Author Report for: Hu KNo contact information in database for Hu K
Li R, Ye Z, She D, Fang P, Zong G, Hu K, Kong D, Xu W, Li L and Xue Y <2 more author(s)> Li R, Ye Z, She D, Fang P, Zong G, Hu K, Kong D, Xu W, Li L, Zhou Y, Zhang K, Xue Y (- 2) Ref: Drug Des Devel Ther, 16:3557, 2022 : PubMed ESTHER: Li_2022_Drug.Des.Devel.Ther_16_3557 PubMedSearch: Li 2022 Drug.Des.Devel.Ther 16 3557 PubMedID: 36238196 Abstract OBJECTIVE: Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) has been extensively studied, the role of its underlying pathogenesis remains unclear, and there is currently no approved therapeutic strategy for NAFLD. The purpose of this study was to observe the beneficial effects of Semaglutide on NAFLD in vivo and in vitro, as well as its potential molecular mechanisms. METHODS: Semaglutide was used to treat type 2 diabetes mellitus (T2DM) combined with NAFLD mice for 12 weeks. Hepatic function and structure were evaluated by liver function, blood lipids, liver lipids, H&E staining, oil red staining and Sirius staining. The expression of alpha/beta hydrolase domain-6 (ABHD6) was measured by qPCR and Western blotting in vivo and in vitro. Then, dual-luciferase reporter assay was performed to verify the regulation of the upstream miR-5120 on ABHD6. RESULTS: Our data revealed that Semaglutide administration significantly improved liver function and hepatic steatosis in T2DM combined with NAFLD mice. Furthermore, compared with controls, up-regulation of ABHD6 and down-regulation of miR-5120 were found in the liver of T2DM+NAFLD mice and HG+FFA-stimulated Hepa 1-6 hepatocytes. Interestingly, after Semaglutide intervention, ABHD6 expression was significantly decreased in the liver of T2DM+NAFLD mice and in HG+FFA-stimulated Hepa 1-6 hepatocytes, while miR-5120 expression was increased. We also found that miR-5120 could regulate the expression of ABHD6 in hepatocytes, while Semaglutide could modulate the expression of ABHD6 through miR-5120. In addition, GLP-1R was widely expressed in mouse liver tissues and Hepa 1-6 cells. Semaglutide could regulate miR-5120/ABHD6 expression through GLP-1R. CONCLUSION: Our data revealed the underlying mechanism by which Semaglutide improves hepatic steatosis in T2DM+NAFLD, and might shed new light on the pathological role of miR-5120/ABHD6 in the pathogenesis of T2DM+NAFLD. Title: Development of a highly-specific (18)F-labeled irreversible positron emission tomography tracer for monoacylglycerol lipase mapping Chen Z, Mori W, Rong J, Schafroth MA, Shao T, Van RS, Ogasawara D, Yamasaki T, Hiraishi A and Liang SH <12 more author(s)> Chen Z, Mori W, Rong J, Schafroth MA, Shao T, Van RS, Ogasawara D, Yamasaki T, Hiraishi A, Hatori A, Chen J, Zhang Y, Hu K, Fujinaga M, Sun J, Yu Q, Collier TL, Shao Y, Cravatt BF, Josephson L, Zhang MR, Liang SH (- 12) Ref: Acta Pharm Sin B, 11:1686, 2021 : PubMed ESTHER: Chen_2021_Acta.Pharm.Sin.B_11_1686 PubMedSearch: Chen 2021 Acta.Pharm.Sin.B 11 1686 PubMedID: 34221877 Gene_locus related to this paper: human-MGLL Inhibitor(s) related to this paper: PF-06795071 Abstract As a serine hydrolase, monoacylglycerol lipase (MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS), leading to the formation of arachidonic acid (AA). Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms, including neuroinflammation, cognitive impairment, epileptogenesis, nociception and neurodegenerative diseases. Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions, and a MAGL positron emission tomography (PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors. Herein, we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates. Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound, which was then radiolabeled with fluorine-18 via a facile S(N)Ar reaction to form 2-[(18)F]fluoropyridine scaffold. Good blood-brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [(18)F]14 (also named as [(18)F]MAGL-1902). This work may serve as a roadmap for clinical translation and further design of potent (18)F-labeled MAGL PET tracers. Title: Novel Reversible-Binding PET Ligands for Imaging Monoacylglycerol Lipase Based on the Piperazinyl Azetidine Scaffold Rong J, Mori W, Xia X, Schafroth MA, Zhao C, Van RS, Yamasaki T, Chen J, Xiao Z and Liang SH <23 more author(s)> Rong J, Mori W, Xia X, Schafroth MA, Zhao C, Van RS, Yamasaki T, Chen J, Xiao Z, Haider A, Ogasawara D, Hiraishi A, Shao T, Zhang Y, Chen Z, Pang F, Hu K, Xie L, Fujinaga M, Kumata K, Gou Y, Fang Y, Gu S, Wei H, Bao L, Xu H, Collier TL, Shao Y, Carson RE, Cravatt BF, Wang L, Zhang MR, Liang SH (- 23) Ref: Journal of Medicinal Chemistry, :, 2021 : PubMed ESTHER: Rong_2021_J.Med.Chem__ PubMedSearch: Rong 2021 J.Med.Chem PubMedID: 34569803 Gene_locus related to this paper: human-MGLL Inhibitor(s) related to this paper: ZYH-deriv-F Abstract Monoacylglycerol lipase (MAGL) is a 33 kDa serine protease primarily responsible for hydrolyzing 2-arachidonoylglycerol into the proinflammatory eicosanoid precursor arachidonic acid in the central nervous system. Inhibition of MAGL constitutes an attractive therapeutic concept for treating psychiatric disorders and neurodegenerative diseases. Herein, we present the design and synthesis of multiple reversible MAGL inhibitor candidates based on a piperazinyl azetidine scaffold. Compounds 10 and 15 were identified as the best-performing reversible MAGL inhibitors by pharmacological evaluations, thus channeling their radiolabeling with fluorine-18 in high radiochemical yields and favorable molar activity. Furthermore, evaluation of [(18)F]10 and [(18)F]15 ([(18)F]MAGL-2102) by autoradiography and positron emission tomography (PET) imaging in rodents and nonhuman primates demonstrated favorable brain uptakes, heterogeneous radioactivity distribution, good specific binding, and adequate brain kinetics, and [(18)F]15 demonstrated a better performance. In conclusion, [(18)F]15 was found to be a suitable PET radioligand for the visualization of MAGL, harboring potential for the successful translation into humans. Title: Current insights into the microbial degradation for pyrethroids: strain safety, biochemical pathway, and genetic engineering Zhao T, Hu K, Li J, Zhu Y, Liu A, Yao K, Liu S Ref: Chemosphere, 279:130542, 2021 : PubMed ESTHER: Zhao_2021_Chemosphere_279_130542 PubMedSearch: Zhao 2021 Chemosphere 279 130542 PubMedID: 33866100 Abstract As a biologically inspired insecticide, pyrethroids (PYRs) exert evident toxic side effects on non-target organisms. PYRs and their general toxic intermediate 3-phenoxybenzoic acid (3-PBA) have shown high detection rates/levels in human beings recently, for which diet was identified as the major exposure route. Microbial mineralization has emerged as a versatile strategy in addressing such escalating concern. Herein, PYRs and 3-PBA biodegradation with regards to strain safety, application and surfactant were summarized. Numerous PYRs-degrading microbes have been reported yet with a minority focused on 3-PBA. Most isolates were from contaminated sites while several microbial food cultures (MFCs) have been investigated. MFCs such as Bacillus spp. and Aspergillus spp. that dominate in PYRs-degrading microbial pools are applicable candidates for agricultural by-products detoxification during the postharvest process. Subsequently, we discussed committed degradation steps, wherein hydrolase responsible for PYRs ester linkage cleavage and oxygenase for 3-PBA diphenyl ether bond rupture play vital roles. Finally, comprehensive information of the key enzyme genes is outlined along with methodologies concerning gene cloning. Cytochrome P450 monooxygenases (CYP) is competent for diphenyl ether scission. Newly-developed omics has become a feasible gene and enzyme mining technology. To achieve PYRs mineralization in feed and food commodities, the screening of MFCs rich in related enzymes and the construction of MFCs-derived genetically modified microbes (GMMs) exhibit great potential considering the safety issues. Title: Positive correlation between human exposure to organophosphate esters and gastrointestinal cancer in patients from Wuhan, China Li Y, Fu Y, Hu K, Zhang Y, Chen J, Zhang S, Zhang B, Liu Y Ref: Ecotoxicology & Environmental Safety, 196:110548, 2020 : PubMed ESTHER: Li_2020_Ecotoxicol.Environ.Saf_196_110548 PubMedSearch: Li 2020 Ecotoxicol.Environ.Saf 196 110548 PubMedID: 32278140 Abstract As kinds of endocrine disruptors, organophosphate esters (OPEs) pollution in the environment had received increasing attention recently. Food and water intake were two important exposure pathways for OPEs. However, the studies about the potential association between OPEs and gastrointestinal cancer were limited. This study investigated the possible association between OPEs and gastrointestinal cancer. All cancer patients were diagnosed with gastrointestinal cancer from a Grade 3 A hospital in Wuhan, China, while the control group was non-cancer healthy persons. The results showed that 6 OPEs were found in the control samples, while 8 in the samples from patients with gastrointestinal cancer. The detection frequencies of OPEs in gastrointestinal cancer patients were significantly higher than those in the control group (p < 0.05 or p < 0.01), except for triethyl phosphate (TEP) and tris (methylphenyl) phosphate (TMPP) in the gastric cancer group. The concentrations of OPEs in the control group were significantly lower than those in the gastric cancer group and colorectal cancer group (p < 0.01). In the control group and gastrointestinal cancer group, TEP was the dominant pollutant. Correlation analysis found that concentrations of TEP, tris(2-chloroisopropyl) phosphate (TCIPP), triphenyl phosphate (TPHP), TMPP, tris(2-ethylhexyl) phosphate (TEHP), and 2-ethylhexyl diphenyl phosphate (EHDPP) were associated with gastric cancer (p < 0.01), and concentrations of TEP, TCIPP, TPHP, TMPP and TEHP were associated with colorectal cancer (p < 0.01). A cluster analysis divided the 34 patients with gastric cancer and 40 patients with colorectal cancer in four groups. The results showed that the elderly male patients with gastric cancer were more sensitive to the exposure of EHDPP, while the TEP exposure was more sensitive to the relatively young gastrointestinal cancer patients. These findings indicated that OPEs might play a role in developing gastrointestinal cancer. Title: Serum Cholinesterases, a Novel Marker of Clinical Activity in Inflammatory Bowel Disease: A Retrospective Case-Control Study Shao X, Yang L, Hu K, Shen R, Ye Q, Yuan X, Zhao Q, Shen J Ref: Mediators Inflamm, 2020:4694090, 2020 : PubMed ESTHER: Shao_2020_Mediators.Inflamm_2020_4694090 PubMedSearch: Shao 2020 Mediators.Inflamm 2020 4694090 PubMedID: 32733165 Abstract BACKGROUND: The aim of our study was to investigate whether serum cholinesterase (ChE) levels were associated with inflammatory bowel disease (IBD). MATERIALS AND METHODS: We conducted a retrospective case-control study to clarify the relationship between serum ChE levels and IBD that included 142 patients with ulcerative colitis (UC), 60 patients with Crohn's disease (CD), and 264 healthy controls (HCs). We used ROC curves to evaluate the diagnostic value of serum ChE levels for IBD. RESULTS: Substantially lower serum ChE levels were detected in patients with UC than in HCs (6376 U/L versus 8418 U/L, P < 0.001) and in patients with CD than in HCs (5181 U/L versus 8418 U/L, P < 0.001). Additionally, patients with CD displayed significantly lower serum ChE levels than patients with UC (5181 U/L versus 6376 U/L, P < 0.01). We also found that there was a negative association between serum ChE levels and the Crohn's Disease Activity Index (CDAI) score of patients with CD (P = 0.011) and the Simple Clinical Colitis Activity Index (SCCAI) score of patients with UC (P = 0.018). The area under the curve (AUC) for serum ChE for the diagnosis of IBD was 0.826, and the AUCs of serum ChE for the diagnosis of CD and UC were 0.890 and 0.800, respectively. CONCLUSIONS: Serum ChE levels have important clinical significance in the diagnosis and assessment of clinical activity in patients with IBD, and the cholinergic anti-inflammatory pathway may provide new ideas for targeted treatment of IBD. Title: Safety and efficacy assessment of allogeneic human dental pulp stem cells to treat patients with severe COVID-19: structured summary of a study protocol for a randomized controlled trial (Phase I / II) Ye Q, Wang H, Xia X, Zhou C, Liu Z, Xia ZE, Zhang Z, Zhao Y, Yehenala J and He Y <5 more author(s)> Ye Q, Wang H, Xia X, Zhou C, Liu Z, Xia ZE, Zhang Z, Zhao Y, Yehenala J, Wang S, Zhou G, Hu K, Wu B, Wu CT, He Y (- 5) Ref: Trials, 21:520, 2020 : PubMed ESTHER: Ye_2020_Trials_21_520 PubMedSearch: Ye 2020 Trials 21 520 PubMedID: 32532356 Abstract OBJECTIVES: To assess the safety and therapeutic effects of allogeneic human dental pulp stem cells (DPSCs) in treating severe pneumonia caused by COVID-19. TRIAL DESIGN: This is a single centre, two arm ratio 1:1, triple blinded, randomized, placebo-controlled, parallel group, clinical trial. PARTICIPANTS: Twenty serious COVID-19 cases will be enrolled in the trial from April 6th to December 31st 2020. INCLUSION CRITERIA: hospitalised patients at Renmin Hospital of Wuhan University satisfy all criteria as below: 1)Adults aged 18-65 years;2)Voluntarily participate in this clinical trial and sign the "informed consent form" or have consent from a legal representative.3)Diagnosed with severe pneumonia of COVID-19: nucleic acid test SARS-CoV-2 positive; respiratory distress (respiratory rate > 30 times / min); hypoxia (resting oxygen saturation < 93% or arterial partial pressure of oxygen / oxygen concentration < 300 mmHg).4)COVID-19 featured lung lesions in chest X-ray image. EXCLUSION CRITERIA: Patients will be excluded from the study if they meet any of the following criteria. 1.Patients have received other experimental treatment for COVID-19 within the last 30 days;2.Patients have severe liver condition (e.g., Child Pugh score >=C or AST> 5 times of the upper limit);3.Patients with severe renal insufficiency (estimated glomerular filtration rate <=30mL / min/1.73 m(2)) or patients receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis;4.Patients who are co-infected with HIV, hepatitis B, tuberculosis, influenza virus, adenovirus or other respiratory infection viruses;5.Female patients who have no sexual protection in the last 30 days prior to the screening assessment;6.Pregnant or lactating women or women using estrogen contraception;7.Patients who are planning to become pregnant during the study period or within 6 months after the end of the study period;8.Other conditions that the researchers consider not suitable for participating in this clinical trial. INTERVENTION AND COMPARATOR: There will be two study groups: experimental and control. Both will receive all necessary routine treatment for COVID-19. The experimental group will receive an intravenous injection of dental pulp stem cells suspension (3.0x10(7) human DPSCs in 30ml saline solution) on day 1, 4 and 7; The control group will receive an equal amount of saline (placebo) on the same days. Clinical and laboratory observations will be performed for analysis during a period of 28 days for each case since the commencement of the study. MAIN OUTCOMES: 1. Primary outcome The primary outcome is Time To Clinical Improvement (TTCI). By definition, TTCI is the time (days) it takes to downgrade two levels from the following six ordered grades [(grade 1) discharge to (grade 6) death] in the clinical state of admission to the start of study treatments (hDPSCs or placebo). Six grades of ordered variables: GradeDescriptionGrade 1:Discharged of patient;Grade 2:Hospitalized without oxygen supplement;Grade 3:Hospitalized, oxygen supplement is required, but NIV / HFNC is not required;Grade 4:Hospitalized in intensive care unit, and NIV / HFNC treatment is required;Grade 5:Hospitalized in intensive care unit, requiring ECMO and/or IMV;Grade 6:Death. ABBREVIATIONS: NIV, non-invasive mechanical ventilation; HFNC, high-flow nasal catheter; IMV, invasive mechanical ventilation. 2. Secondary outcomes 2.1 vital signs: heart rate, blood pressure (systolic blood pressure, diastolic blood pressure). During the screening period, hospitalization every day (additional time points of D1, D4, D7 30min before injection, 2h +/- 30min, 24h +/- 30min after the injection) and follow-up period D90 +/- 3 days. 2.2 Laboratory examinations: during the screening period, 30 minutes before D1, D4, D7 infusion, 2h +/- 30min, 24h +/- 30min after the end of infusion, D10, D14, D28 during hospitalization or discharge day and follow-up period D90 +/- 3 days. 2.3 Blood routine: white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, neutrophils, lymphocytes, monocytes, eosinophils Acidic granulocyte count, basophil count, red blood cell, hemoglobin, hematocrit, average volume of red blood cells, average red blood cell Hb content, average red blood cell Hb concentration, RDW standard deviation, RDW coefficient of variation, platelet count, platelet specific platelet average Volume, platelet distribution width,% of large platelets; 2.4 Liver and kidney function tests: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, prealbumin, total protein, albumin, globulin, white / globule ratio , Total bilirubin, direct bilirubin, cholinesterase, urea, creatinine, total carbon dioxide, uric acid glucose, potassium, sodium, chlorine, calcium, corrected calcium, magnesium, phosphorus, calcium and phosphorus product, anion gap, penetration Pressure, total cholesterol, triacylglycerol, high density lipoprotein cholesterol, Low density lipoprotein cholesterol, lipoprotein a, creatine kinase, lactate dehydrogenase, estimated glomerular filtration rate. 2.5 Inflammation indicators: hypersensitive C-reactive protein, serum amyloid (SAA); 2.6 Infectious disease testing: Hepatitis B (HBsAg, HBsAb, HBeAg, HBeAb, HBcAb), Hepatitis C (Anti-HCV), AIDS (HIVcombin), syphilis (Anti-TP), cytomegalovirus CMV-IgM, cytomegalovirus CMV-IgG; only during the screening period and follow-up period D90 +/- 3. 2.7 Immunological testing: Collect peripheral blood to detect the phenotype of T lymphocyte, B lymphocyte, natural killer cell, Macrophage and neutrophil by using flow cytometry. Collect peripheral blood to detect the gene profile of mononuclear cells by using single-cell analyses. Collect peripheral blood serum to detect various immunoglobulin changes: IgA, IgG, IgM, total IgE; Collect peripheral blood serum to explore the changes of cytokines, Th1 cytokines (IL-1 beta, IL-2, TNF-a, ITN-gamma), Th2 cytokines (IL-4, IL-6, IL -10). 2.8 Pregnancy test: blood beta-HCG, female subjects before menopause are examined during the screening period and follow-up period D90 +/- 3. 2.9 Urine routine: color, clarity, urine sugar, bilirubin, ketone bodies, specific gravity, pH, urobilinogen, nitrite, protein, occult blood, leukocyte enzymes, red blood cells, white blood cells, epithelial cells, non-squamous epithelial cells , Transparent cast, pathological cast, crystal, fungus; 2.10 Stool Routine: color, traits, white blood cells, red blood cells, fat globules, eggs of parasites, fungi, occult blood (chemical method), occult blood (immune method), transferrin (2h +/- 30min after the injection and not detected after discharge). RANDOMIZATION: Block randomization method will be applied by computer to allocate the participants into experimental and control groups. The random ratio is 1:1. BLINDING (MASKING): Participants, outcomes assessors and investigators (including personnel in laboratory and imaging department who issue the sample report or image observations) will be blinded. Injections of cell suspension and saline will be coded in accordance with the patient's randomisation group. The blind strategy is kept by an investigator who does not deliver the medical care or assess primary outcome results. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Twenty participants will be randomized to the experimental and control groups (10 per group). TRIAL STATUS: Protocol version number, hDPSC-CoVID-2019-02-2020 Version 2.0, March 13, 2020. Patients screening commenced on 16(th) April and an estimated date of the recruitment of the final participants will be around end of July. . TRIAL REGISTRATION: Registration: World Health Organization Trial Registry: ChiCTR2000031319; March 27,2020. ClinicalTrials.gov Identifier: NCT04336254; April 7, 2020 Other Study ID Numbers: hDPSC-CoVID-2019-02-2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. Title: Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a Tail Switching Strategy on a Piperazinyl Azetidine Skeleton Chen Z, Mori W, Deng X, Cheng R, Ogasawara D, Zhang G, Schafroth MA, Dahl K, Fu H and Liang SH <24 more author(s)> Chen Z, Mori W, Deng X, Cheng R, Ogasawara D, Zhang G, Schafroth MA, Dahl K, Fu H, Hatori A, Shao T, Zhang Y, Yamasaki T, Zhang X, Rong J, Yu Q, Hu K, Fujinaga M, Xie L, Kumata K, Gou Y, Chen J, Gu S, Bao L, Wang L, Collier TL, Vasdev N, Shao Y, Ma JA, Cravatt BF, Fowler C, Josephson L, Zhang MR, Liang SH (- 24) Ref: Journal of Medicinal Chemistry, 62:3336, 2019 : PubMed ESTHER: Chen_2019_J.Med.Chem_62_3336 PubMedSearch: Chen 2019 J.Med.Chem 62 3336 PubMedID: 30829483 Gene_locus related to this paper: human-MGLL Abstract Monoacylglycerol lipase (MAGL) is a serine hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions, including chronic pain, inflammation, cancer, and neurodegeneration. Herein, we disclose a novel array of reversible and irreversible MAGL inhibitors by means of "tail switching" on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with (11)C or (18)F. [(11)C]8 ([(11)C]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [(11)C]17 ([(11)C]PAD) and [(18)F]37 ([(18)F]MAGL-4-11) also demonstrated excellent in vivo binding specificity toward MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography tracers with tunability in reversible and irreversible binding mechanisms. Title: Design, Synthesis, and Evaluation of (18)F-Labeled Monoacylglycerol Lipase Inhibitors as Novel Positron Emission Tomography Probes Chen Z, Mori W, Fu H, Schafroth MA, Hatori A, Shao T, Zhang G, Van RS, Zhang Y and Liang SH <17 more author(s)> Chen Z, Mori W, Fu H, Schafroth MA, Hatori A, Shao T, Zhang G, Van RS, Zhang Y, Hu K, Fujinaga M, Wang L, Belov V, Ogasawara D, Giffenig P, Deng X, Rong J, Yu Q, Zhang X, Papisov MI, Shao Y, Collier TL, Ma JA, Cravatt BF, Josephson L, Zhang MR, Liang SH (- 17) Ref: Journal of Medicinal Chemistry, 62:8866, 2019 : PubMed ESTHER: Chen_2019_J.Med.Chem_62_8866 PubMedSearch: Chen 2019 J.Med.Chem 62 8866 PubMedID: 31518130 Inhibitor(s) related to this paper: PF-06795071 Abstract Dysfunction of monoacylglycerol lipase (MAGL) is associated with several psychopathological disorders, including drug addiction and neurodegenerative diseases. Herein we design, synthesize, and evaluate several irreversible fluorine-containing MAGL inhibitors for positron emission tomography (PET) ligand development. Compound 6 (identified from a therapeutic agent) was advanced for (18)F-labeling via a novel spirocyclic iodonium ylide (SCIDY) strategy, which demonstrated high brain permeability and excellent specific binding. This work supports further development of novel (18)F-labeled MAGL PET probes. Title: A potential biomarker of isofenphos-methyl in humans: A chiral view Gao B, Zhao S, Zhang Z, Li L, Hu K, Kaziem AE, He Z, Hua X, Shi H, Wang M Ref: Environ Int, 127:694, 2019 : PubMed ESTHER: Gao_2019_Environ.Int_127_694 PubMedSearch: Gao 2019 Environ.Int 127 694 PubMedID: 30991225 Inhibitor(s) related to this paper: Isocarbophos, Isofenphos-methyl Abstract Isofenphos-methyl (IFP) is a very active and persistent chiral insecticide. However, IFP has lower activity against acetylcholinesterases (AChEs). Previously, it was confirmed that phosphorothioate organophosphorus pesticides with N-alkyl (POPN) require activation by oxidative desulfuration and N-dealkylation. In this work, we demonstrated that IFP could be metabolized in human liver microsomes to isofenphos-methyl oxon (IFPO, 52.7%), isocarbophos (ICP, 14.2%) and isocarbophos oxon (ICPO, 11.2%). It was found that (R)-IFP was preferentially degraded compared to the (S)-enantiomer, and the enantiomeric fraction (EF) value reached 0.61 at 60min. However, (S)-enantiomers of the three metabolites, were degraded preferentially, and the EF values ranged from 0.34 to 0.45. Cytochrome P450 (CYP) isoforms CYP3A4, CYP2E1, and CYP1A2 and carboxylesterase enzyme have an essential role in the enantioselective metabolism of IFP; but, the enzymes that participate in the degradation of IFP metabolites are different. The AChE inhibition bioassay indicated that ICPO is the only effective inhibitor of AChE. The covalent molecular docking has proposed that the metabolites of IFP and its analogs after N-dealkylation and oxidative desulfuration will possess the highest inhibitory activity against AChE. This study is the first to demonstrate that ICPO can be regarded as a potential biomarker for the biomonitoring of IFP and ICP exposure in humans. Title: Identification of Carassius auratus gibelio liver cell proteins interacting with the GABAA receptor gamma2 subunit using a yeast two-hybrid system Ma RR, Sun J, Fang WH, Dong YP, Ruan JM, Yang XL, Hu K Ref: Fish Physiol Biochem, 45:199, 2019 : PubMed ESTHER: Ma_2019_Fish.Physiol.Biochem_45_199 PubMedSearch: Ma 2019 Fish.Physiol.Biochem 45 199 PubMedID: 30242696 Abstract The gamma-aminobutyric acid type A (GABAA) receptor is an important pentameric inhibitory neurotransmitter receptor, and the gamma2 subunit of this receptor plays a key role in potentiation of the GABAA response. We previously detected that the expression of GABAA receptor in the livers of Carassius auratus gibelio significantly increased after medication (avermectin and difloxacin treatment). In order to better understand the mechanism of action of the GABAA receptor gamma2 subunit in the livers of C. auratus gibelio, we constructed a C. auratus gibelio liver cDNA library (the titer value of 1.2 x 10(6) cfu/mL) and identified the proteins that interact with the GABAA receptor gamma2 subunit by using a yeast two-hybrid assay. The yeast two-hybrid screening yielded seven positive clones, namely, prelid3b, cdc42, sgk1, spg21, proteasome, chia.5, and AP-3 complex subunit beta-1, all of which have been annotated by the NCBI database. The functions of these proteins are complex; therefore, additional studies are required to determine the specific interactions of these proteins with the GABAA receptor gamma2 subunit in the liver of C. auratus gibelio. Although the interactions identified by the yeast two-hybrid system should be considered as preliminary results, the findings of this study may provide further direction and a foundation for future research focusing on the mechanisms of the GABAA receptor gamma2 subunit in C. auratus gibelio livers. Title: Radiosynthesis and evaluation of a novel monoacylglycerol lipase radiotracer: 1,1,1,3,3,3-hexafluoropropan-2-yl-3-(1-benzyl-1H-pyrazol-3-yl)azetidine-1-[(11)C]carboxylate Mori W, Hatori A, Zhang Y, Kurihara Y, Yamasaki T, Xie L, Kumata K, Hu K, Fujinaga M, Zhang MR Ref: Bioorganic & Medicinal Chemistry, 27:3568, 2019 : PubMed ESTHER: Mori_2019_Bioorg.Med.Chem_27_3568 PubMedSearch: Mori 2019 Bioorg.Med.Chem 27 3568 PubMedID: 31278005 Abstract Monoacylglycerol lipase (MAGL) is a major serine hydrolase that hydrolyses 2-arachidonoylglycerol (2-AG) into arachidonic acid (AA) and glycerol in the brain. Because 2-AG and AA are endogenous biologically active ligands in the brain, the inhibition of MAGL is an attractive therapeutic target for neurodegenerative diseases. In this study, to visualize MAGL via positron emission tomography (PET), we report a new carbon-11-labeled radiotracer, namely 1,1,1,3,3,3-hexafluoropropan-2-yl-3-(1-benzyl-1H-pyrazol-3-yl)azetidine-1-[(11)C]carboxylate ([(11)C]6). Compound 6 exhibited high in vitro binding affinity (IC(50) = 0.41 nM) to MAGL in the brain with a suitable lipophilicity (cLogD = 3.29). [(11)C]6 was synthesized by reacting 1,1,1,3,3,3-hexafluoropropanol (7) with [(11)C]phosgene ([(11)C]COCl(2)), followed by a reaction with 3-(1-benzyl-1H-pyrazol-3-yl)azetidine hydrochloride (8), which resulted in a 15.0 +/- 6.8% radiochemical yield (decay-corrected, n = 7) based on [(11)C]CO(2) and a 45 min synthesis time from the end of bombardment. A biodistribution study in mice showed high uptake of radioactivity in MAGL-rich organs, including the lungs, heart, and kidneys. More than 90% of the total radioactivity was irreversibly bound in the brain homogenate of rats 5 min and 30 min after the radiotracer injection. PET summation images of rat brains showed high radioactivity in all brain regions. Pretreatment with 6 or MAGL-selective inhibitor JW642 significantly reduced the uptake of radioactivity in the brain. [(11)C]6 is a promising PET tracer which offers in vivo specific binding and selectivity for MAGL in rodent brains. Title: Lysosomal Signaling Promotes Longevity by Adjusting Mitochondrial Activity Ramachandran PV, Savini M, Folick AK, Hu K, Masand R, Graham BH, Wang MC Ref: Dev Cell, 48:685, 2019 : PubMed ESTHER: Ramachandran_2019_Dev.Cell_48_685 PubMedSearch: Ramachandran 2019 Dev.Cell 48 685 PubMedID: 30713071 Gene_locus related to this paper: caeel-K04A8.5 Abstract Lysosomes and mitochondria are both crucial cellular organelles for metabolic homeostasis and organism health. However, mechanisms linking their metabolic activities to promote organism longevity remain poorly understood. We discovered that the induction of specific lysosomal signaling mediated by a LIPL-4 lysosomal acid lipase and its lipid chaperone LBP-8 increases mitochondrial -oxidation to reduce lipid storage and promote longevity in Caenorhabditis elegans. We further discovered that increased mitochondrial -oxidation reduces mitochondrial electron transport chain complex II activity, contributing to the induction of reactive oxygen species in mitochondria (mtROS) and the longevity effect conferred by LIPL-4-LBP-8 signaling. Moreover, by activating the JUN-1 transcription factor downstream of mtROS, the LIPL-4-LBP-8 signaling pathway induces antioxidant targets and oxidative stress tolerance. Together, these results reveal regulatory mechanisms by which lysosomal signaling triggers adjustments in mitochondrial activity and suggest the significance of these metabolic adjustments for improving metabolic fitness, redox homeostasis, and longevity. Title: Transcriptional responses in the hepatopancreas of Eriocheir sinensis exposed to deltamethrin Yang Z, Zhang Y, Jiang Y, Zhu F, Zeng L, Wang Y, Lei X, Yao Y, Hou Y and Hu K <3 more author(s)> Yang Z, Zhang Y, Jiang Y, Zhu F, Zeng L, Wang Y, Lei X, Yao Y, Hou Y, Xu L, Xiong C, Yang X, Hu K (- 3) Ref: PLoS ONE, 12:e0184581, 2017 : PubMed ESTHER: Yang_2017_PLoS.One_12_e0184581 PubMedSearch: Yang 2017 PLoS.One 12 e0184581 PubMedID: 28910412 Abstract Deltamethrin is an important pesticide widely used against ectoparasites. Deltamethrin contamination has resulted in a threat to the healthy breeding of the Chinese mitten crab, Eriocheir sinensis. In this study, we investigated transcriptional responses in the hepatopancreas of E. sinensis exposed to deltamethrin. We obtained 99,087,448, 89,086,478, and 100,117,958 raw sequence reads from control 1, control 2, and control 3 groups, and 92,094,972, 92,883,894, and 92,500,828 raw sequence reads from test 1, test 2, and test 3 groups, respectively. After filtering and quality checking of the raw sequence reads, our analysis yielded 79,228,354, 72,336,470, 81,859,826, 77,649,400, 77,194,276, and 75,697,016 clean reads with a mean length of 150 bp from the control and test groups. After deltamethrin treatment, a total of 160 and 167 genes were significantly upregulated and downregulated, respectively. Gene ontology terms "biological process," "cellular component," and "molecular function" were enriched with respect to cell killing, cellular process, other organism part, cell part, binding, and catalytic. Pathway analysis using the Kyoto Encyclopedia of Genes and Genomes showed that the metabolic pathways were significantly enriched. We found that the CYP450 enzyme system, carboxylesterase, glutathione-S-transferase, and material (including carbohydrate, lipid, protein, and other substances) metabolism played important roles in the metabolism of deltamethrin in the hepatopancreas of E. sinensis. This study revealed differentially expressed genes related to insecticide metabolism and detoxification in E. sinensis for the first time and will help in understanding the toxicity and molecular metabolic mechanisms of deltamethrin in E. sinensis. Title: Ameliorative effect of lotus seedpod proanthocyanidins on cognitive impairment and brain aging induced by d-galactose Gong YS, Guo J, Hu K, Gao YQ, Xie BJ, Sun ZD, Yang EN, Hou FL Ref: Experimental Gerontology, 74:21, 2016 : PubMed ESTHER: Gong_2016_Exp.Gerontol_74_21 PubMedSearch: Gong 2016 Exp.Gerontol 74 21 PubMedID: 26657492 Abstract This study mainly investigated the ameliorative effect of lotus seedpod proanthocyanidins (LSPC) and the mechanism underlying such effect on cognitive impairment and brain aging induced by d-galactose. Aging mice induced by d-galactose (150mg/kg, sc injection daily for 6weeks) were chosen for the experiment. LSPCs (30, 60, and 90mg/kg, ig) were provided after d-galactose injection. Learning and memory functions were detected by Y-maze and step-down avoidance tests. Then, some biochemical indexes related to cognitive ability and aging were measured. Histopathological feature and P53 protein expression in the hippocampus were observed. Results showed that the three different doses of LSPC could significantly ameliorate the learning and memory abilities impaired by d-galactose. LSPC significantly reduced the levels of malondialdehyde and nitric oxide (i.e. 90mg/kg LSPC group vs. model group, P=0.008), reduced the content of beta-amyloid peptide 1-42 (i.e. 90mg/kg LSPC group vs. model group, P=0.009), decreased the activities of acetylcholinesterase, monoamine oxidase B, total nitric oxide synthase (i.e. 90mg/kg LSPC group vs. model group, P=0.006), and neuronal nitric oxide synthase and synchronously increased the activities of superoxide dismutase and glutathione peroxidase in the brain. Furthermore, LSPC could prevent neuron damage and could lessen the expression of P53 protein in the hippocampus. These findings demonstrated that LSPC effectively attenuated cognitive damage and improved parameters related to brain aging in senescent mice induced by d-galactose, and may be used to treat Alzheimer's disease. Title: Design, synthesis and evaluation of novel ferulic acid-memoquin hybrids as potential multifunctional agents for the treatment of Alzheimer's disease Pan W, Hu K, Bai P, Yu L, Ma Q, Li T, Zhang X, Chen C, Peng K and Sang Z <1 more author(s)> Pan W, Hu K, Bai P, Yu L, Ma Q, Li T, Zhang X, Chen C, Peng K, Liu W, Sang Z (- 1) Ref: Bioorganic & Medicinal Chemistry Lett, 26:2539, 2016 : PubMed ESTHER: Pan_2016_Bioorg.Med.Chem.Lett_26_2539 PubMedSearch: Pan 2016 Bioorg.Med.Chem.Lett 26 2539 PubMedID: 27072909 Inhibitor(s) related to this paper: Memoquin Abstract A novel series of ferulic acid-memoquin hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro studies showed that most of the compounds exhibited a significant ability to inhibit acetylcholinesterase (AChE) (IC50 of 3.2-34.7muM) and self-induced beta-amyloid (Abeta1-42) aggregation (30.8-39.1%, 25muM), to act as potential antioxidants (ORAC-FL value of 0.9-1.3). In particular, compound 17d had the greatest ability to inhibit AChE (IC50=3.2muM), and Abeta1-42 aggregation (30.8%) was also an excellent antioxidant and neuroprotectant. Moreover, it is capable of disaggregating self-induced Abeta aggregation. Furthermore, 17d could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 17d is a potential multifunctional agent for the treatment of AD. Title: Whole-genome sequencing of cultivated and wild peppers provides insights into Capsicum domestication and specialization Qin C, Yu C, Shen Y, Fang X, Chen L, Min J, Cheng J, Zhao S, Xu M and Zhang Z <58 more author(s)> Qin C, Yu C, Shen Y, Fang X, Chen L, Min J, Cheng J, Zhao S, Xu M, Luo Y, Yang Y, Wu Z, Mao L, Wu H, Ling-Hu C, Zhou H, Lin H, Gonzalez-Morales S, Trejo-Saavedra DL, Tian H, Tang X, Zhao M, Huang Z, Zhou A, Yao X, Cui J, Li W, Chen Z, Feng Y, Niu Y, Bi S, Yang X, Cai H, Luo X, Montes-Hernandez S, Leyva-Gonzalez MA, Xiong Z, He X, Bai L, Tan S, Liu D, Liu J, Zhang S, Chen M, Zhang L, Zhang Y, Liao W, Wang M, Lv X, Wen B, Liu H, Luan H, Yang S, Wang X, Xu J, Li X, Li S, Wang J, Palloix A, Bosland PW, Li Y, Krogh A, Rivera-Bustamante RF, Herrera-Estrella L, Yin Y, Yu J, Hu K, Zhang Z (- 58) Ref: Proc Natl Acad Sci U S A, 111:5135, 2014 : PubMed ESTHER: Qin_2014_Proc.Natl.Acad.Sci.U.S.A_111_5135 PubMedSearch: Qin 2014 Proc.Natl.Acad.Sci.U.S.A 111 5135 PubMedID: 24591624 Gene_locus related to this paper: capch-q75qh4, capan-a0a1u8fuf5, capan-a0a1u8gmz3, capan-a0a1u8f879, capan-a0a1u8ftr2, capan-a0a1u8g8s6 Abstract As an economic crop, pepper satisfies people's spicy taste and has medicinal uses worldwide. To gain a better understanding of Capsicum evolution, domestication, and specialization, we present here the genome sequence of the cultivated pepper Zunla-1 (C. annuum L.) and its wild progenitor Chiltepin (C. annuum var. glabriusculum). We estimate that the pepper genome expanded approximately 0.3 Mya (with respect to the genome of other Solanaceae) by a rapid amplification of retrotransposons elements, resulting in a genome comprised of approximately 81% repetitive sequences. Approximately 79% of 3.48-Gb scaffolds containing 34,476 protein-coding genes were anchored to chromosomes by a high-density genetic map. Comparison of cultivated and wild pepper genomes with 20 resequencing accessions revealed molecular footprints of artificial selection, providing us with a list of candidate domestication genes. We also found that dosage compensation effect of tandem duplication genes probably contributed to the pungent diversification in pepper. The Capsicum reference genome provides crucial information for the study of not only the evolution of the pepper genome but also, the Solanaceae family, and it will facilitate the establishment of more effective pepper breeding programs. Title: Activation and allosteric modulation of a muscarinic acetylcholine receptor Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hubner H, Pardon E, Valant C and Kobilka BK <8 more 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 (- 8) Ref: Nature, 504:101, 2013 : PubMed ESTHER: Kruse_2013_Nature_504_101 PubMedSearch: Kruse 2013 Nature 504 101 PubMedID: 24256733 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. Title: Muscarinic receptors as model targets and antitargets for structure-based ligand discovery 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 : PubMed ESTHER: Kruse_2013_Mol.Pharmacol_84_528 PubMedSearch: Kruse 2013 Mol.Pharmacol 84 528 PubMedID: 23887926 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. Title: Solvent-free enzymatic synthesis of 1, 3-diacylglycerols by direct esterification of glycerol with saturated fatty acids Zhong N, Gui Z, Xu L, Huang J, Hu K, Gao Y, Zhang X, Xu Z, Su J, Li B Ref: Lipids Health Dis, 12:65, 2013 : PubMed ESTHER: Zhong_2013_Lipids.Health.Dis_12_65 PubMedSearch: Zhong 2013 Lipids.Health.Dis 12 65 PubMedID: 23656739 Abstract BACKGROUND: Pure 1, 3-diacylglycerols (1, 3-DAG) have been considered to be significant surfactants in food, cosmetics and pharmaceutical industries, as well as the effect on obesity prevention. METHODS: In this study, a vacuum-driven air bubbling operation mode was developed and evaluated for the enzymatic synthesis of 1, 3-DAG of saturated fatty acids, by direct esterification of glycerol with fatty acids in a solvent-free system. The employed vacuum-driven air bubbling operation mode was comparable to vacuum-driven N2 bubbling protocol, in terms of lauric acid conversion and 1, 3-dilaurin content. RESULTS: Some operation parameters were optimized, and 95.3% of lauric acid conversion and 80.3% of 1, 3-dilaurin content was obtained after 3-h reaction at 50 degC, with 5 wt% of Lipozyme RM IM (based on reactants) amount. Of the lipases studied, both Lipozyme RM IM and Novozym 435 exhibited good performance in terms of lauric acid conversion. Lipozyme TL IM, however, showed low activity. Lipozyme RM IM showed good operational stability in this operation protocol, 80.2% of the original catalytic activity remained after 10 consecutive batch applications. Some other 1, 3-DAG were prepared and high content was obtained after purification: 98.5% for 1, 3-dicaprylin, 99.2% for 1, 3-dicaprin, 99.1% for 1, 3-dilaurin, 99.5 for 1, 3-dipalmitin and 99.4% for 1, 3-disterin. CONCLUSION: The established vacuum-driven air bubbling operation protocol had been demonstrated to be a simple-operating, cost-effective, application practical and efficient methodology for 1, 3-DAG preparation. | |||||||
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