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Serum urate is associated with an increased risk of inflammatory bowel disease: A bidirectional Mendelian randomization study

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World Journal of Clinical Cases 2024年第5期12卷 891-902页

作者： Song Zhang Xue Fang Le Kang Xiang-Yu Sui Miao Liu Yu-Jia Luo Shuo Fu Zhao-Shen Li Sheng-BingZhao Yu Bai Department of Gastroenterology Changhai HospitalShanghai 200433China Department of Gastroenterology Changhai HospitalSecond Military Medical University/Naval Medical UniversityShanghai 200433China Digestive Endoscopy center Changhai HospitalNaval/Second Military Medical UniversityShanghai 200433China National Clinical Research center for Digestive Diseases Shanghai 200433China

BACKGROUND Previous studies have indicated bidirectional associations between urate levels and inflammatory bowel disease(IBD),including ulcerative colitis(UC)and Crohn’s disease(CD).However,it remains unclear whether the observations are causal because of confounding factors.AIM To investigate the causal associations between urate levels and IBD using bidirec-tional Mendelian randomization(MR).METHODS Independent genetic variants for urate levels and IBD were selected as instru-mental variables from published genome-wide association studies(GWASs).Summary statistics for instrument-outcome associations were retrieved from three separate databases for IBD(the UK Biobank,the FinnGen database and a large GWAS meta-analysis)and one for urate levels(a large GWAS meta-analysis).MR analyses included the inverse-variance-weighted method,weighted-median estimator,MR-Egger and sensitivity analyses(MR-PRESSO).A meta-analysis was also conducted to merge the data from separate outcome databases using a fixed-effects model.RESULTS Genetically higher serum urate levels were strongly associated with an increased risk of UC[odds ratio(OR):1.95,95%confidence interval(CI):1.86-2.05]after outlier correction,and the ORs(95%CIs)for IBD and CD were 0.94(95%CI:0.86-1.03)and 0.91(95%CI:0.80-1.04),respectively.Animal studies have confirmed the positive association between urate levels and UC.Moreover,genetically predicted IBD was inversely related to urate levels(OR:0.97,95%CI:0.94-0.99).However,no association was observed between genetically influenced UC or CD and urate levels.CONCLUSION Urate levels might be risk factors for UC,whereas genetically predicted IBD was inversely associated with urate levels.These findings provide essential new insight for treating and preventing IBD.

关键词： Inflammatory bowel disease Urate levels Antioxidant Mendelian randomization Single nucleotide polymorphism

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The functions of exosomes targeting astrocytes and astrocyte-derived exosomes targeting other cell types

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Neural Regeneration Research 2024年第9期19卷 1947-1953页

作者： Hongye Xu He Li Ping Zhang Yuan Gao Hongyu Ma Tianxiang Gao Hanchen Liu Weilong Hua Lei Zhang Xiaoxi Zhang Pengfei Yang Jianmin Liu Neurovascular center Changhai HospitalNaval Medical UniversityShanghaiChina Department of Emergency Naval Hospital of Eastern TheaterZhoushanZhejiang ProvinceChina

Astrocytes are the most abundant glial cells in the central nervous system;they participate in crucial biological processes,maintain brain structure,and regulate nervous system function.Exosomes are cell-derived extracellular vesicles containing various bioactive molecules including proteins,peptides,nucleotides,and lipids secreted from their cellular sources.Increasing evidence shows that exosomes participate in a communication network in the nervous system,in which astrocyte-derived exosomes play important roles.In this review,we have summarized the effects of exosomes targeting astrocytes and the astrocyte-derived exosomes targeting other cell types in the central nervous system.We also discuss the potential research directions of the exosome-based communication network in the nervous system.The exosome-based intercellular communication focused on astrocytes is of great significance to the biological and/or pathological processes in different conditions in the brain.New strategies may be developed for the diagnosis and treatment of neurological disorders by focusing on astrocytes as the central cells and utilizing exosomes as communication mediators.

关键词： astrocytes communication exosomes neurological disorders targeting mechanism

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Association between physical activity and risk of gastroesophageal reflux disease:A systematic review and meta-analysis

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Journal of Sport and Health Science 2024年第5期13卷 687-698页

作者： Chuting Yu Tinglu Wang Ye Gao Yunfei Jiao Huishan Jiang Yan Bian Wei Wang Han Lin Lei Xin Luowei Wang Department of Gastroenterology Changhai HospitalNaval Medical UniversityShanghai 200433China National Clinical Research center for Digestive Diseases(Shanghai) Shanghai 200433China

Background:Lifestyle plays an important role in preventing and managing gastroesophageal reflux disease(GERD).In response to the conflicting results in previous studies,we performed a systematic review and meta-analysis to investigate this association.Methods:Relevant studies published until January 2023 were retrieved from 6 databases,and the prevalence of symptomatic gastroesophageal reflux(GER)or GERD was determined from the original studies.A random effects model was employed to meta-analyze the association by computing the pooled relative risk(RR)with 95%confidence intervals(95%CIs).Furthermore,subgroup and dose-response analyses were performed to explore subgroup differences and the association between cumulative physical activity(PA)time and GERD.Results:This meta-analysis included 33 studies comprising 242,850 participants.A significant negative association was observed between PA and the prevalence of symptomatic GER(RR=0.74,95%CI:0.66-0.83;p<0.01)or GERD(RR=0.80,95%CI:0.76-0.84;p<0.01),suggesting that engaging in PA might confer a protective benefit against GERD.Subgroup analyses consistently indicated the presence of this association across nearly all subgroups,particularly among the older individuals(RR_(<40 years):RR_(≥40 years)=0.85:0.69,p<0.01)and smokers(RR_(smoker):RR_(non-smoker)=0.67:0.82,p=0.03).Furthermore,a dose-response analysis revealed that individuals who engaged in 150 min of PA per week had a 72.09%lower risk of developing GERD.Conclusion:Maintaining high levels of PA decreased the risk of GERD,particularly among older adults and smokers.Meeting the recommended PA level of 150 min per week may significantly decrease the prevalence of GERD.

关键词： Physical activity Gastroesophageal reflux disease Prevalence Systematic review

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Lactobacillus plantarum AR113 attenuates liver injury in D-galactose-induced aging mice via the inhibition of oxidative stress and endoplasmic reticulum stress

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Food Science and Human Wellness 2024年第2期13卷 885-897页

作者： Yongjun Xia Yujie Gong Xiangna Lin Yijin Yang Xin Song Guangqiang Wang Zhiqiang Xiong Yangyang Qian Zhuan Liao Hui Zhang Lianzhong Ai School of Health Science and Engineering Shanghai Engineering Research Center of Food MicrobiologyUniversity of Shanghai for Science and TechnologyShanghai 200093China College of Life Sciences Linyi UniversityLinyi 276000China Department of Gastroenterol. Digestive Endoscopy CenterChanghai HospitalShanghai 200082China

Probiotics could effectively eliminate excess reactive oxygen species(ROS)generated during aging or lipid metabolism disorders,but their mechanism is unclear.The major purpose of this study was to investigate the mechanism of Lactiplantibacillus plantarun AR113 alleviating oxidative stress injury in the D-galactose induced aging mice.The result showed that pretreatment with L.plantarun AR113 significantly relieving H_(2)O_(2)induced cytotoxicity in HepG2 cells by maintain cell membrane integrity and increasing antioxidant enzyme activities.In D-galactose induced aging mice,L.plantarun AR113 could significantly attenuate liver damage and inflammatory infiltration by promoting endogenous glutathione(GSH)synthesis and activating the Nrf2/Keap1 signaling pathway in mice,and increasing the expression of regulated phaseⅡdetoxification enzymes and antioxidant enzymes.Further analysis shown that gavage of L.plantarun AR113 could significantly reduce the expression of G protein-coupled receptor 78(GPR78)and C/EBP homologous protein(CHOP)proteins,and promote the restoration of endoplasmic reticulum(ER)homeostasis,thereby activating cell anti-apoptotic pathways.These results were also confirmed in H_(2)O_(2)-treated HepG2 experiments.It indicated that L.plantarun AR113 could inhibit D-galactose-induced liver injury through dual inhibition of ER stress and oxidative stress.L.plantarun AR113 have good application potential in anti-aging and alleviating metabolic disorders.

关键词： Lactiplantibacillus plantarun AR113 HepG2 D-galactose Oxidative stress ER stress

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G protein-coupled receptors(GPCRs):advances in structures,mechanisms,and drug discovery

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1938-1980页

作者： Mingyang Zhang Ting Chen Xun Lu Xiaobing Lan Ziqiang Chen Shaoyong Lu Key Laboratory of Protection Development and Utilization of Medicinal Resources in Liupanshan AreaMinistry of EducationPeptide&Protein Drug Research CenterSchool of PharmacyNingxia Medical UniversityYinchuan 750004China Medicinal Chemistry and Bioinformatics center Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of Cardiology Changzheng HospitalAffiliated to Naval Medical UniversityShanghai 200003China Department of Orthopedics Changhai HospitalAffiliated to Naval Medical UniversityShanghai 200433China

G protein-coupled receptors(GPCRs),the largest family of human membrane proteins and an important class of drug targets,play a role in maintaining numerous physiological processes.Agonist or antagonist,orthosteric effects or allosteric effects,and biased signaling or balanced signaling,characterize the complexity of GPCR dynamic features.In this study,we first review the structural advancements,activation mechanisms,and functional diversity of GPCRs.We then focus on GPCR drug discovery by revealing the detailed drug-target interactions and the underlying mechanisms of orthosteric drugs approved by the US Food and Drug Administration in the past five years.Particularly,an up-to-date analysis is performed on available GPCR structures complexed with synthetic small-molecule allosteric modulators to elucidate key receptor-ligand interactions and allosteric mechanisms.Finally,we highlight how the widespread GPCR-druggable allosteric sites can guide structure-or mechanism-based drug design and propose prospects of designing bitopic ligands for the future therapeutic potential of targeting this receptor family.

关键词： steric designing mechanisms

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Lipid nanovehicles overcome barriers to systemic RNA delivery: Lipid components, fabrication methods, and rational design

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Acta Pharmaceutica Sinica B 2024年第2期14卷 579-601页

作者： Jing Yan Hao Zhang Guangfeng Li Jiacan Su Yan Wei Can Xu Institute of Translational Medicine Shanghai UniversityShanghai 200444China Institute of Medicine Shanghai UniversityShanghai 200444China Department of Orthopedics Xinhua HospitalShanghai Jiao Tong University School of MedicineShanghai 200092China Department of Orthopedics Shanghai Zhongye HospitalShanghai 200941China Organoid Research center Shanghai UniversityShanghai 200444China Department of Gastroenterology Changhai HospitalShanghai 200433China

Lipid nanovehicles are currently the most advanced vehicles used for RNA delivery,as demonstrated by the approval of patisiran for amyloidosis therapy in 2018.To illuminate the unique superiority of lipid nanovehicles in RNA delivery,in this review,we first introduce various RNA therapeutics,describe systemic delivery barriers,and explain the lipid components and methods used for lipid nanovehicle preparation.Then,we emphasize crucial advances in lipid nanovehicle design for overcoming barriers to systemic RNA delivery.Finally,the current status and challenges of lipid nanovehicle-based RNA therapeutics in clinical applications are also discussed.Our objective is to provide a comprehensive overview showing how to utilize lipid nanovehicles to overcome multiple barriers to systemic RNA delivery,inspiring the development of more high-performance RNA lipid nanovesicles in the future.

关键词： Lipid nanovehicles RNAtherapeutics Barriers to systemicRNA delivery Lipid components Fabricationmethods Lipid nanovehicledesign Extrahepatictissue targeting Organ tropism

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Loss of GATA6-mediated up-regulation of UTX promotes pancreatic tumorigenesis and progression

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Genes & Diseases 2024年第2期11卷 921-934页

作者： Hui-Qing Zhang Fanyang Kong Xiangyu Kong Tingting Jiang Muyuan Ma Shaojiang Zheng Junli Guo Keping Xie The Third Department of Medical Oncology Jiangxi Cancer HospitalNanchangJiangxi 330006China Departments of Gastroenterology Changhai HospitalSecond Military Medical UniversityShanghai 200433China center for Pancreatic Cancer Research The South China University of Technology School of MedicineGuangzhouGuangdong 510006China Hainan Clinical Medical Research center of the First Affiliated Hospital Hainan Women and Children's Medical CenterHainan Medical UniversityHaikouHainan 570102China Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province Key Laboratory of Emergency and Trauma of Ministry of EducationHainan Medical UniversityHaikouHainan 571199China

Ubiquitously transcribed tetratricopeptide repeat on chromosome X(UTX),also known as lysine(K)-specific demethylase 6A(KDM6A),functions as a tumor suppressor gene or oncogene depending on the tumor type and context.However,its tumor-suppressive mechanisms remain largely unknown.Here,we investigated the clinical significance and biological effects of UTX expression in pancreatic ductal adenocarcinoma(PDA)and determined the potential mechanisms of its dysregulation.UTX expression and its association with clinicopathologic characteristics of PDA patients were analyzed using immunohistochemistry.UTX mRNA and protein expression and their regulation in PDA cell lines were measured using quantitative polymerase chain reaction and Western blot analyses.The biological functions of UTX in PDA cell growth,migration,and invasion were determined using gain-and loss-of-function assays with both in vitro and in vivo animal models.UTX expression was reduced in human PDA cell lines and specimens.Low UTX expression was associated with poor differentiation and prognosis in PDA.Forced UTX expression inhibited PDA proliferation,migration,and invasion in vitro and PDA growth and metastasis in vivo,whereas knockdown of UTX expression did the opposite.Mechanistically,UTX expression was trans-activated by GATA6 activation.GATA6-mediated PDA progression could be blocked,at least partially,by silencing UTX expression.In conclusion,loss of GATA6-mediated UTX expression was evident in human PDA and restored UTX expression suppressed PDA growth and metastasis.Thus,UTX is a tumor suppressor in PDA and may serve as a prognostic biomarker and therapeutic target.

关键词： Growth Invasion Metastasis Pancreatic cancer UTX

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Influence of sintering time on microstructure and properties of hot oscillatory pressing sintered W–Cu refractory alloys

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Tungsten 2024年第2期6卷 323-332页

作者： Zi-Qian Wu Wei Zhao Ka Gao Shi-Hao Du Qing-Quan Kong De-Jian Sun Yang Gao School of Materials Science and Engineering Zhengzhou University of AeronauticsZhengzhou 450015China School of Mechanical Engineering University of Shanghai for Science and TechnologyShanghai 200093China Department of General Medicine Changhai HospitalShanghai 200000China Hubei Key Laboratory of Mechanical Transmission and Manufacturing Engineering Wuhan University of Science and TechnologyWuhan 430081China Sichuan Province Engineering Technology Research center of Powder Metallurgy Chengdu UniversityChengdu 610106China

W–Cu refractory alloys are widely used in aerospace,aviation,electronics,power,and other fi elds.However,because of its large melting point diff erence between alloy elements,the conventional powder metallurgy method required a long time of high temperature sintering is very likely to cause low density and abnormal grain size growth.Therefore,90W-10Cu refractory alloys were successfully prepared by hot oscillatory pressing(HOP)under diff erent sintering time in this work.Then the infl uence of sintering time on the microstructure,grain size,density,Vickers hardness,room-tensile property,and electrical conductivity of the W–Cu refractory alloy was systematically invested.The results showed that during the short sintering time(30–90 min),the density,Vickers hardness,tensile strength,and electrical conductivity of the W–Cu refractory alloy increased signifi cantly to 98.7%,163.29 HV 30,507.3 MPa,and 14.2%International Annealed Copper Standard with the sintering time increasing,respectively,while its grain size showed no obvious change.When the sintering time further increased to 120 min,the density was basically consistent with the sintering time of 90 min.Nevertheless,the prolonged high temperature sintering resulted in the grain growth of the samples,which caused the deterioration of the Vickers hardness,room-tensile strength,and conductivity properties of the W–Cu refractory alloy.At the same sintering time,the density,Vickers hardness,and electrical conductivity of the HOP sintered W–Cu refractory alloy were signifi cantly higher than those of the HP sintered sample.It was indicated that high density,fi ne-grain,and excellent properties W–Cu refractory alloys could be prepared by hot oscillatory pressing under appropriate sintering time.

关键词： W–Cu refractory alloy Hot oscillatory pressing Sintering time Microstructure Property

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Melittin analog p5RHH enhances recombinant adeno-associated virus transduction efficiency

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Journal of Integrative Medicine 2024年第1期22卷 72-82页

作者： Jing-shun Meng Yun He Heng-bin Yang Li-ping Zhou Si-yuan Wang Xi-lin Feng Omar Yahya Al-shargi Xiao-min Yu Li-qing Zhu Chang-quan Ling Shanghai University of Traditional Chinese Medicine Shanghai 201203China Oncology Department of Traditional Chinese Medicine Changhai HospitalNaval Medical UniversityShanghai 200433China Faculty of Traditional Chinese Medicine Naval Medical UniversityShanghai 200043China State Key Laboratory of Genetic Engineering and Engineering Research center of Gene Technology(Ministry of Education) School of Life SciencesZhongshan HospitalFudan UniversityShanghai 200438China Yantai Fuheng Biological Technology Co. Ltd.YantaiShandong Province 264006China. Department of Clinical Laboratory the First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000Zhejiang ProvinceChina

Objective Melittin and its derivatives have been characterized to establish effective gene delivery systems.Their capability of facilitating endosomal release enhances the nanoparticles-based gene delivery.Nevertheless,little investigation has been conducted to explore its potential application in the context of viral vectors.Methods Various melittin-derived peptides were inserted into the loop VIII of the capsid proteins of recombinant adeno-associated virus vectors.These vectors carrying either gfp or fluc genes were subjected to qPCR assays and transduction assays of HEK293T cells to investigate the efficiency of vector production and gene delivery.In addition,the ability of a specific p5RHH-rAAV vector to deliver genes was examined through in vitro transduction of different cultured cells and in vivo tail vein administration to C57BL/6 mice.Finally,the intricate details of the vector-mediated transduction mechanisms were revealed by specific pharmacological inhibitors of every stage of the rAAV2 intracellular life cycle.Results A total of 76 melittin-related peptides were compiled from existing literature.Among them,cMA2,Melt13,p5RHH and aAR3 were found to significantly enhance the gene delivery efficiency of rAAV2 vectors.The p5RHH-rAAV2 vectors efficiently transduced not only rAAV-potent cell lines but also cell lines previously considered resistant to rAAV.Mechanistically,bafilomycin A1,a vacuolar endosome acidification inhibitor,completely inhibited the transgene expression mediated by the p5RHH-rAAV2 vectors.Most importantly,p5RHH-rAAV8 vectors also demonstrated increased hepatic transduction in vivo in C57BL/6 mice.Conclusion The incorporation of melittin analogues into the rAAV capsids results in a significant improvement in rAAV-mediated transgene expression.While further modifications remain an area of interest,our studies have substantially broadened the pharmacological prospects of melittin in the context of viral vector-mediated gene delivery.

关键词： Melittin Recombinant adeno-associated virus Capsid engineering Transduction efficiency

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Endovascular treatment of acute M1 occlusions due to underlying intracranial atherosclerotic severe stenosis

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Chinese Neurosurgical Journal 2022年第4期8卷 215-220页

作者： Yazhou Yan Li Du Xiliang He Qinghai Huang Yuan Pan Tao Xin stroke center of 971 Hospital of PLA Qingdao 266071China Department of Neurosurgery of changhai Hospital affiliated to the Naval Military Medical University ShanghaiChina

Background:Endovascular treatment(EVT)for acute ischemic stroke with an occlusion of the M1 segment due to intracranial atherosclerotic severe stenosis(ICASS)remains challenging.This study aimed to evaluate the safety and efficacy of EVT for ICASS-related M1 acute occlusion.Methods:We retrospectively reviewed all patients with an ICASS-related M1 acute occlusion who underwent EVT at our institution between January 2015 and December 2020.Clinical presentation,baseline characteristics,angiographic and clinical results,technical feasibility,perioperative complications,and follow-up results were evaluated.Results:Twenty-two patients with ICASS-related M1 acute occlusion were included.Eight patients(36.4%)received bridging therapy,and the other 14 patients(63.6%)directly underwent EVT.Fifteen patients(68.2%)treated with balloon dilations and stenting as rescue treatment.Six patients(27.3%)received single balloon angioplasty,and 5 of these patients were treated with staged stenting.One case(4.5%)failed recanalization at the first EVT,and successful revascularization was achieved a month later.The mean procedure time was 67.2±20.8 min.Successful revascularization(mTICI≥2b)was achieved in 95.5%(21/22)of patients.Perioperative complications developed in two patients(9.1%)including one hemorrhagic event and one thromboembolic event.Angiographic follow-up was available in 20 patients(90.9%)at an average of 8.6±3.0 months.The degree of stenosis was worse(10-30%)in 6 cases(30%)compared with the initial outcomes.The favorable outcomes(mRS≤2)at 3-month follow-up was achieved in 19 patients(86.4%).Conclusions:ICASS-related occlusion in the M1 segment often required a rescue therapy including balloon angioplasty with/without stenting,and this treatment strategy was safe and effective.But single balloon angioplasty at the first EVT generally cannot achieve satisfactory results and often needed staged stenting treatment.

关键词： Endovascular treatment M1 occlusion Intracranial severe stenosis Rescue therapy

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