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Causal Relationship Between Gut Microbiota and Liver Cirrhosis:16S rRNA Sequencing and Mendelian Randomization Analyses

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Journal of Clinical and Translational Hepatology 2024年第2期12卷 123-133页

作者： Mengqin Yuan Xue Hu Lichao Yao Ping Chen Zheng Wang Pingji Liu Zhiyu Xiong Yingan Jiang Lanjuan Li Department of infectious diseases Renmin Hospital of Wuhan UniversityWuhanHubeiChina State Key Laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Centre for Infectious DiseasesCollaborative Innovation Centre for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina

Background and Aims:Accumulating evidence highlights the association between the gut microbiota and liver ***,the role of the gut microbiota in liver cirrhosis remains ***:We first assessed the differences in the composition of the bacterial community between CCl4-induced liver cirrhosis and control mice using 16S rRNA *** then performed a two-sample Mendelian randomization(MR)analysis to reveal the underlying causal relationship between the gut microbiota and liver *** relationships were analyzed using primary inverse variance weighting(IVW)and other supplemental MR ***,fecal samples from liver cirrhosis patients and healthy controls were collected to validate the results of the MR ***:Analysis of 16S rRNA sequencing indicated significant differences in gut microbiota composition between the cirrhosis and control *** analyses suggested that Alphaproteobacteria,Bacillales,NB1n,Rhodospirillales,Dorea,Lachnospiraceae,and Rhodospirillaceae were positively correlated with the risk of liver cirrhosis,whereas Butyricicoccus,Hungatella,Marvinbryantia,and Lactobacillaceae displayed the opposite ***,the weighted median and MR-PRESSO estimates further showed that only Butyricicoccus and Marvinbryantia presented stable negative associations with liver *** significant heterogeneity or horizontal pleiotropy was observed in the sensitivity ***,the result of 16S rRNA sequencing also showed that healthy controls had a higher relative abundance of Butyricicoccus and Marvinbryantia than liver cirrhosis ***:Our study provides new causal evidence for the link between gut microbiota and liver cirrhosis,which may contribute to the discovery of novel strategies to prevent liver cirrhosis.

关键词： 16S rRNA gene sequencing Liver cirrhosis Gut microbiota Causality Two-sample Mendelian randomization study

Eliciting CD4-mimicking broadly neutralizing antibodies:new avenues towards the rational design of an HIV vaccine

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Signal Transduction and Targeted Therapy 2024年第3期9卷 836-838页

作者： Frauke Muecksch Oliver T.Fackler Department of infectious diseases Heidelberg UniversityMedical Faculty HeidelbergVirologyCenter for Integrative Infectious Disease Research(CIID)HeidelbergGermany Chica and Heinz Schaller(CHS)Research Group Department of Infectious DiseasesVirologyUniversity Hospital HeidelbergHeidelbergGermany Department of infectious diseases Heidelberg UniversityMedical Faculty HeidelbergIntegrative VirologyCenter for Integrative Infectious Disease Research(CIID)HeidelbergGermany German centre for Infection Research(DZIF) Partner Site HeidelbergHeidelbergGermany

In a study recently published in Cell,Saunders et *** that a new anti-HIV vaccine triggers antibody responses resembling CD4-binding site broadly neutralizing antibody precursors in rhesus macaques.1 This study provid... 详细信息

关键词： al. vaccine rational

Metadherin-driven promotion of cancer stem cell phenotypes and its effect on immunity in hepatocellular carcinoma

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World Journal of Gastroenterology 2024年第20期30卷 2624-2628页

作者： Nevena Todorović Amedeo Amedei Department of Experimental and Clinical Medicine University of FlorenceFlorence 50134Italy Clinic for infectious and Tropical diseases University Clinical Centre of SerbiaBelgrade 11000Serbia

In this editorial we provide commentary on the article published by Wang et al,featured in the recent issue of the World Journal of Gastroenterology in *** focus on the metadherin(MTDH),also known as astrocyte elevated gene-1 or lysine rich CEACAM1,and its effects on cancer stem cells(CSCs)and immunity in hepatocellular carcinoma(HCC).HCC is the most common primary liver cancer and one of the leading causes of cancer-related deaths *** HCC cases develop in the context of liver *** the pivotal mechanisms of carcinogenesis are gene mutations,dysregulation of diverse signaling pathways,epigenetic alterations,hepatitis B virus-induced hepatocarcinogenesis,chronic inflammation,impact of tumor microenvironment,oxidative *** the years,extensive research has been conducted on the MTDH role in various tumor pathologies,such as lung,breast,ovarian,gastric,hepatocellular,colorectal,renal carcinoma,neuroblastoma,melanoma,and ***,its involvement in tumor development processes including transformation,apoptosis evasion,angiogenesis,invasion,and metastasis via multiple signaling *** has been demonstrated that knockdown or knockout of MTDH disrupt tumor development and *** addition,numerous reports have been carried out regarding the MTDH influence on HCC,demonstrating its role as a predictor of poor prognosis,aggressive tumor phenotypes prone to metastasis and recurrence,and exhibiting significant potential for therapy ***,more studies finely investigated the influence of MTDH on *** CSCs are a small subpopulation of tumor cells that sharing traits with normal stem cells like self-renewal and differentiation abilities,alongside a high plasticity that alters their *** their presumed role in tumor initiation,they can drive also disease relapse,metastasis,and resistance to chemo and radiotherapy.

关键词： Hepatocellular carcinoma Metadherin Astrocyte elevated gene-1 Lysine rich

The Relationship between Viral Replication and the Severity of Hepatic Necroinflammatory Damage Changed before HBeAg Loss in Patients with Chronic Hepatitis B Virus Infection

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Journal of Clinical and Translational Hepatology 2024年第4期12卷 381-388页

作者： Leijie Wang Jian Wang Kunyu Zhao Lina Jiang Xinxin Zhang Jingming Zhao Jie Li Fengmin Lu Department of microbiology and Immunology College of Basic Medical SciencesZhengzhou UniversityZhengzhouHenanChina Department of microbiology&infectious Disease Center School of Basic Medical SciencesPeking UniversityBeijingChina Department of infectious diseases Nanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsuChina Department of Pathology and Hepatology The Fifth Medical Center of PLA General HospitalBeijingChina Department of infectious diseases Rui Jin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina

Background and Aims:Disease progression of chronic hepatitis B virus(HBV)infection is driven by the interactions between viral replication and the host immune response against the *** study aimed to clarify the relationship between HBV replication and hepatic inflammation during disease ***:Two cross-sectional,one validation cohort,and meta-analyses were used to explore the relationship between HBV replication and liver *** analysis,multiple linear regression,and logistic regression were used to explore the relationship between ***:In the cross-sectional cohorts A and B including 1,350 chronic hepatitis B patients,Spearman analysis revealed a negative relationship between HBV replication(such as HBV DNA)and liver inflammation(such as ALT)in HBeAg-positive patients with higher HBV DNA>2×10^(6) IU/mL(rho=0.278 and 0.260)and HBeAg-negative patients(rho=0.450 and 0.363).After adjustment for sex,age,and anti-HBe,results from logistic regression and multiple linear regression showed the opposite relationship still existed in HBeAg-positive patients with different DNA levels;the opposite relationship in HBeAg-positive patients with different DNA levels was validated in a third cohort;the opposite relationship in patients with different HBeAg status was partially confirmed by meta-analysis(overall R:-0.004 vs 0.481).Conclusions:These results suggested a negative relationship between viral replication and liver inflammation in HBeAgpositive patients with high HBV DNA,which changed to a positive relationship for those HBeAg-positive patients with DNA less than 2×10^(6) IU/mL and HBeAg-negative patients.

关键词： Chronic hepatitis B HBeAg HBV DNA ALT.

Hypertension and NAFLD risk:Insights from the NHANES 2017-2018 and Mendelian randomization analyses

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Chinese Medical Journal 2024年第4期137卷 457-464页

作者： Mengqin Yuan Jian He Xue Hu Lichao Yao Ping Chen Zheng Wang Pingji Liu Zhiyu Xiong Yingan Jiang Lanjuan Li Department of infectious diseases Renmin Hospital of Wuhan UniversityWuhanHubei 430000China Department of Gastroenterology Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdong 510010China State Key Laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Centre for Infectious DiseasesCollaborative Innovation Centre for Diagnosis and Treatment of Infectious DiseasesDepartment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiang 310000China

Background:Hypertension and non-alcoholic fatty liver disease(NAFLD)share several pathophysiologic risk factors,and the exact relationship between the two remains *** study aims to provide evidence concerning the relationship between hypertension and NAFLD by analyzing data from the National Health and Nutrition Examination Survey(NHANES)2017-2018 and Mendelian randomization(MR)***:Weighted multivariable-adjusted logistic regression was applied to assess the relationship between hypertension and NAFLD risk by using data from the NHANES ***,a two-sample MR study was performed using the genome-wide association study(GWAS)summary statistics to identify the causal association between hypertension,systolic blood pressure(SBP),diastolic blood pressure(DBP),and *** primary inverse variance weighted(IVW)and other supplementary MR approaches were conducted to verify the causal association between hypertension and *** analyses were adopted to confirm the robustness of the ***:A total of 3144 participants were enrolled for our observational study in *** multivariable-adjusted logistic regression analysis suggested that hypertension was positively related to NAFLD risk(odds ratio[OR]=1.677;95%confidence interval[CI],1.159-2.423).SBP≥130 mmHg and DBP≥80 mmHg were also significantly positively correlated with ***,hypertension was independently connected with liver steatosis(β=7.836[95%CI,2.334-13.338]).The results of MR analysis also supported a causal association between hypertension(OR=7.203[95%CI,2.297-22.587])and *** results were observed for the causal exploration between SBP(OR=1.024[95%CI,1.003-1.046]),DBP(OR=1.047[95%CI,1.005-1.090]),and *** sensitive analysis further confirmed the robustness and reliability of these findings(all P>0.05).Conclusion:Hypertension was associated with an increased risk of NAFLD.

关键词： Hypertension Non-alcoholic fatty liver disease National Health and Nutrition Examination Survey Mendelian randomization analysis Causality

The immune response to SARS-CoV-2 in people with HIV

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Cellular & Molecular Immunology 2024年第2期21卷 184-196页

作者： Maxine A.Höft Wendy A.Burgers Catherine Riou Institute of infectious Disease and Molecular Medicine University of Cape TownCape TownSouth Africa Division of Medical Virology Department of PathologyUniversity of Cape TownCape TownSouth Africa Wellcome centre for infectious diseases Research in Africa University of Cape TownCape TownSouth Africa

This review examines the intersection of the HIV and SARS-CoV-2 *** with HIV(PWH)are a heterogeneous group that differ in their degree of immune suppression,immune reconstitution,and viral *** COVID-19 in those with wellcontrolled HIV infection poses no greater risk than that for HIV-uninfected individuals,people with advanced HIV disease are more vulnerable to poor COVID-19 ***-19 vaccines are effective and well tolerated in the majority of PWH,though reduced vaccine efficacy,breakthrough infections and faster waning of vaccine effectiveness have been demonstrated in *** is likely a result of suboptimal humoral and cellular immune responses after *** with advanced HIV may also experience prolonged infection that may give rise to new epidemiologically significant variants,but initiation or resumption of antiretroviral therapy(ART)can effectively clear persistent ***-19 vaccine guidelines reflect these increased risks and recommend prioritization for vaccination and additional booster doses for PWH who are moderately to severely *** recommend continued research and monitoring of PWH with SARS-CoV-2 infection,especially in areas with a high HIV burden.

关键词： SARS-CoV-2 HIV Immune dysfunction Vaccine efficacy Prolonged infection Immunogenicity

LRP1 facilitates hepatic glycogenesis by improving the insulin signaling pathway in HFD-fed mice

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Animal Models and Experimental Medicine 2024年第5期 696-706页

作者： Xingxian Guo Jiangxia Pu Ziqi Tang Can Jia Fan Yang Tianyi Liu Yinyuan Ding centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Department of Infectious Diseases Institute for Viral Hepatitis The Second Affiliated Hospital Chongqing Medical University

Background: LDL receptor-related protein-1(LRP1) is a cell-surface receptor that functions in diverse physiological pathways. We previously demonstrated that hepatocyte-specific LRP1 deficiency(hLRP1KO) promotes diet-induced insulin resistance and increases hepatic gluconeogenesis in mice. However, it remains unclear whether LRP1 regulates hepatic ***: Insulin signaling, glycogenic gene expression, and glycogen content were assessed in mice and HepG2 cells. The pcDNA 3.1 plasmid and adeno-associated virus serotype 8 vector(AAV8) were used to overexpress the truncated β-chain(βΔ) of LRP1 both in vitro and in ***: On a normal chow diet, hLRP1KO mice exhibited impaired insulin signaling and decreased glycogen content. Moreover, LRP1 expression in HepG2 cells was significantly repressed by palmitate in a dose-and time-dependent manner. Both LRP1 knockdown and palmitate treatment led to reduced phosphorylation of Akt and GSK3β, increased levels of phosphorylated glycogen synthase(GYS), and diminished glycogen synthesis in insulin-stimulated HepG2 cells, which was restored by exogenous expression of the βΔ-chain. By contrast, AAV8-mediated hepatic βΔ-chain overexpression significantly improved the insulin signaling pathway, thus activating glycogenesis and enhancing glycogen storage in the livers of high-fat diet(HFD)-fed ***: Our data revealed that LRP1, especially its β-chain, facilitates hepatic glycogenesis by improving the insulin signaling pathway, suggesting a new therapeutic strategy for hepatic insulin resistance-related diseases.

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Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4028-4044页

作者： Chris Chun-Yiu Chan Qian Guo Jasper Fuk-Woo Chan Kaiming Tang Jian-Piao Cai Kenn Ka-Heng Chik Yixin Huang Mei Dai Bo Qin Chon Phin Ong Allen Wing-Ho Chu Wan-Mui Chan Jonathan Daniel Ip Lei Wen Jessica Oi-Ling Tsang Tong-Yun Wang Yubin Xie Zhenzhi Qin Jianli Cao Zi-Wei Ye Hin Chu Kelvin Kai-Wang To Xing-Yi Ge Tao Ni Dong-Yan Jin Sheng Cui Kwok-Yung Yuen Shuofeng Yuan State Key Laboratory of Emerging infectious diseases Carol Yu Centre for InfectionDepartment of MicrobiologySchool of Clinical MedicineLi Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China Department of infectious diseases and microbiology the University of Hong Kong-Shenzhen HospitalShenzhen 518000China centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong SAR 999077China Academician Workstation of Hainan Province Hainan Medical University-the University of Hong Kong Joint Laboratory of Tropical Infectious DiseasesHaikou 571100China School of Biomedical Sciences Li Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China NHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen Biology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China College of Biology Hunan Provincial Key Laboratory of Medical VirologyHunan UniversityChangsha 410082China

There are only eight approved small molecule antiviral drugs for treating *** them,four are nucleotide analogues(remdesivir,JT001,molnupiravir,and azvudine),while the other four are protease inhibitors(nirmatrelvir,ensitrelvir,leritrelvir,and simnotrelvir-ritonavir).Antiviral resistance,unfavourable drug‒drug interaction,and toxicity have been reported in previous *** there is a dearth of new treatment options for *** this work,a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 *** compound,designated 172,demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of *** studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease(3CLpro)by binding to an allosteric site and reduces 3CLpro dimerization.A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in *** vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 ***,this study identified an alternative druggable site on the SARS-CoV-23CLpro,proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

关键词： SARS-CoV-2 High throughput screening Broad-spectrum antiviral treatment 3CLpro inhibitor Allosteric-site inhibitor Animal models Chemical genetics Reverse genetics

The interplay of drug therapeutics and immune responses to SARS-CoV-2

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Cellular & Molecular Immunology 2024年第2期21卷 197-200页

作者： Valeria Fumagalli Matteo Iannacone Division of Immunology Transplantationand Infectious DiseasesIRCCS San Raffaele Scientific InstituteMilanItaly Vita-Salute San Raffaele University MilanItaly Experimental Imaging centre IRCCS San Raffaele Scientific InstituteMilanItaly

The SARS-CoV-2 pandemic has necessitated rapid therapeutic and preventative *** vaccines form the frontline of defense,antiviral treatments such as nirmatrelvir have emerged as vital adjunctive measures,particularly for those unable or unwilling to be *** review delves into the potential influence of nirmatrelvir on enduring *** parallel,the potential of drug repurposing is explored,with bisphosphonates being examined for their possible effects against COVID-19 due to their immunomodulatory *** importance of rigorous clinical trials and careful interpretation of preliminary data is emphasized.

关键词： SARS-CoV-2 Nirmatrelvir Bisphosphonates Adaptive immunity Drug repurposing