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Longitudinal gut fungal alterations and potential fungal biomarkers for the progression of primary liver disease

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Science China(life Sciences) 2024年第6期67卷 1183-1198页

作者： Shiman Jiang Lvwan Xu Yanfei Chen Zheyue Shu Longxian Lv Yuxi Zhao Kefan Bi Sisi Yang Qiangqiang Wang lanjuan li State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Division of Hepatobiliary and Pancreatic Surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

liver disease,a major health concern worldwide,is a serious and progressive disorder.Herein,we not only established a mouse model of DEN+CCl4-induced primary liver disease but also collected clinical human samples to investigate longitudinal alterations in the gut mycobiome.As liver disease advanced,gut integrity was disrupted,and the mycobiota was disturbed in the mouse models.The metabolites associated with hepatocellular carcinoma(HCC)differed from those associated with the cirrhotic phase as follows:levels of stercobilin and aflatoxin B1 dialcohol were reduced,while levels of triterpenoids,bafilomycin A1,and DHEA were increased in the HCC group.The abundance of the phylum Chytridiomycota increased as the chronic liver disease progressed and was then replaced by the phylum Ascomycota in HCC.Based on the results from clinical human samples,the genus Candida(Ascomycota)(in humans)and the genus Kazachstania(Ascomycota)(in mice)occupied a dominant position in the HCC group,while other fungi were depleted.The increased abundance of C.albicans and depletion of S.cerevisiae may be hallmarks of the progression of liver cirrhosis to early HCC.Moreover,the administration of C.albicans and S.cerevisiae in the LC-HCC progression could accelerate or retard the progression of HCC.Therefore,gut fungi have the potential to serve as a noninvasive clinical biomarker and even a treatment method.

关键词： gut mycobiome liver disease longitudinal studies hepatocarcinogenesis fungal biomarker

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 unclear.Our 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)analyses.Methods:Weighted multivariable-adjusted logistic regression was applied to assess the relationship between hypertension and NAFLD risk by using data from the NHANES 2017-2018.Subsequently,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 NAFLD.The primary inverse variance weighted(IVW)and other supplementary MR approaches were conducted to verify the causal association between hypertension and NAFLD.Sensitivity analyses were adopted to confirm the robustness of the results.Results:A total of 3144 participants were enrolled for our observational study in NHANES.Weighted 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 NAFLD.Moreover,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 NAFLD.Similar 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 NAFLD.The 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

MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation

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Asian Journal of Pharmaceutical Sciences 2024年第1期19卷 119-134页

作者： Wenyi Chen Feiyan lin Xudong Feng Qigu Yao Yingduo Yu Feiqiong Gao Jiahang Zhou Qiaoling Pan Jian Wu Jinfeng Yang Jiong Yu Hongcui Cao lanjuan li State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesNational Medical Center for Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Jinan Microecological Biomedicine Shandong Laboratory Jinan 250117China Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province Hangzhou 310003China

Primary sclerosing cholangitis(PSC)is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis,with no curative treatment available,and liver transplantation is inevitable for end-stage patients.Human placentalmesenchymal stem cell(hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis,inhibit collagen production and possess immunomodulatory properties in autoimmune liver disease.Here,we prepared hpMSC-derived exosomes(Exo^(MSC))and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2^(−/−)mice and multicellular organoids established from PSC patients.The results showed that Exo^(MSC) ameliorated liver fibrosis in Mdr2^(−/−)mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis,and the percentage of CD4+IL-17A+T cells was reduced both in Exo^(MSC)-treated Mdr2^(−/−)mice(Mdr2^(−/−)-Exo)in vivo and Exo^(MSC)-treated Th17 differentiation progressed in vitro.Furthermore,Exo^(MSC) improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular organoids.Thus,our data demonstrate the antifibrosis effect of Exo^(MSC) in PSC disease by inhibiting Th17 differentiation,and ameliorating the Th17-induced microenvironment,indicating the promising potential therapeutic role of Exo^(MSC) in liver fibrosis of PSC or Th17-related diseases.

关键词： Mesenchymal stem cell Exosomes Primary sclerosing cholangitis Fibrosis Organoids Th17

Role of Akkermansia muciniphila in the development of nonalcoholic fatty liver disease: current knowledge and perspectives

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Frontiers of Medicine 2022年第5期16卷 667-685页

作者： Yuqiu Han lanjuan li Baohong Wang State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Research Units of Infectious disease and Microecology Chinese Academy of Medical SciencesHangzhou 310003China Jinan Microecological Biomedicine Shandong Laboratory Jinan 250117China

Nonalcoholic fatty liver disease(NAFLD)is a hepatic manifestation of metabolic syndrome and a common cause of liver cirrhosis and cancer.Akkermansia muciniphila(A.muciniphila)is a next-generation probiotic that has been reported to improve metabolic disorders.Emerging evidence indicates the therapeutic potential of A.muciniphila for NAFLD,especially in the inflammatory stage,nonalcoholic steatohepatitis.Here,the current knowledge on the role of A.muciniphila in the progression of NAFLD was summarized.A.muciniphila abundancy is decreased in animals and humans with NAFLD.The recovery of A.muciniphila presented benefits in preventing hepatic fat accumulation and inflammation in NAFLD.The details of how microbes regulate hepatic immunity and lipid accumulation in NAFLD were further discussed.The modulation mechanisms by which A.muciniphila acts to improve hepatic inflammation are mainly attributed to the alleviation of inflammatory cytokines and LPS signals and the downregulation of microbiota-related innate immune cells(such as macrophages).This review provides insights into the roles of A.muciniphila in NAFLD,thereby providing a blueprint to facilitate clinical therapeutic applications.

关键词： Akkermansia muciniphila NAFLD NASH steatosis inflammation

Safety and efficacy of omalizumab for antihistamine-resistant chronic urticaria in children:a case series and literature review

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World Journal of Pediatrics 2024年第3期20卷 294-298页

作者： Wei-Fang Zhu Chen Wang Jian-Jun Qiao Lan-Juan li Department of Dermatology First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Chronic urticaria(CU)is a common skin disease characterized by the occurrence of wheals,with or without angioedema,lasting more than 6 weeks.The prevalence of CU is about 0.7%[1],but higher in children,with an incidence of 1.38%[1].The occurrence of severe pruritus and unpredictable wheals may severely impact patients'quality of life,cause psychological problems,including sleep disorders and depression,and lead to economic burden due to limitation on daily life and work[2,3].

关键词： edema prevalence children

Integrative Proteomic Analysis of Multiple Posttranslational Modifications in Inflammatory Response

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Genomics, Proteomics & Bioinformatics 2022年第1期20卷 163-176页

作者： Feiyang Ji Menghao Zhou Huihui Zhu Zhengyi Jiang Qirui li Xiaoxi Ouyang Yiming Lv Sainan Zhang Tian Wu lanjuan li State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310003China The First Affiliated Hospital College of MedicineZhejiang UniversityHangzhou 310003China Department of Colorectal Surgery Sir Run Run Shaw HospitalCollege of MedicineZhejiang UniversityHangzhou 310003China Quzhou Second People’s Hospital Quzhou 324000China

Posttranslational modifications(PTMs)of proteins,particularly acetylation,phosphorylation,and ubiquitination,play critical roles in the host innate immune response.PTMs’dynamic changes and the crosstalk among them are complicated.To build a comprehensive dynamic network of inflammation-related proteins,we integrated data from the whole-cell proteome(WCP),acetylome,phosphoproteome,and ubiquitinome of human and mouse macrophages.Our datasets of acetylation,phosphorylation,and ubiquitination sites helped identify PTM crosstalk within and across proteins involved in the inflammatory response.Stimulation of macrophages by lipopolysaccharide(LPS)resulted in both degradative and non-degradative ubiquitination.Moreover,this study contributes to the interpretation of the roles of known inflammatory molecules and the discovery of novel inflammatory proteins.

关键词： Proteome Crosstalk Inflammation lipopolysaccharide Macrophage

1,5-Anhydroglucitol Predicts Mortality in Patients with HBV-Related Acute-on-chronic liver Failure

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Journal of Clinical and Translational Hepatology 2022年第4期10卷 651-659页

作者： lingjian Zhang Yalei Zhao Zhongyang Xie Lanlan Xiao Qingqing Hu Qian li Shima Tang Jie Wang lanjuan li State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiangChina

Background and Aims:1,5-Anhydroglucitol(1,5AG)activ-ity has been reported in chronic liver disease.Hepatitis B vi-rus(HBV)-related acute-on-chronic liver failure(HBV-ACLF)patients have a high mortality.We aimed to discover the re-lationship between serum 1,5AG and the prognosis of HBV-ACLF.Methods:Serum 1,5AG levels were determined in 333 patients with HBV-ACLF,300 without diabetes were allo-cated to derivation(n=206)and validation cohorts(n=94),and 33 were recruited to evaluate 1,5AG in those with diabe-tes.Forty patients with chronic hepatitis B,40 with liver cir-rhosis,and 40 healthy people were controls in the validation cohort.Results:In the derivation and validation cohorts,serum 1,5AG levels were significantly lower in nonsurvivors than in survivors.The AUC of 1,5AG for 28-day mortality was 0.811.In patients with diabetes,serum 1,5AG levels were also significantly lower in nonsurvivors than in survi-vors.In multivariate Cox regression analysis,serum 1,5AG levels were independently associated with 28-day mortal-ity.A novel predictive model(ACTIG)based on 1,5AG,age,TB,cholesterol,and INR was derived to predict mortality.In ACTIG,the AUC for 28-day mortality was 0.914,which was superior to some prognostic score models.ACTIG was also comparable to those prognostic score models in pre-dicting 6-month mortality.In mice with D-galactosamine/lipopolysaccharide-induced liver failure,1,5AG levels were significantly reduced in serum and significantly increased in urine and liver tissue.Conclusions:Serum 1,5AG levels are a promising predictor of short-term mortality in HBV-ACLF patients.The 1,5AG distribution changed in mice with D-galactosamine/lipopolysaccharide-induced liver failure.

关键词： Acute-on-chronic liver failure 1,5-anhydroglucitol Prognosis

Role of main RNA modifications in cancer:N^(6)-methyladenosine,5-methylcytosine,and pseudouridine

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Signal Transduction and Targeted Therapy 2022年第5期7卷 1555-1585页

作者： Chen Xue Qingfei Chu Qiuxian Zheng Shiman Jiang Zhengyi Bao Yuanshuai Su Juan Lu lanjuan li State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310003China

Cancer is one of the major diseases threatening human life and health worldwide.Epigenetic modification refers to heritable changes in the genetic material without any changes in the nucleic acid sequence and results in heritable phenotypic changes.Epigenetic modifications regulate many biological processes,such as growth,aging,and various diseases,including cancer.With the advancement of next-generation sequencing technology,the role of RNA modifications in cancer progression has become increasingly prominent and is a hot spot in scientific research.This review studied several common RNA modifications.

关键词： diseases cancer Cancer

Evolving cognition of the JAK-STAT signaling pathway:autoimmune disorders and cancer

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Signal Transduction and Targeted Therapy 2023年第6期8卷 2749-2772页

作者： Chen Xue Qinfan Yao Xinyu Gu Qingmiao Shi Xin Yuan Qingfei Chu Zhengyi Bao Juan Lu lanjuan li State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina Kidney Disease Center The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina

The Janus kinase(JAK)signal transducer and activator of transcription(JAK-STAT)pathway is an evolutionarily conserved mechanism of transmembrane signal transduction that enables cells to communicate with the exterior environment.Various cytokines,interferons,growth factors,and other specific molecules activate JAK-STAT signaling to drive a series of physiological and pathological processes,including proliferation,metabolism,immune response,inflammation,and malignancy.Dysregulated JAK-STAT signaling and related genetic mutations are strongly associated with immune activation and cancer progression.Insights into the structures and functions of the JAK-STAT pathway have led to the development and approval of diverse drugs for the clinical treatment of diseases.Currently,drugs have been developed to mainly target the JAK-STAT pathway and are commonly divided into three subtypes:cytokine or receptor antibodies,JAK inhibitors,and STAT inhibitors.And novel agents also continue to be developed and tested in preclinical and clinical studies.The effectiveness and safety of each kind of drug also warrant further scientific trials before put into being clinical applications.Here,we review the current understanding of the fundamental composition and function of the JAK-STAT signaling pathway.We also discuss advancements in the understanding of JAK-STAT–related pathogenic mechanisms;targeted JAK-STAT therapies for various diseases,especially immune disorders,and cancers;newly developed JAK inhibitors;and current challenges and directions in the field.

关键词： drugs metabolism approval