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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

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

Challenges in pediatric inherited/metabolic Liver disease: Focus on the disease spectrum, diagnosis and management of relatively common disorders

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World Journal of Gastroenterology 2023年第14期29卷 2114-2126页

作者： Yi-Gui Zou Huan Wang Wen-Wen Li Dong-Ling Dai Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System diseases and Endoscopy Center Shenzhen Children's HospitalShenzhen 518026Guangdong ProvinceChina

The clinical scenario of pediatric Liver disease is becoming more intricate due to changes in the disease spectrum,in which an increasing number of inherited/metabolic Liver diseases are reported,while infectious diseases show a decreasing trend.The similar clinical manifestations caused by inherited/metabolic diseases might be under-recognized or misdiagnosed due to nonspecific characteristics.A delayed visit to a doctor due to a lack of symptoms or mild symptoms at an early stage will result in late diagnosis and treatment.Moreover,limited diagnostic approaches,especially liver biopsy,are not easily accepted by pediatric patients,leading to challenges in etiological diagnosis.liver dysfunction due to inherited/metabolic diseases is often caused by a variety of metabolites,so precision treatment is difficult;symptomatic treatment is a compelling option for inherited disorders.

关键词： Hepatitis Genetic Liver disease Cholestasis Challenge Pediatric

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

Beneficial effects of coffee in non-alcoholic fatty Liver disease:a narrative review

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Hepatoma Research 2020年第10期6卷 36-44页

作者： Alessio Calabrò Anna Caterina Procopio Francesco Primerano Tiziana Larussa Francesco Luzza Laura Di Renzo Antonino De Lorenzo Paola Gualtieri Ludovico Abenavoli Indipendent Nutritionist Viale dei Bizantini 25Catanzaro 88100Italy Department of Health Sciences University“Magna Graecia”of CatanzaroViale EuropaCatanzaro 88100Italy Indipendent Biomedical Engineer Viale degli Aurunci 988060 MontepaoneCatanzaro 88100Italy Department of Biomedicine and Prevention University of Rome“Tor Vergata”Rome 00133Italy

Non-alcoholic fatty Liver disease(NAFLD)is one of the most common Liver diseases and is related to unhealthy lifestyle habits,characterized by a diet rich in sugars and fats leading to excessive calorie intake,and lack of exercise.In recent years,there is a growing incidence of this pathology,raising the attention of hepatologists,endocrinologists,diabetologists,and nutritionists.In this context,the alimentary regimen adopted by patients with NAFLD has become an increasingly scrutinised parameter.Diet is now considered a crucial factor in the treatment of NAFLD since it has been observed that some functional foods play a beneficial role.These include coffeewhose health effects have already been amply demonstrated.Here we describe the beneficial effects of coffee consumption reported in the NAFLD literature.

关键词： Caffeine steatosis functional food Liver disease antioxidant chlorogenic-acid

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

Dysregulation of glutathione synthesis in Liver disease

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liver Research 2020年第2期4卷 64-73页

作者： Shelly C.Lu Division of Digestive and Liver diseases Cedars-Sinai Medical CenterLos AngelesCAUSA

Glutathione(GSH),a tripeptide that is present in all mammalian tissues,is especially highly concentrated in the liver.GSH synthesis occurs via two adenosine triphosphate(ATP)-requiring enzymatic steps:the first is rate-limiting,catalyzed by glutamate-cysteine ligase,generates g-glutamylcysteine from gluta-mate and cysteine;the second is catalyzed by GSH synthetase,generates GSH from g-glutamylcysteine and glycine.GSH defends against oxidative stress,participates in detoxification of xenobiotics,de-termines the redox status of the cell,and regulates vital processes such as growth and apoptosis.Hepatic GSH plays a central role in the interorgan GSH homeostasis because sinusoidal efflux of hepatic GSH determines plasma GSH level.In Liver diseases GSH homeostasis is perturbed by multiple mechanisms.Hepatic GSH biosynthesis is impaired in cholestatic liver injury,endotoxemia,and fibrotic injury largely because the expression of the GSH synthetic enzymes falls.Lower hepatic GSH level further exacerbates and perpetuates ongoing liver injury.However,in hepatocellular carcinoma GSH synthetic enzymes are upregulated and this may play a role in chemoresistance.This review focuses on the current under-standing of hepatic GSH synthesis in health and disease.

关键词： Glutathione(GSH) Glutamate-cysteine ligase(GCL) Glutathione synthetase(GS) Nuclear factor-erythroid 2 related factor 2 (NRF2) MAF BZIP transcription factor G(MAFG) c-MAF Antioxidant-response element Liver disease

Advances in traditional Chinese medicine for Liver disease therapy in 2021

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Traditional Medicine Research 2022年第6期7卷 100-117页

作者： Jun-Yu Luo Jia-Bao Liao Yu-Ming Wang Jie Zhao Xue-Hua Xie Fei Qu Xi-Xing Fang Wei-Bo Wen Shu-Quan Lyu Yunnan University of Traditional Chinese Medicine Kunming 650500China Jiaxing Hospital of Traditional Chinese Medicine Jiaxing 314033China Tianjin University of Traditional Chinese Medicine Tianjin 300000China Changchun University of Traditional Chinese Medicine Changchun 130117China Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine in Hebei Province Cangzhou 061001China

Liver diseases and their co-morbidities represent a major public health problem.Owing to its progressive pathogenesis and lack of effective treatment,Liver disease has become one of the most important causes of death worldwide.Traditional Chinese medicine(TCM)has potential advantages in the prevention and treatment of Liver diseases,including high safety,remarkable curative effects,and low toxicity and side effects.In 2021,TCM extracts and their derivatives,TCM compounds,and ethnic medicines showed good efficacy in the treatment of Liver diseases.The main mechanisms and representative drugs of TCM can be summarized by the use of amygdalin,dicoumarol,quercetin,and ancient ephedrine decoction to treat hepatitis by inhibiting viral replication,as well as the use of Gentianae Radix,lupeol,Zornia diphylla(L.)Pers.,and Chinese patent medicine Liuwei Wuling tablet to alleviate acute liver injury by improving oxidative stress and inflammatory responses in the body.In the treatment of alcoholic Liver disease and metabolic-associated fatty Liver disease,the mechanism of TCM is the inhibition of oxidative stress,improving metabolism,regulating intestinal microflora,and enhancing intestinal barrier function.The representative TCM for alcoholic Liver disease includes astragaloside,puerarin,patchouli alcohol,and Mori Fructus polysaccharide,while those for metabolic-associated fatty Liver disease include saikosaponin,dehydroabietic acid,hesperetin,berberine,and Panax Notoginseng saponins.Additionally,germacrone,forsythin,geniposide,and protocatechuic acid can inhibit the activation or migration of stellate cells and improve liver fibrosis.Toosendanin,paeoniflorin,chrysin,and the classical prescription Huanglian decoction can significantly inhibit the proliferation of liver cancer cells and promote their apoptosis for the treatment of hepatocellular carcinoma.The activation of the farnesol X receptor pathway can improve bile metabolism in the liver,thus,significantly alleviating cholestatic Liver disease.Its representative drugs

关键词： Liver disease traditional Chinese medicine extracts therapeutic mechanism intestinal barrier intestinal flora

Metabolic-associated fatty Liver disease:New nomenclature and approach with hot debate

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World Journal of Hepatology 2023年第2期15卷 123-128页

作者： Yasser Fouad Department of Gastroenterology and Endemic Medicine Minia UniversityMinia 19111Egypt

An international panel recently proposed an update to the terminology and diagnostic criteria for fatty Liver disease.The experts proposed a change in the nomenclature from non-alcoholic fatty Liver disease(NAFLD)to metabolic(dysfunction)-associated fatty Liver disease(MAFLD).This single-letter change,we believe,heralds the dawn of a new era in clinical practice and in clinical and basic research as well.The new nomenclature with the easily applicable approach has stimulated the enthusiasm of the researchers worldwide,resulting in a large number of publications over the past two years.Several recent studies have provided tremendous evidence of the superiority of the MAFLD criteria over the NAFLD criteria.Many studies in different geographic areas of the world including the United States,Europe,and Asia on a large number of patients proved that the utility of MAFLD criteria was higher than that of the NAFLD criteria in different aspects of fatty Liver diseases.Consequently,many societies,physician and nurse groups,health stakeholders,representatives of regulatory sciences,and others endorsed the new nomenclature.Here we highlight the endorsement of the new name by different societies and groups and the outcome of different studies on the new nomenclature in addition to a short discussion of the debate by some experts.

关键词： Non-alcoholic fatty Liver disease Metabolic-associated fatty Liver disease Liver disease Fibrosis New nomenclature Redefinition