochem.Physiol_90_70
PubMedID: 25983007

Title : Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer's disease - Zhou_2015_J.Mol.Model_21_277
Author(s) : Zhou A , Hu J , Wang L , Zhong G , Pan J , Wu Z , Hui A
Ref : J Mol Model , 21 :277 , 2015
Abstract : Acetylcholinesterase (AChE) is one of the key targets of drugs for treating Alzheimer's disease (AD). Tacrine is an approved drug with AChE-inhibitory activity. In this paper, 3D-QSAR, molecular docking, and molecular dynamics were carried out in order to study 60 tacrine derivatives and their AChE-inhibitory activities. 3D-QSAR modeling resulted in an optimal CoMFA model with q (2) = 0.552 and r (2) = 0.983 and an optimal CoMSIA model with q (2) = 0.581 and r (2) = 0.989. These QSAR models also showed that the steric and H-bond fields of these compounds are important influences on their activities. The interactions between these inhibitors and AChE were further explored through molecular docking and molecular dynamics simulation. A few key residues (Tyr70, Trp84, Tyr121, Trp279, and Phe330) at the binding site of AChE were identified. The results of this study improve our understanding of the mechanisms of AChE inhibitors and afford valuable information that should aid the design of novel potential AChE inhibitors. Graphical Abstract Superposition of backbone atoms of the lowest-energy structure obtained from MD simulation (magenta) onto those of the structure of the initial molecular docking model (green).
ESTHER : Zhou_2015_J.Mol.Model_21_277
PubMedSearch : Zhou_2015_J.Mol.Model_21_277
PubMedID: 26438408

Title : Muscarinic acetylcholine receptor X-ray structures: potential implications for drug development - Kruse_2014_Curr.Opin.Pharmacol_16_24
Author(s) : Kruse AC , Hu J , Kobilka BK , Wess J
Ref : Curr Opin Pharmacol , 16 :24 , 2014
Abstract : Muscarinic acetylcholine receptor antagonists are widely used as bronchodilating drugs in pulmonary medicine. The therapeutic efficacy of these agents depends on the blockade of M3 muscarinic receptors expressed on airway smooth muscle cells. All muscarinic antagonists currently used as bronchodilating agents show high affinity for all five muscarinic receptor subtypes, thus increasing the likelihood of unwanted side effects. Recent X-ray crystallographic studies have provided detailed structural information about the nature of the orthosteric muscarinic binding site (the conventional acetylcholine binding site) and an 'outer' receptor cavity that can bind allosteric (non-orthosteric) drugs. These new findings should guide the development of selective M3 receptor blockers that have little or no effect on other muscarinic receptor subtypes.
ESTHER : Kruse_2014_Curr.Opin.Pharmacol_16_24
PubMedSearch : Kruse_2014_Curr.Opin.Pharmacol_16_24
PubMedID: 24662799

Title : Complete Genome Sequence of Magnetospirillum gryphiswaldense MSR-1 - Wang_2014_Genome.Announc_2_e00171
Author(s) : Wang X , Wang Q , Zhang W , Wang Y , Li L , Wen T , Zhang T , Zhang Y , Xu J , Hu J , Li S , Liu L , Liu J , Jiang W , Tian J , Li Y , Schuler D , Wang L , Li J
Ref : Genome Announc , 2 : , 2014
Abstract : We report the complete genomic sequence of Magnetospirillum gryphiswaldense MSR-1 (DSM 6361), a type strain of the genus Magnetospirillum belonging to the Alphaproteobacteria. Compared to the reported draft sequence, extensive rearrangements and differences were found, indicating high genomic flexibility and "domestication" by accelerated evolution of the strain upon repeated passaging.
ESTHER : Wang_2014_Genome.Announc_2_e00171
PubMedSearch : Wang_2014_Genome.Announc_2_e00171
PubMedID: 24625872
Gene_locus related to this paper: maggm-v6ezc0

Title : Novel Multipotent AChEI-CCB Attenuates Hyperhomocysteinemia-Induced Memory Deficits and Neuropathologies in Rats - Xia_2014_J.Alzheimers.Dis_42_1029
Author(s) : Xia Y , Liu R , Chen R , Tian Q , Zeng K , Hu J , Liu X , Wang Q , Wang P , Wang XC , Wang JZ
Ref : J Alzheimers Dis , 42 :1029 , 2014
Abstract : Alzheimer's disease (AD) has multiple etiopathogenic factors, yet the definitive cause remains unclear and the therapeutic strategies have been elusive. Combination therapy, as one of the promising treatments, has been studied for years and may exert synergistic beneficial effects on AD through polytherapeutic targets. In this study, we tested the effects of a synthesized juxtaposition (named SCR1693) composed of an acetylcholinesterase inhibitor (AChEI) and a calcium channel blocker (CCB) on the hyperhomocysteinemia (HHcy)-induced AD rat model, and found that SCR1693 remarkably improved the HHcy-induced memory deficits and preserved dendrite morphologies as well as spine density by upregulating synapse-associated proteins PSD95 and synapsin-1. In addition, SCR1693 attenuated HHcy-induced tau hyperphosphorylation at multiple AD-associated sites by regulating the activity of protein phosphatase-2A and glycogen synthase kinase-3beta. Furthermore, SCR1693 was more effective than individual administration of both donepezil and nilvadipine which were used as AChEI and CCB, respectively, in the clinical practice. In conclusion, our data suggest that the polytherapeutic targeting juxtaposition SCR1693 (AChEI-CCB) is a promising therapeutic candidate for AD.
ESTHER : Xia_2014_J.Alzheimers.Dis_42_1029
PubMedSearch : Xia_2014_J.Alzheimers.Dis_42_1029
PubMedID: 25024319

Title : Novel insights into m3 muscarinic acetylcholine receptor physiology and structure - Kruse_2014_J.Mol.Neurosci_53_316
Author(s) : Kruse AC , Li J , Hu J , Kobilka BK , Wess J
Ref : Journal of Molecular Neuroscience , 53 :316 , 2014
Abstract : Recent studies with M3 muscarinic acetylcholine receptor (M3R) mutant mice suggest that drugs selectively targeting this receptor subtype may prove useful for the treatment of various pathophysiological conditions. Moreover, the use of M3R-based designer G protein-coupled receptors (GPCRs) has provided novel insights into how Gq-coupled GPCRs can modulate whole-body glucose homeostasis by acting on specific peripheral cell types. More recently, we succeeded in using X-ray crystallography to determine the structure of the M3R bound to the bronchodilating drug tiotropium, a muscarinic antagonist (inverse agonist). This new structural information should facilitate the development of orthosteric or allosteric M3R-selective drugs that are predicted to have considerable therapeutic potential.
ESTHER : Kruse_2014_J.Mol.Neurosci_53_316
PubMedSearch : Kruse_2014_J.Mol.Neurosci_53_316
PubMedID: 24068573

Title : Optimal dose of zinc supplementation for preventing aluminum-induced neurotoxicity in rats - Lu_2013_Neural.Regen.Res_8_2754
Author(s) : Lu H , Hu J , Li J , Pang W , Hu Y , Yang H , Li W , Huang C , Zhang M , Jiang Y
Ref : Neural Regen Res , 8 :2754 , 2013
Abstract : Zinc supplementation can help maintain learning and memory function in rodents. In this study, we hypothesized that zinc supplementation could antagonize the neurotoxicity induced by aluminum in rats. Animals were fed a diet containing different doses of zinc (50, 100, 200 mg/kg) for 9 weeks, and orally administered aluminum chloride (300 mg/kg daily) from the third week for 7 consecutive weeks. Open-field behavioral test results showed that the number of rearings in the group given the 100 mg/kg zinc supplement was significantly increased compared with the group given the 50 mg/kg zinc supplement. Malondialdehyde content in the cerebrum was significantly decreased, while dopamine and 5-hydroxytryptamine levels were increased in the groups given the diet supplemented with 100 and 200 mg/kg zinc, compared with the group given the diet supplemented with 50 mg/kg zinc. The acetylcholinesterase activity in the cerebrum was significantly decreased in the group given the 100 mg/kg zinc supplement. Hematoxylin-eosin staining revealed evident pathological damage in the hippocampus of rats in the group given the diet supplemented with 50 mg/kg zinc, but the damage was attenuated in the groups given the diet supplemented with 100 and 200 mg/kg zinc. Our findings suggest that zinc is a potential neuroprotective agent against aluminum-induced neurotoxicity in rats, and the optimal dosages are 100 and 200 mg/kg.
ESTHER : Lu_2013_Neural.Regen.Res_8_2754
PubMedSearch : Lu_2013_Neural.Regen.Res_8_2754
PubMedID: 25206586

Title : Genome and transcriptome sequencing of the halophilic fungus Wallemia ichthyophaga: haloadaptations present and absent - Zajc_2013_BMC.Genomics_14_617
Author(s) : Zajc J , Liu Y , Dai W , Yang Z , Hu J , Gostincar C , Gunde-Cimerman N
Ref : BMC Genomics , 14 :617 , 2013
Abstract : BACKGROUND: The basidomycete Wallemia ichthyophaga from the phylogenetically distinct class Wallemiomycetes is the most halophilic fungus known to date. It requires at least 10% NaCl and thrives in saturated salt solution. To investigate the genomic basis of this exceptional phenotype, we obtained a de-novo genome sequence of the species type-strain and analysed its transcriptomic response to conditions close to the limits of its lower and upper salinity range.
RESULTS: The unusually compact genome is 9.6 Mb large and contains 1.67% repetitive sequences. Only 4884 predicted protein coding genes cover almost three quarters of the sequence. Of 639 differentially expressed genes, two thirds are more expressed at lower salinity. Phylogenomic analysis based on the largest dataset used to date (whole proteomes) positions Wallemiomycetes as a 250-million-year-old sister group of Agaricomycotina. Contrary to the closely related species Wallemia sebi, W. ichthyophaga appears to have lost the ability for sexual reproduction. Several protein families are significantly expanded or contracted in the genome. Among these, there are the P-type ATPase cation transporters, but not the sodium/ hydrogen exchanger family. Transcription of all but three cation transporters is not salt dependent. The analysis also reveals a significant enrichment in hydrophobins, which are cell-wall proteins with multiple cellular functions. Half of these are differentially expressed, and most contain an unusually large number of acidic amino acids. This discovery is of particular interest due to the numerous applications of hydrophobines from other fungi in industry, pharmaceutics and medicine.
CONCLUSIONS: W. ichthyophaga is an extremophilic specialist that shows only low levels of adaptability and genetic recombination. This is reflected in the characteristics of its genome and its transcriptomic response to salt. No unusual traits were observed in common salt-tolerance mechanisms, such as transport of inorganic ions or synthesis of compatible solutes. Instead, various data indicate a role of the cell wall of W. ichthyophaga in its response to salt. Availability of the genomic sequence is expected to facilitate further research into this unique species, and shed more light on adaptations that allow it to thrive in conditions lethal to most other eukaryotes.
ESTHER : Zajc_2013_BMC.Genomics_14_617
PubMedSearch : Zajc_2013_BMC.Genomics_14_617
PubMedID: 24034603

Title : Activation and allosteric modulation of a muscarinic acetylcholine receptor - Kruse_2013_Nature_504_101
Author(s) : Kruse AC , Ring AM , Manglik A , Hu J , Hu K , Eitel K , Hubner H , Pardon E , Valant C , Sexton PM , Christopoulos A , Felder CC , Gmeiner P , Steyaert J , Weis WI , Garcia KC , Wess J , Kobilka BK
Ref : Nature , 504 :101 , 2013
Abstract : Despite recent advances in crystallography and the availability of G-protein-coupled receptor (GPCR) structures, little is known about the mechanism of their activation process, as only the beta2 adrenergic receptor (beta2AR) and rhodopsin have been crystallized in fully active conformations. Here we report the structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display. In addition to the expected changes in the intracellular surface, the structure reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the beta2AR and rhodopsin. We also report the structure of the M2 receptor simultaneously bound to the orthosteric agonist iperoxo and the positive allosteric modulator LY2119620. This structure reveals that LY2119620 recognizes a largely pre-formed binding site in the extracellular vestibule of the iperoxo-bound receptor, inducing a slight contraction of this outer binding pocket. These structures offer important insights into the activation mechanism and allosteric modulation of muscarinic receptors.
ESTHER : Kruse_2013_Nature_504_101
PubMedSearch : Kruse_2013_Nature_504_101
PubMedID: 24256733

Title : Muscarinic receptors as model targets and antitargets for structure-based ligand discovery - Kruse_2013_Mol.Pharmacol_84_528
Author(s) : Kruse AC , Weiss DR , Rossi M , Hu J , Hu K , Eitel K , Gmeiner P , Wess J , Kobilka BK , Shoichet BK
Ref : Molecular Pharmacology , 84 :528 , 2013
Abstract : G protein-coupled receptors (GPCRs) regulate virtually all aspects of human physiology and represent an important class of therapeutic drug targets. Many GPCR-targeted drugs resemble endogenous agonists, often resulting in poor selectivity among receptor subtypes and restricted pharmacologic profiles. The muscarinic acetylcholine receptor family exemplifies these problems; thousands of ligands are known, but few are receptor subtype-selective and nearly all are cationic in nature. Using structure-based docking against the M2 and M3 muscarinic receptors, we screened 3.1 million molecules for ligands with new physical properties, chemotypes, and receptor subtype selectivities. Of 19 docking-prioritized molecules tested against the M2 subtype, 11 had substantial activity and 8 represented new chemotypes. Intriguingly, two were uncharged ligands with low micromolar to high nanomolar Ki values, an observation with few precedents among aminergic GPCRs. To exploit a single amino-acid substitution among the binding pockets between the M2 and M3 receptors, we selected molecules predicted by docking to bind to the M3 and but not the M2 receptor. Of 16 molecules tested, 8 bound to the M3 receptor. Whereas selectivity remained modest for most of these, one was a partial agonist at the M3 receptor without measurable M2 agonism. Consistent with this activity, this compound stimulated insulin release from a mouse beta-cell line. These results support the ability of structure-based discovery to identify new ligands with unexplored chemotypes and physical properties, leading to new biologic functions, even in an area as heavily explored as muscarinic pharmacology.
ESTHER : Kruse_2013_Mol.Pharmacol_84_528
PubMedSearch : Kruse_2013_Mol.Pharmacol_84_528
PubMedID: 23887926

Title : CutA divalent cation tolerance homolog (Escherichia coli) (CUTA) regulates beta-cleavage of beta-amyloid precursor protein (APP) through interacting with beta-site APP cleaving protein 1 (BACE1) - Zhao_2012_J.Biol.Chem_287_11141
Author(s) : Zhao Y , Wang Y , Hu J , Zhang X , Zhang YW
Ref : Journal of Biological Chemistry , 287 :11141 , 2012
Abstract : Accumulation of the neurotoxic beta-amyloid (Abeta) peptide in the brain is central to the pathogenesis of Alzheimer disease. Abeta is derived from the beta-amyloid precursor protein (APP) through sequential cleavages by beta- and gamma-secretases, and the production of Abeta is greatly affected by the subcellular localization of these factors. CUTA, the mammalian CutA divalent cation tolerance homolog (E. coli), has been proposed to mediate acetylcholinesterase activity and copper homeostasis, which are important in Alzheimer disease pathology. However, the exact function of CUTA remains largely unclear. Here we show that human CUTA has several variants that differ in their N-terminal length and are separated as heavy (H) and light (L) components. The H component has the longest N terminus and is membrane-associated, whereas the L component is N-terminally truncated at various sites and localized in the cytosol. Importantly, we demonstrate that the H component of CUTA interacts through its N terminus with the transmembrane domain of beta-site APP cleaving enzyme 1 (BACE1), the putative beta-secretase, mainly in the Golgi/trans-Golgi network. Overexpression and RNA interference knockdown of CUTA can reduce and increase BACE1-mediated APP processing/Abeta secretion, respectively. RNA interference of CUTA decelerates intracellular trafficking of BACE1 from the Golgi/trans-Golgi network to the cell surface and reduces the steady-state level of cell surface BACE1. Our results identify the H component of CUTA as a novel BACE1-interacting protein that mediates the intracellular trafficking of BACE1 and the processing of APP to Abeta.
ESTHER : Zhao_2012_J.Biol.Chem_287_11141
PubMedSearch : Zhao_2012_J.Biol.Chem_287_11141
PubMedID: 22351782

Title : alpha7 nicotinic acetylcholine receptor-mediated neuroprotection against dopaminergic neuron loss in an MPTP mouse model via inhibition of astrocyte activation - Liu_2012_J.Neuroinflammation_9_98
Author(s) : Liu Y , Hu J , Wu J , Zhu C , Hui Y , Han Y , Huang Z , Ellsworth K , Fan W
Ref : J Neuroinflammation , 9 :98 , 2012
Abstract : BACKGROUND: Although evidence suggests that the prevalence of Parkinson's disease (PD) is lower in smokers than in non-smokers, the mechanisms of nicotine-induced neuroprotection remain unclear. Stimulation of the alpha7 nicotinic acetylcholine receptor (alpha7-nAChR) seems to be a crucial mechanism underlying the anti-inflammatory potential of cholinergic agonists in immune cells, including astrocytes, and inhibition of astrocyte activation has been proposed as a novel strategy for the treatment of neurodegenerative disorders such as PD. The objective of the present study was to determine whether nicotine-induced neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model occurs via alpha7-nAChR-mediated inhibition of astrocytes.
METHODS: Both in vivo (MPTP) and in vitro (1-methyl-4-phenylpyridinium ion (MPP+) and lipopolysaccharide (LPS)) models of PD were used to investigate the role(s) of and possible mechanism(s) by which alpha7-nAChRs protect against dopaminergic neuron loss. Multiple experimental approaches, including behavioral tests, immunochemistry, and stereology experiments, astrocyte cell cultures, reverse transcriptase PCR, laser scanning confocal microscopy, tumor necrosis factor (TNF)-alpha assays, and western blotting, were used to elucidate the mechanisms of the alpha7-nAChR-mediated neuroprotection.
RESULTS: Systemic administration of nicotine alleviated MPTP-induced behavioral symptoms, improved motor coordination, and protected against dopaminergic neuron loss and the activation of astrocytes and microglia in the substantia nigra. The protective effects of nicotine were abolished by administration of the alpha7-nAChR-selective antagonist methyllycaconitine (MLA). In primary cultured mouse astrocytes, pretreatment with nicotine suppressed MPP(+)-induced or LPS-induced astrocyte activation, as evidenced by both decreased production of TNF-alpha and inhibition of extracellular regulated kinase1/2 (Erk1/2) and p38 activation in astrocytes, and these effects were also reversed by MLA. CONCLUSION: Taken together, our results suggest that alpha7-nAChR-mediated inhibition of astrocyte activation is an important mechanism underlying the protective effects of nicotine.
ESTHER : Liu_2012_J.Neuroinflammation_9_98
PubMedSearch : Liu_2012_J.Neuroinflammation_9_98
PubMedID: 22624500

Title : Molecular mechanism and structural basis of interactions of dipeptidyl peptidase IV with adenosine deaminase and human immunodeficiency virus type-1 transcription transactivator - Fan_2012_Eur.J.Cell.Biol_91_265
Author(s) : Fan H , Tansi FL , Weihofen WA , Bottcher C , Hu J , Martinez J , Saenger W , Reutter W
Ref : European Journal of Cell Biology , 91 :265 , 2012
Abstract : Dipeptidyl peptidase IV (DPPIV or CD26) is a multifunctional membrane glycoprotein. As an exopeptidase it regulates the activity of a series of biologically important peptides. Through its interaction with specific proteins and peptides, DPPIV is also involved in a wide range of biologically relevant processes such as cell adhesion, T cell activation and apoptosis. In this paper, we review our recent studies on the interactions of DPPIV with adenosine deaminase (ADA) and the transcription transactivator of the human immunodeficiency virus type-1 (HIV-1 Tat) as revealed by three-dimensional structure reconstructed by single particle analysis of cryo-electron microscopy (EM) and crystal structures of the human DPPIV-bovine ADA complex as well as the crystal structures of DPPIV in complex with HIV-1 Tat-derived nonapeptides. These results contribute importantly to the clarification of the molecular mechanisms of this multifunctional protein. The biological relevance of these interactions is discussed.
ESTHER : Fan_2012_Eur.J.Cell.Biol_91_265
PubMedSearch : Fan_2012_Eur.J.Cell.Biol_91_265
PubMedID: 21856036

Title : Intravenous high-dose enzyme replacement therapy with recombinant palmitoyl-protein thioesterase reduces visceral lysosomal storage and modestly prolongs survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis - Hu_2012_Mol.Genet.Metab_107_213
Author(s) : Hu J , Lu JY , Wong AM , Hynan LS , Birnbaum SG , Yilmaz DS , Streit BM , Lenartowicz EM , Thompson TC , Cooper JD , Hofmann SL
Ref : Mol Genet Metab , 107 :213 , 2012
Abstract : PPT1-related neuronal ceroid lipofuscinosis (NCL) is a lysosomal storage disorder caused by deficiency in a soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1). Enzyme replacement therapy (ERT) has not been previously examined in a preclinical animal model. Homozygous PPT1 knockout mice reproduce the known features of the disease, developing signs of motor dysfunction at 5 months of age and death by around 8 months. In the current study, PPT1 knockout mice were treated with purified recombinant PPT1 (0.3 mg, corresponding to 12 mg/kg or 180 U/kg for a 25 g mouse) administered intravenously weekly either 1) from birth; or 2) beginning at 8 weeks of age. The treatment was surprisingly well tolerated and neither anaphylaxis nor antibody formation was observed. In mice treated from birth, survival increased from 236 to 271 days (p<0.001) and the onset of motor deterioration was similarly delayed. In mice treated beginning at 8 weeks, no increases in survival or motor performance were seen. An improvement in neuropathology in the thalamus was seen at 3 months in mice treated from birth, and although this improvement persisted it was attenuated by 7 months. Outside the central nervous system, substantial clearance of autofluorescent storage material in many tissues was observed. Macrophages in spleen, liver and intestine were especially markedly improved, as were acinar cells of the pancreas and tubular cells of the kidney. These findings suggest that ERT may be an option for addressing visceral storage as part of a comprehensive approach to PPT1-related NCL, but more effective delivery methods to target the brain are needed.
ESTHER : Hu_2012_Mol.Genet.Metab_107_213
PubMedSearch : Hu_2012_Mol.Genet.Metab_107_213
PubMedID: 22704978
Gene_locus related to this paper: mouse-ppt

Title : Structure and dynamics of the M3 muscarinic acetylcholine receptor - Kruse_2012_Nature_482_552
Author(s) : Kruse AC , Hu J , Pan AC , Arlow DH , Rosenbaum DM , Rosemond E , Green HF , Liu T , Chae PS , Dror RO , Shaw DE , Weis WI , Wess J , Kobilka BK
Ref : Nature , 482 :552 , 2012
Abstract : Acetylcholine, the first neurotransmitter to be identified, exerts many of its physiological actions via activation of a family of G-protein-coupled receptors (GPCRs) known as muscarinic acetylcholine receptors (mAChRs). Although the five mAChR subtypes (M1-M5) share a high degree of sequence homology, they show pronounced differences in G-protein coupling preference and the physiological responses they mediate. Unfortunately, despite decades of effort, no therapeutic agents endowed with clear mAChR subtype selectivity have been developed to exploit these differences. We describe here the structure of the G(q/11)-coupled M3 mAChR ('M3 receptor', from rat) bound to the bronchodilator drug tiotropium and identify the binding mode for this clinically important drug. This structure, together with that of the G(i/o)-coupled M2 receptor, offers possibilities for the design of mAChR subtype-selective ligands. Importantly, the M3 receptor structure allows a structural comparison between two members of a mammalian GPCR subfamily displaying different G-protein coupling selectivities. Furthermore, molecular dynamics simulations suggest that tiotropium binds transiently to an allosteric site en route to the binding pocket of both receptors. These simulations offer a structural view of an allosteric binding mode for an orthosteric GPCR ligand and provide additional opportunities for the design of ligands with different affinities or binding kinetics for different mAChR subtypes. Our findings not only offer insights into the structure and function of one of the most important GPCR families, but may also facilitate the design of improved therapeutics targeting these critical receptors.
ESTHER : Kruse_2012_Nature_482_552
PubMedSearch : Kruse_2012_Nature_482_552
PubMedID: 22358844

Title : [Effects of early intervention with Huannao Yicong formula effective components on behavior and cholinergic system of beta-amyloid precursor protein transgenic mice] - Cai_2011_Zhong.Xi.Yi.Jie.He.Xue.Bao_9_292
Author(s) : Cai LL , Li H , Liu JG , Liu LT , Guan J , Liu MF , Hu J , Wei Y
Ref : Zhong Xi Yi Jie He Xue Bao , 9 :292 , 2011
Abstract : OBJECTIVE: To observe the effects of early intervention with effective components from a Chinese herbal formula (Huannao Yicong formula, HNYCF) on behavior and related indicators of cholinergic system in beta-amyloid precursor protein (APP) transgenic mice. METHODS: Sixty 3-month-old APP695 V717I transgenic mice were randomly divided into model group, high-dose HNYCF group (2.80 g/(kg.d)), low-dose HNYCF group (1.40 g/(kg.d)) and donepezil group (0.65 mg/(kg.d)), with 15 mice in each group. Fifteen non-transgenic mice of the same genetic background were used as normal group. The model group and normal group were fed with equal volume of distilled water by gavage. After 6-month continuous medication, the Morris water maze and the passive avoidance test were used to detect the visual spatial learning and memory ability of each mouse. Then the mice were decapitated and their cerebral cortex and hippocampus were isolated to homogenate by sonication. Contents of acetylcholine (ACh) and acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) activity in the homogenate were determined by enzyme-linked immunosorbent assay, and protein contents of cerebral cortex and hippocampus were measured by Coomassie brilliant blue method. RESULTS: Compared with the model group, high- and low-dose HNYCF and donepezil hydrochloride all improved spatial learning of APP mice in the Morris water maze. The ratio of swimming distance in the central area in the high-dose HNYCF group was longer than that in the model group (P<0.05). In the passive avoidance test, high- and low-dose HNYCF and donepezil hydrochloride improved memory function of APP mice by improving the escape latency and reducing the number of errors (P<0.05, P<0.01). High- and low-dose HNYCF and donepezil hydrochloride reduced the content of AChE, increased the activity of ChAT (P<0.01, P<0.05) and improved the content of ACh in hippocampus (P<0.05); high- and low-dose HNYCF and donepezil hydrochloride increased the content of ACh in cortex (P<0.05). Donepezil hydrochloride reduced the content of AChE in cortex (P<0.05), however, high- and low-dose HNYCF had no obvious influence (P>0.05). High- and low-dose HNYCF increased the content of ChAT in cortex (P<0.05), whereas donepezil hydrochloride had no obvious influence (P>0.05). CONCLUSION: Early intervention with HNYCF effective components can improve the learning and memory ability of APP transgenic mice. The mechanism may be related to enhancing the function of cholinergic system.
ESTHER : Cai_2011_Zhong.Xi.Yi.Jie.He.Xue.Bao_9_292
PubMedSearch : Cai_2011_Zhong.Xi.Yi.Jie.He.Xue.Bao_9_292
PubMedID: 21419082

Title : A sensitive enzymatic method for paraoxon detection based on enzyme inhibition and fluorescence quenching - Wang_2011_Talanta_84_400
Author(s) : Wang K , Wang L , Jiang W , Hu J
Ref : Talanta , 84 :400 , 2011
Abstract : A sensitive and selective method for the paraoxon detection based on enzyme inhibition and fluorescence quenching was presented in this study. Under the catalytic effect of acetylcholinesterase (AChE), acetylthiocholine (ATCh) hydrolysis released thiocholine (TCh) which could react with N-(7-dimethylamino-4-methylcoumarin-3-yl) maleimide (DACM) to produce a blue fluorescence compound. Subsequently, AChE catalytic activity was inhibited with the addition of paraoxon, which caused TCh decreased, leading to a significant decrease of the blue fluorescent compound. Meanwhile, p-nitrophenol, the hydrolysis product of paraoxon, would lead to a quenching of the fluorescence. Therefore, fluorescence intensity of the system would decrease dramatically by a combined effect of enzyme inhibition and fluorescence quenching. Under optimal experimental conditions, an excellent linear relationship between the decrease of fluorescence intensity and paraoxon concentration over the range from 5.5 x 10(-12) to 1.8 x 10(-10) mol L(-1) was obtained. Fluorescence background caused by nonenzymatic hydrolysis of ATCh or other matters was relatively low, the proposed approach offered adequate sensitivity for the detection of paraoxon at 3.5 x 10(-12) mol L(-1).
ESTHER : Wang_2011_Talanta_84_400
PubMedSearch : Wang_2011_Talanta_84_400
PubMedID: 21376964

Title : Dynamic alterations of gene expression of nicotinic acetylcholine receptor alpha7, alpha4 and beta2 subunits in an acute MPTP-lesioned mouse model - Hu_2011_Neurosci.Lett_494_232
Author(s) : Hu J , Zhu C , Liu Y , Wang F , Huang Z , Fan W , Wu J
Ref : Neuroscience Letters , 494 :232 , 2011
Abstract : Epidemiologic studies show that the prevalence of Parkinson's disease (PD) is lower in smokers than in nonsmokers. Nicotine, a potent agonist of nicotinic acetylcholine receptors (nAChRs), excites midbrain dopaminergic neurons and this may contribute to the anti-parkinsonian effects. However, the alterations in gene expression of nAChR subunits using an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model remain unclear. In the present study, we profile the time course of nAChR alpha7, alpha4 and beta2 subunit expression levels using a comparative RT-PCR approach after acute MPTP injection. The results fall into four categories. (1) MPTP treatment transiently increased nAChR alpha7 (after last injection of MPTP 3 and 24 h), alpha4 and beta2 (24 h) mRNA expression in the substantia nigra (SN) and striatum. (2) Compared to cortical and hippocampal tissues, this transient increase of nAChR subunit expression specifically occurred in the SN and striatum. (3) In the acute MPTP model, time-courses of altered expression for nAChR alpha7, alpha4 and beta2 subunits closely mirrored the deficits observed in animal motor activity. (4) Stereological data showed that after administration of MPTP for 24h, there was a robust astrogliosis in the SN associated with significant dopaminergic neurodegeneration. These changes followed or paralleled MPTP-induced elevation in the levels of alpha7, alpha4 and beta2 mRNAs. Collectively, our results demonstrate that nAChRs are important targets in the MPTP neurotoxic process. These data suggest that therapeutic strategies targeted toward nAChR alpha7, alpha4 and beta2 subunits may have potential for developing new treatments for PD.
ESTHER : Hu_2011_Neurosci.Lett_494_232
PubMedSearch : Hu_2011_Neurosci.Lett_494_232
PubMedID: 21406211

Title : An in vivo tethered toxin approach for the cell-autonomous inactivation of voltage-gated sodium channel currents in nociceptors - Sturzebecher_2010_J.Physiol_588_1695
Author(s) : Sturzebecher AS , Hu J , Smith ES , Frahm S , Santos-Torres J , Kampfrath B , Auer S , Lewin GR , Ibanez-Tallon I
Ref : Journal of Physiology , 588 :1695 , 2010
Abstract : Understanding information flow in sensory pathways requires cell-selective approaches to manipulate the activity of defined neurones. Primary afferent nociceptors, which detect painful stimuli, are enriched in specific voltage-gated sodium channel (VGSC) subtypes. Toxins derived from venomous animals can be used to dissect the contributions of particular ion currents to cell physiology. Here we have used a transgenic approach to target a membrane-tethered isoform of the conotoxin MrVIa (t-MrVIa) only to nociceptive neurones in mice. T-MrVIa transgenic mice show a 44 +/- 7% reduction of tetrodotoxin-resistant (TTX-R) VGSC current densities. This inhibition is permanent, reversible and does not result in functional upregulation of TTX-sensitive (TTX-S) VGSCs, voltage-gated calcium channels (VGCCs) or transient receptor potential (TRP) channels present in nociceptive neurones. As a consequence of the reduction of TTX-R VGSC currents, t-MrVIa transgenic mice display decreased inflammatory mechanical hypersensitivity, cold pain insensitivity and reduced firing of cutaneous C-fibres sensitive to noxious cold temperatures. These data validate the use of genetically encoded t-toxins as a powerful tool to manipulate VGSCs in specific cell types within the mammalian nervous system. This novel genetic methodology can be used for circuit mapping and has the key advantage that it enables the dissection of the contribution of specific ionic currents to neuronal function and to behaviour.
ESTHER : Sturzebecher_2010_J.Physiol_588_1695
PubMedSearch : Sturzebecher_2010_J.Physiol_588_1695
PubMedID: 20308253

Title : Human recombinant palmitoyl-protein thioesterase-1 (PPT1) for preclinical evaluation of enzyme replacement therapy for infantile neuronal ceroid lipofuscinosis - Lu_2010_Mol.Genet.Metab_99_374
Author(s) : Lu JY , Hu J , Hofmann SL
Ref : Mol Genet Metab , 99 :374 , 2010
Abstract : Infantile neuronal ceroid lipofuscinosis (INCL, also known as Haltia-Santavuori disease) is a lysosomal storage disorder of infants and children characterized by blindness, seizures and a progressive neurodegenerative course. Recent clinical trials have involved neural stem cells and gene therapy directed to the central nervous system; however, enzyme replacement therapy has never been addressed. In the current paper, we describe the production of human recombinant PPT1 (the defective enzyme in INCL) by standard methods in Chinese Hamster Ovary (CHO) cells. The enzyme is largely mannose 6-phosphorylated as assessed by mannose 6-phosphate receptor binding (80% bound) and taken up rapidly by immortalized patient lymphoblasts, where clearance of PPT substrates was demonstrated (EC(50) of 0.25 nM after overnight incubation). When injected intravenously into PPT1-deficient mice, the clearance of recombinant human PPT1 from plasma was rapid, with a half-life of 10 min. Most of the injected dose was distributed to the kidney and liver and potentially corrective levels were also observed in heart, lung and spleen. Brain uptake was minimal, as expected based on experience with other intravenously administered lysosomal enzymes. The enzyme may be useful as an adjunct to central nervous system-directed therapies and could be used as a starting point for modifications designed to improve brain delivery.
ESTHER : Lu_2010_Mol.Genet.Metab_99_374
PubMedSearch : Lu_2010_Mol.Genet.Metab_99_374
PubMedID: 20036592
Gene_locus related to this paper: mouse-ppt

Title : Distinctive nicotinic acetylcholine receptor functional phenotypes of rat ventral tegmental area dopaminergic neurons - Yang_2009_J.Physiol_587_345
Author(s) : Yang K , Hu J , Lucero L , Liu Q , Zheng C , Zhen X , Jin G , Lukas RJ , Wu J
Ref : Journal of Physiology , 587 :345 , 2009
Abstract : Dopaminergic (DAergic) neuronal activity in the ventral tegmental area (VTA) is thought to contribute generally to pleasure, reward, and drug reinforcement and has been implicated in nicotine dependence. nAChRs expressed in the VTA exhibit diverse subunit compositions, but the functional and pharmacological properties are largely unknown. Here, using patch-clamp recordings in single DAergic neurons freshly dissociated from rat VTA, we clarified three functional subtypes of nAChRs (termed ID, IID and IIID receptors) based on whole-cell current kinetics and pharmacology. Kinetic analysis demonstrated that comparing to ID, IID receptor-mediated current had faster activation and decay constant and IIID receptor-mediated current had larger current density. Pharmacologically, ID receptor-mediated current was sensitive to the alpha4beta2-nAChR agonist RJR-2403 and antagonist dihydro-beta-erythroidine (DHbetaE); IID receptor-mediated current was sensitive to the selective alpha7-nAChR agonist choline and antagonist methyllycaconitine (MLA); while IIID receptor-mediated current was sensitive to the beta4-containing nAChR agonist cytisine and antagonist mecamylamine (MEC). The agonist concentration-response relationships demonstrated that IID receptor-mediated current exhibited the highest EC(50) value compared to ID and IIID receptors, suggesting a relatively low agonist affinity of type IID receptors. These results suggest that the type ID, IID and IIID nAChR-mediated currents are predominately mediated by activation of alpha4beta2-nAChR, alpha7-nAChR and a novel nAChR subtype(s), respectively. Collectively, these findings indicate that the VTA DAergic neurons express diversity and multiplicity of functional nAChR subtypes. Interestingly, each DAergic neuron predominantly expresses only one particularly functional nAChR subtype, which may have distinct but important roles in regulation of VTA DA neuronal function, DA transmission and nicotine dependence.
ESTHER : Yang_2009_J.Physiol_587_345
PubMedSearch : Yang_2009_J.Physiol_587_345
PubMedID: 19047205

Title : Protection of PMS777, a new AChE inhibitor with PAF antagonism, against amyloid-beta-induced neuronal apoptosis and neuroinflammation - Li_2009_Cell.Mol.Neurobiol_29_589
Author(s) : Li J , Hu J , Shao B , Zhou W , Cui Y , Dong C , Ezoulin JM , Zhu X , Ding W , Heymans F , Chen H
Ref : Cellular Molecular Neurobiology , 29 :589 , 2009
Abstract : Amyloid-beta (Abeta) plays a central role in the neuroinflammation and cholinergic neuronal apoptosis in Alzheimer's disease, and thus has been considered as a main determinant of this disease. In the previous study, we reported that PMS777, a novel bis-interacting ligand for acetylcholinesterase (AChE) inhibition and platelet-activating factor (PAF) receptor antagonism, could significantly attenuate PAF-induced neurotoxicity. Continuing our efforts, we further investigated the protective effect of PMS777 on Abeta-induced neuronal apoptosis in vitro and neuroinflammation in vivo. PMS777 (1-100 microM) was found to inhibit Abeta-induced human neuroblastoma SH-SY5Y cell apoptosis in a concentration-dependent manner. Concurrently, PMS777 increased ratio of bcl-2 to bax mRNA, and inhibited both mRNA expression and activity of caspase-3 in SH-SY5Y cells after the exposure with Abeta. In vivo experimental study demonstrated that PMS777 could attenuate Abeta-induced microglial and astrocytic activation in the rat hippocampus after systemic administration. These results suggest that PMS777 potently protects against Abeta-induced neuronal apoptosis and neuroinflammation, and warrants further investigations in connection with its potential value in the treatment of Alzheimer's disease.
ESTHER : Li_2009_Cell.Mol.Neurobiol_29_589
PubMedSearch : Li_2009_Cell.Mol.Neurobiol_29_589
PubMedID: 19194797

Title : [The efficacy of multiple fixed dosage of administration of extraneous cholinesterase in the treatment of the acute organophosphorus pesticide poisoning.] -
Author(s) : Zhong HZ , Qian DC , Li Z , Wang Q , Hu J
Ref : Zhongguo Wei Zhong Bing Ji Jiu Yi Xue , 21 :695 , 2009
PubMedID:

Title : Association between polymorphisms of microsomal epoxide hydrolase and COPD: results from meta-analyses - Hu_2008_Respirology_13_837
Author(s) : Hu G , Shi Z , Hu J , Zou G , Peng G , Ran P
Ref : Respirology , 13 :837 , 2008
Abstract : BACKGROUND AND OBJECTIVE: COPD is a complex polygenic disease in which gene-environment interactions are very important. The gene encoding microsomal epoxide hydrolase (EPHX1) is one of several candidate loci for COPD pathogenesis and is highly polymorphic. Based chi on the polymorphisms of EPHX1 gene (tyrosine/histidine 113, histidine/arginine 139), the population can be classified into four groups of putative EPHX1 phenotypes (fast, normal, slow and very slow). A number of studies have investigated the association between the genotypes and phenotypes of EPHX1 and COPD susceptibility in different populations, with inconsistent results. A systematic review and meta-analysis of the published data was performed to gain a clearer understanding of this association. METHODS: The MEDLINE database was searched for case-control studies published from 1966 to August 2007. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS: Sixteen eligible studies, comprising 1847 patients with COPD and 2455 controls, were included in the meta-analysis. The pooled result showed that the EPHX1 113 mutant homozygote was significantly associated with an increased risk of COPD (OR 1.59, 95% CI: 1.14-2.21). Subgroup analysis supported the result in the Asian population, but not in the Caucasian population. When the analysis was limited to only the larger-sample-size studies, studies in which controls were in Hardy-Weinberg equilibrium and studies in which controls were smokers/ex-smokers, the pooled results supported the conclusion. The EPHX1 139 heterozygote protected against the development of COPD in the Asian population, but not in the Caucasian population. The other gene types of EPHX1 113 and EPHX1 139 were not associated with an increased risk of COPD. The slow activity phenotype of EPHX1 was associated with an increased risk of COPD. The fast activity phenotype of EPHX1 was a protective factor for developing COPD in the Asian population, but not in the Caucasian population. However, the very slow activity phenotype of EPHX1 was a risk for developing COPD in the Caucasian population, but not in the Asian population. CONCLUSIONS: The polymorphisms of EPHX1 113 and EPHX1 139 are genetic contributors to COPD susceptibility in Asian populations. The phenotypes of EPHX1 were contributors to overall COPD susceptibility.
ESTHER : Hu_2008_Respirology_13_837
PubMedSearch : Hu_2008_Respirology_13_837
PubMedID: 18811882

Title : Candida antarctica lipase B chemically immobilized on epoxy-activated micro- and nanobeads: catalysts for polyester synthesis - Chen_2008_Biomacromolecules_9_463
Author(s) : Chen B , Hu J , Miller EM , Xie W , Cai M , Gross RA
Ref : Biomacromolecules , 9 :463 , 2008
Abstract : Candida antarctica Lipase B (CALB) was covalently immobilized onto epoxy-activated macroporous poly(methyl methacrylate) Amberzyme beads (235 microm particle size, 220 A pore size) and nanoparticles (nanoPSG, diameter 68 nm) with a poly(glycidyl methacrylate) outer region. Amberzyme beads allowed CALB loading up to 0.16 g of enzyme per gram of support. IR microspectroscopy generated images of Amberzyme-CALB beads showed CALB is localized within a 50 microm thick loading front. IR microspectroscopy images, recorded prior to and after treatment of Amberzyme-CALB with DMSO/aqueous Triton X-100, are similar, confirming that CALB is largely chemically linked to Amberzyme. The activity of CALB immobilized on Amberzyme, Lewatit (i.e., Novozym 435 catalyst), and nanoPSG was assessed for lactone ring-opening and step-condensation polymerizations. For example, the percent conversion of -caprolactone using the same amount of enzyme catalyzed by Amberzym-CALB, Novozym 435, and nanoPSG-CALB for 20 min was 7.0, 16, and 65%, respectively. Differences in CALB reactivity were discussed based on resin physical parameters and availability of active sites determined by active site titrations. Regardless of the matrix used and chemical versus physical immobilization, -CL ring-opening polymerizations occur by a chain growth mechanism without chain termination. To test Amberzyme-CALB stability, the catalyst was reused over three reaction cycles for -CL ring-opening polymerization (70 degrees C, 70 min reactions) and glycerol/1,8-octanediol/adipic acid polycondensation reactions (90 degrees C, 64 h). Amberzyme-CALB was found to have far better stability for reuse relative to Novozym 435 for the polycondensation reaction.
ESTHER : Chen_2008_Biomacromolecules_9_463
PubMedSearch : Chen_2008_Biomacromolecules_9_463
PubMedID: 18197630
Gene_locus related to this paper: canar-LipB

Title : Roles of nicotinic acetylcholine receptor beta subunits in function of human alpha4-containing nicotinic receptors - Wu_2006_J.Physiol_576_103
Author(s) : Wu J , Liu Q , Yu K , Hu J , Kuo YP , Segerberg M , St John PA , Lukas RJ
Ref : Journal of Physiology , 576 :103 , 2006
Abstract : Naturally expressed nicotinic acetylcholine receptors (nAChR) containing alpha4 subunits (alpha4*-nAChR) in combination with beta2 subunits (alpha4beta2-nAChR) are among the most abundant, high-affinity nicotine binding sites in the mammalian brain. beta4 subunits are also richly expressed and colocalize with alpha4 subunits in several brain regions implicated in behavioural responses to nicotine and nicotine dependence. Thus, alpha4beta4-nAChR also may exist and play important functional roles. In this study, properties were determined of human alpha4beta2- and alpha4beta4-nAChR heterologously expressed de novo in human SH-EP1 epithelial cells. Whole-cell currents mediated via human alpha4beta4-nAChR have approximately 4-fold higher amplitude than those mediated via human alpha4beta2-nAChR and exhibit much slower acute desensitization and functional rundown. Nicotinic agonists induce peak whole-cell current responses typically with higher functional potency at alpha4beta4-nAChR than at alpha4beta2-nAChR. Cytisine and lobeline serve as full agonists at alpha4beta4-nAChR but are only partial agonists at alpha4beta2-nAChR. However, nicotinic antagonists, except hexamethonium, have comparable affinities for functional alpha4beta2- and alpha4beta4-nAChR. Whole-cell current responses show stronger inward rectification for alpha4beta2-nAChR than for alpha4beta4-nAChR at a positive holding potential. Collectively, these findings demonstrate that human nAChR beta2 or beta4 subunits can combine with alpha4 subunits to generate two forms of alpha4*-nAChR with distinctive physiological and pharmacological features. Diversity in alpha4*-nAChR is of potential relevance to nervous system function, disease, and nicotine dependence.
ESTHER : Wu_2006_J.Physiol_576_103
PubMedSearch : Wu_2006_J.Physiol_576_103
PubMedID: 16825297

Title : beta-Amyloid directly inhibits human alpha4beta2-nicotinic acetylcholine receptors heterologously expressed in human SH-EP1 cells - Wu_2004_J.Biol.Chem_279_37842
Author(s) : Wu J , Kuo YP , George AA , Xu L , Hu J , Lukas RJ
Ref : Journal of Biological Chemistry , 279 :37842 , 2004
Abstract : Amyloid-beta (Abeta) accumulation and aggregation are thought to contribute to the pathogenesis of Alzheimer's disease (AD). In AD, there is a selective decrease in the numbers of radioligand binding sites corresponding to the most abundant nicotinic acetylcholine receptor (nAChR) subtype, which contains human alpha4 and beta2 subunits (halpha4beta2-nAChR). However, the relationships between these phenomena are uncertain, and effects of Abeta on halpha4beta2-nAChR function have not been investigated in detail. We first confirmed expression of halpha4 and hbeta2 subunits as messenger RNA in transfected, human SHEP1 cells by reverse transcription-polymerase chain reaction and mRNA fluorescence in situ hybridization analyses. Immunoprecipitation Western analyses confirmed alpha4 and beta2 subunit protein expression and co-assembly. Whole cell current recording demonstrated heterologous expression in SH-EP1-halpha4beta2 cells of functional halpha4beta2-nAChRs with characteristic responses to nicotinic agonists or antagonists. Nicotine-induced whole cell currents were suppressed by Abeta(1-42) in a dose-dependent manner. Functional inhibition was selective for Abeta(1-42) compared with the functionally inactive, control peptide Abeta(40-1).Abeta(1-42)-mediated inhibition of halpha4beta2-nAChR function was non-competitive, voltage-independent, and use-independent. Pre-loading of cells with guanyl-5'-yl thiophosphate failed to prevent Abeta(1-42)-induced inhibition, suggesting that down-regulation of halpha4beta2-nAChR function by Abeta(1-42) is not mediated by nAChR internalization. Sensitivity to Abeta(1-42) antagonism at 1 nm was evident for halpha4beta2-nAChRs, but not for heterologously expressed human alpha7-nAChRs, although both nAChR subtypes were functionally inhibited by 100 nm Abeta(1-42), with the magnitude of functional block being higher for 100 nm Abeta(1-42) acting on halpha7-nAChRs. These findings suggest that halpha4beta2-nAChRs are sensitive and perhaps pathophysiologically relevant targets for Abeta neurotoxicity in AD.
ESTHER : Wu_2004_J.Biol.Chem_279_37842
PubMedSearch : Wu_2004_J.Biol.Chem_279_37842
PubMedID: 15234980

Title : Glial-derived proteins activate cultured astrocytes and enhance beta amyloid-induced glial activation - Hu_1999_Brain.Res_842_46
Author(s) : Hu J , Van Eldik LJ
Ref : Brain Research , 842 :46 , 1999
Abstract : A prominent feature of Alzheimer's disease (AD) pathology is an abundance of activated glia (astrocytes and microglia) in close proximity to the amyloid plaques. These activated glia overexpress a number of proteins that may participate in the progression of the disease, possibly by propagation of inflammatory and oxidative stress responses. The beta-amyloid peptide 1-42 (Abeta), a major constituent of neuritic plaques, can itself induce glial activation. However, little is known about whether other plaque components, especially the upregulated glial proteins, can induce glial activation or modulate the effects of Abeta on glia. In this study, we focused on four glial proteins that are abundant in amyloid plaques and/or that are known to interact with Abeta: alpha1-antichymotrypsin (ACT), interleukin-1beta (IL-1beta), S100beta, and butyrylcholinesterase (BChE). We examined the ability of these proteins to activate rat cortical astrocyte cultures and to influence the ability of Abeta to activate astrocytes. Treatment of astrocytes with ACT, IL-1beta, or S100beta resulted in glial activation, as assessed by reactive morphology, upregulation of IL-1beta, and production of inducible nitric oxide synthase and nitric oxide. The ability of Abeta to induce astrocyte activation was also enhanced in the presence of each of these three proteins. In contrast, BChE alone did not activate astrocytes and had no effect on Abeta-induced activation. These results suggest that certain proteins produced by activated glia may contribute to the chronic glial activation seen in AD through their ability to stimulate astrocytes directly or through their ability to modulate Abeta-induced activation.
ESTHER : Hu_1999_Brain.Res_842_46
PubMedSearch : Hu_1999_Brain.Res_842_46
PubMedID: 10526094

Title : Poster: Comparison of muscarinic receptor-mediated activation of cyclic GMP synthesis and nitric oxide release in a neuronal clone -
Author(s) : El-Fakahany EE , Hu J
Ref : Life Sciences , 52(5-6) :566 , 1993
PubMedID:

Title : Modulation by certain conserved aspartate residues of the allosteric interaction of gallamine at the m1 muscarinic receptor - Lee_1992_J.Pharmacol.Exp.Ther_262_312
Author(s) : Lee NH , Hu J , El-Fakahany EE
Ref : Journal of Pharmacology & Experimental Therapeutics , 262 :312 , 1992
Abstract : Muscarinic acetylcholine receptors belong to a superfamily of G-protein coupled receptors and contain within their structure several conserved aspartate residues. These residues have been implicated to play important roles in the interaction of agonists and their competitive antagonists with the receptor. In the present work, we investigated whether the same residues might also serve as important contact points for allosteric antagonists of muscarinic receptors, because the majority of these compounds are cationic in nature, or if such residues are involved in modification of receptor conformation by these antagonists. Gallamine was used as a prototype for these antagonists. Site-directed mutagenesis of the m1 muscarinic receptor subtype was utilized to define some of the molecular determinants involved in cooperative allosteric interactions. We report that substitution of the aspartate residue at position 71, but not at positions 99 and 122 with asparagine, affected the affinity of gallamine for the unliganded m1 receptor. A similar substitution at positions 71 and 99 decreased the magnitude of its cooperative effects on the binding of [3H]N-methylscopolamine. Our data suggest that these residues are implicated in cooperative interactions. At present, however, we cannot discount a more pivotal role of other residues on the receptor sequence in allosteric interactions. The data also support the notion that different molecular entities are required for the binding of allosteric antagonists as compared to the interaction of agonists and competitive antagonists at the receptor.
ESTHER : Lee_1992_J.Pharmacol.Exp.Ther_262_312
PubMedSearch : Lee_1992_J.Pharmacol.Exp.Ther_262_312
PubMedID: 1625205

Title : Complex allosteric modulation of cardiac muscarinic receptors by protamine: potential model for putative endogenous ligands - Hu_1992_Mol.Pharmacol_42_311
Author(s) : Hu J , Wang SZ , Forray C , El-Fakahany EE
Ref : Molecular Pharmacology , 42 :311 , 1992
Abstract : A large number of diverse pharmacological agents bind to a secondary domain on the muscarinic receptor, to influence allosterically the interaction of ligands at the primary binding site. Based on common structural features of these antagonists, we examined the interaction of protamine, an endogenous polycationic peptide, and of polyamines with muscarinic receptors in rat heart. Our results provide several lines of qualitative evidence that protamine allosterically modulates the conformation of muscarinic receptors, in a marked negatively cooperative manner. It decelerated the dissociation of N-[3H]methylscopolamine ([3H] NMS) initiated by atropine, in a concentration-dependent fashion. Inhibition by protamine of [3H]NMS binding at equilibrium showed a distinct plateau, which increased in magnitude at higher ligand concentrations. Scatchard analysis of saturation isotherms of [3H]NMS binding in the absence and presence of protamine indicated that protamine did not alter Bmax in a statistically significant fashion, although there was a trend of a concentration-dependent increase in this parameter. On the other hand, it caused a marked concentration-dependent decrease in the affinity of [3H]NMS, and this effect reached a ceiling limit. However, there were marked quantitative deviations of the interaction of protamine from a simple ternary allosteric model. Some of these discrepancies could be explained by the tendency of protamine to increase Bmax. The allosteric actions of protamine demonstrated in kinetic and equilibrium experiments were selective for m1 and m2 muscarinic receptors, compared with m3, m4, and m5 receptors, as studied in Chinese hamster ovary cells transfected with the genes of the different muscarinic receptors. Arginine residues play an important role in the allosteric interaction of protamine, inasmuch as poly-L-arginine qualitatively mimicked the effects of protamine. In contrast, no effects of the polyamines spermine, spermidine, and putrescine were observed on [3H]NMS binding. This is the first report on the allosteric modulation of muscarinic receptors by an endogenous peptide.
ESTHER : Hu_1992_Mol.Pharmacol_42_311
PubMedSearch : Hu_1992_Mol.Pharmacol_42_311
PubMedID: 1513329