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

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

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Interleukins in liver disease treatment

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World Journal of Hepatology 2024年第2期16卷 140-145页

作者： Ming Yang Chun-Ye Zhang Department of Surgery University of MissouriColumbiaMO 65212United States Bond Life Sciences Center University of MissouriColumbiaMO 65212United States

Cytokines play pleiotropic roles in human health and disease by regulating both innate and adaptive immune responses.Interleukins(ILs),a large group of cytokines,can be divided into seven families,including IL-1,IL-2,IL-6,IL-8,IL-10,IL-12,and IL-17 families.Here,we review the functions of ILs in the pathogenesis and resolution of liver diseases,such as liver inflammation(e.g.,IL-35),alcoholrelated liver disease(e.g.,IL-11),non-alcoholic steatohepatitis(e.g.,IL-22),liver fibrosis(e.g.,Il-17a),and liver cancer(e.g.,IL-8).Overall,IL-1 family members are implicated in liver inflammation induced by different etiologies,such as alcohol consumption,high-fat diet,and hepatitis viruses.IL-2 family members mainly regulate T lymphocyte and NK cell proliferation and activation,and the differentiation of T cells.IL-6 family cytokines play important roles in acute phase response in liver infection,liver regeneration,and metabolic regulation,as well as lymphocyte activation.IL-8,also known as CXCL8,is activated in chronic liver diseases,which is associated with the accumulation of neutrophils and macrophages.IL-10 family members contribute key roles to liver immune tolerance and immunosuppression in liver disease.IL-12 family cytokines influence T-cell differentiation and play an essential role in autoimmune liver disease.IL-17 subfamilies contribute to infection defense,liver inflammation,and Th17 cell differentiation.ILs interact with different type I and type II cytokine receptors to regulate intracellular signaling pathways that mediate their functions.However,most clinical studies are only performed to evaluate IL-mediated therapies on alcohol and hepatitis virus infection-induced hepatitis.More pre-clinical and clinical studies are required to evaluate IL-mediated monotherapy and synergistic therapies.

关键词： Interleukins Family members liver disease Treatment Clinical trials

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Ferritinophagy: A new idea for liver diseases regulated by ferroptosis

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Hepatobiliary & Pancreatic diseases International 2024年第2期23卷 160-170页

作者： Zi-Bing Qian Jun-Feng Li Wan-Yuan Xiong Xiao-Rong Mao The First Clinical Medical College of Lanzhou University Lanzhou 730000China Institute of Infectious diseases The First Hospital of Lanzhou UniversityLanzhou 730000China Department of Infectious disease The First Hospital of Lanzhou UniversityLanzhou 730000China

Background:The discovery of regulatory cell death has led to a breakthrough in the therapeutic field.Various forms of cell death,such as necrosis,apoptosis,pyroptosis,autophagy,and ferroptosis,play an important role in the development of liver diseases.In general,more than one form of cell death pathways is responsible for the disease state.Therefore,it is particularly important to study the regulation and interaction of various cell death forms in liver diseases.Data sources:We performed a PubMed search up to November 2022 with the following keywords:ferritinophagy,ferroptosis,and liver disease.We also used terms such as signal path,inducer,and inhibitor to supplement the query results.Results:This review summarized the basic characteristics of ferritinophagy and ferroptosis and the regulation of ferroptosis by ferritinophagy and reviewed the key targets and treatment strategies of ferroptosis in different liver diseases.Conclusions:Ferritinophagy is a potential therapeutic target in ferroptosis-related liver diseases.

关键词： Ferritinophagy Ferroptosis liver disease

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Iron as a therapeutic target in chronic liver disease

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World Journal of Gastroenterology 2023年第4期29卷 616-655页

作者： Elias Kouroumalis Ioannis Tsomidis Argyro Voumvouraki liver Research Laboratory University of Crete Medical SchoolHeraklion 71003Greece First Department of Internal Medicine AHEPA University HospitalThessaloniki 54621Greece

It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease.The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver.In this review,we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin,transferrin,and ferritin in iron homeostasis.The regulation of ferroptosis by endogenous and exogenous modulators will be examined.Furthermore,the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease,chronic hepatitis B and C,liver fibrosis,and hepatocellular carcinoma(HCC)will be analyzed.Finally,experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented.Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC,where induction of ferroptosis is the desired effect.Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.

关键词： Iron overload liver disease Ferroptosis Ferritinophagy Ferroptosis modulators

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High-throughput site-specific N-glycoproteomics reveals glyco-signatures for liver disease diagnosis

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National Science Review 2023年第1期10卷 214-225页

作者： Zhenyu Sun Bin Fu Guoli Wang Lei Zhang Ruofan Xu Ying Zhang Haojie Lu Shanghai Cancer Center and Institutes of Biomedical Sciences Fudan University Department of Chemistry and NHC Key Laboratory of Glycoconjugates Research Fudan University Eleanor Roosevelt College University of California San Diego

The glycoproteome has emerged as a prominent target for screening biomarkers,as altered glycosylation is a hallmark of cancer cells.In this work,we incorporated tandem mass tag labeling into quantitative glycoproteomics by developing a chemical labeling-assisted complementary dissociation method for the multiplexed analysis of intact N-glycopeptides.Benefiting from the complementary nature of two different mass spectrometry dissociation methods for identification and multiplex labeling for quantification of intact N-glycopeptides,we conducted the most comprehensive site-specific and subclass-specific N-glycosylation profiling of human serum immunoglobulin G(IgG) to date.By analysing the serum of 90 human patients with varying severities of liver diseases,as well as healthy controls,we identified that the combination of IgG1-H3N5F1 and IgG4-H4N3 can be used for distinguishing between different stages of liver diseases.Finally,we used targeted parallel reaction monitoring to successfully validate the expression changes of glycosylation in liver diseases in a different sample cohort that included 45 serum samples.

关键词： glycoproteomics high-throughput quantification N-glycopeptides liver disease

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Gastrointestinal and liver disease in patients with schizophrenia:A narrative review

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World Journal of Gastroenterology 2022年第38期28卷 5515-5529页

作者： Rebecca K Grant William M Brindle Mhairi C Donnelly Pauline M McConville Thomas G Stroud Lorenzo Bandieri John N Plevris The Centre for liver and Digestive Disorders Royal Infirmary of EdinburghEdinburghEH164SAUnited Kingdom General Adult Psychiatry Royal Edinburgh HospitalEdinburghEH105HFUnited Kingdom

Schizophrenia is a severe mental illness which can have a devastating impact onan individual’s quality of life. Comorbidities are high amongst patients and lifeexpectancy is approximately 15 years less than the general population. Despite thewell-known increased mortality, little is known about the impact of gastrointestinaland liver disease on patients with schizophrenia. We aimed to reviewthe literature and to make recommendations regarding future care. Literaturesearches were performed on PubMed to identify studies related to gastrointestinaland liver disease in patients with schizophrenia. High rates of chronic liverdisease were reported, with Non-Alcoholic Fatty liver disease being of particularconcern;antipsychotics and metabolic syndrome were contributing factors. Ratesof acute liver failure were low but have been associated with antipsychotic useand paracetamol overdose. Coeliac disease has historically been linked to schizophrenia;however, recent research suggests that a causal link is yet to be proven.Evidence is emerging regarding the relationships between schizophrenia andpeptic ulcer disease, inflammatory bowel disease and irritable bowel syndrome;clinical vigilance regarding these conditions should be high. Patients with schizophreniapoorly engage with bowel cancer screening programmes, leading to latediagnosis and increased mortality. Clozapine induced constipation is a significantissue for many patients and requires close monitoring. There is a significantburden of gastrointestinal and liver disease amongst patients with schizophrenia.Better levels of support from all members of the medical team are essential toensure that appropriate, timely care is provided.

关键词： Schizophrenia Gastrointestinal disease liver disease Mental health

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COVID-19 vaccination and liver disease

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World Journal of Gastroenterology 2022年第48期28卷 6791-6810页

作者： Sotaro Ozaka Takashi Kobayashi Kazuhiro Mizukami Kazunari Murakami Department of Gastroenterology Faculty of MedicineOita UniversityYufu 879-5593OitaJapan Department of Infectious disease Control Faculty of MedicineOita UniversityYufu 879-5593OitaJapan

Various vaccines against severe acute respiratory syndrome coronavirus 2 have been developed in response to the coronavirus disease 2019(COVID-19)global pandemic,several of which are highly effective in preventing COVID-19 in the general population.Patients with chronic liver diseases(CLDs),particularly those with liver cirrhosis,are considered to be at a high risk for severe COVID-19 and death.Given the increased rates of disease severity and mortality in patients with liver disease,there is an urgent need to understand the efficacy of vaccination in this population.However,the data regarding efficacy and safety of COVID-19 vaccination in patients with CLDs is limited.Indeed,several organ-specific or systemic immune-mediated side effects following COVID-19 vaccination,including liver injury similar to autoimmune hepatitis,have been recently reported.Although the number of cases of vaccine-related liver injury is increasing,its frequency,clinical course,and mechanism remain unclear.Here,we review the current findings on COVID-19 vaccination and liver disease,focusing on:(1)The impact of COVID-19 in patients with CLD;(2)The efficacy,safety,and risk-benefit profiles of COVID-19 vaccines in patients with CLD;and(3)liver injury following COVID-19 vaccination.

关键词： COVID-19 vaccine liver disease Side effect liver injury Immune-related hepatitis Autoimmune hepatitis

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Prevention,diagnostic evaluation,management and prognostic implications of liver disease in critically ill patients with COVID-19

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World Journal of Clinical Cases 2023年第3期11卷 514-527页

作者： Asimina Valsamaki Maria Xanthoudaki Katerina G Oikonomou Panagiotis J Vlachostergios AntoniosPapadogoulas Periklis Katsiafylloudis Ioanna Voulgaridi Apostolia-Lemonia Skoura Apostolos Komnos Panagiotis Papamichalis Intensive Care Unit General Hospital of LarissaLarissa 41221Greece Division of Hematology and Medical Oncology Department of MedicineWeill Cornell MedicineNew YorkNY 10065United States Department of Microbiology General Hospital of LarissaLarissa 41221Greece Transfusion Medicine Department University Hospital of LarissaLarissa 41110Greece

Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2,broke out in December 2019 in Wuhan city of China and spread rapidly worldwide.Therefore,by March 2020,the World Health Organization declared the disease a global pandemic.Apart from the respiratory system,various other organs of the human body are also seriously affected by the virus.liver injury in patients with a severe form of COVID-19 is estimated to be 14.8%-53.0%.Elevated levels of total bilirubin,aspartate aminotransferase and alanine aminotransferase and low levels of serum albumin and prealbumin are the main laboratory findings.Patients with pre-existing chronic liver disease and cirrhosis are much more prone to develop severe liver injury.This literature review presented the recent scientific findings regarding the pathophysiological mechanisms responsible for liver injury in critically ill patients with COVID-19,the various interactions between drugs used to treat the disease and the function of the liver and the specific tests providing the possibility of early diagnosis of severe liver injury in these patients.Moreover,it highlighted the burden that COVID-19 put on health systems worldwide and its effect on transplant programs and the care provided to critically ill patients in general and particularly to those with chronic liver disease.

关键词： Coronavirus disease 2019 Severe acute respiratory syndrome coronavirus 2 liver disease Intensive care unit liver unit Prealbumin

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Outcomes of COVID-19 among patients with liver disease

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World Journal of Gastroenterology 2023年第5期29卷 815-824页

作者： Isidora Vujčić Institute of Epidemiology Faculty of MedicineUniversity of BelgradeBelgrade 11000BelgradeSerbia

Coronavirus disease 2019(COVID-19)is primarily a respiratory disease with multi-organ involvement,including impaired liver function.It has been noticed that a significant proportion of COVID-19 patients have liver dysfunction,especially those with a more severe disease course.The coronavirus causes direct damage to the liver using the angiotensin-converting enzyme 2,a cell-surface receptor for cellular entry,that is expressed in the liver.According to previous research,liver enzyme abnormalities were observed in a considerable proportion of COVID-19 patients,and elevated liver transaminases were found in about 20%of these patients,alkaline phosphatase in 6.1%,and gamma-glutamyl transferase in 21.1%.COVID-19 might trigger a deterioration of liver function in patients with pre-existing chronic liver diseases(CLDs)and also in those without previous liver disorders.The majority of COVID-19 patients who develop liver injury are men,the elderly,and those with a higher body mass index.Compared to the general population,COVID-19 is associated with significant morbidity and mortality in patients with liver disease(cirrhosis and liver transplantation recipients).However,some studies indicate that CLDs have a lesser role in determining patient progression towards higher disease severity.

关键词： liver disease COVID-19 Mortality Prognosis liver function

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Microbiome-liver crosstalk:A multihit therapeutic target for liver disease

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World Journal of Gastroenterology 2023年第11期29卷 1651-1668页

作者： Jorum Kirundi Sheida Moghadamrad Camilla Urbaniak Department of Biomedical Research University of BernBern 3014Switzerland Department of Gastroenterology/Hepatology Laboratories for Translational ResearchEnte Ospedaliero CantonaleBellinzona and Faculty of Biomedical SciencesUniversitàdella Svizzera italianaLugano 6900Switzerland Biotechnology and Planetary Protection Group NASA Jet Propulsion LaboratoryPasadenaCA 91011United States ZIN Technologies Middleburg HeightsOH 44130United States

liver disease has become a leading cause of death,particularly in the West,where it is attributed to more than two million deaths annually.The correlation between gut microbiota and liver disease is still not fully understood.However,it is well known that gut dysbiosis accompanied by a leaky gut causes an increase in lipopolysaccharides in circulation,which in turn evoke massive hepatic inflammation promoting liver cirrhosis.Microbial dysbiosis also leads to poor bile acid metabolism and low short-chain fatty acids,all of which exacerbate the inflammatory response of liver cells.Gut microbial homeostasis is maintained through intricate processes that ensure that commensal microbes adapt to the low oxygen potential of the gut and that they rapidly occupy all the intestinal niches,thus outcompeting any potential pathogens for available nutrients.The crosstalk between the gut microbiota and its metabolites also guarantee an intact gut barrier.These processes that protect against destabilization of gut microbes by potential entry of pathogenic bacteria are collectively called colonization resistance and are equally essential for liver health.In this review,we shall investigate how the mechanisms of colonization resistance influence the liver in health and disease and the microbial-liver crosstalk potential as therapeutic target areas.

关键词： Microbiome Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis liver disease Microbiome-host crosstalk Gut homeostasis Microbial metabolites

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