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Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury

World Journal of Gastroenterology 2004年第12期10卷 1699-1708页

作者： neil kaplowitz Gastroenterology/Liver Division Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA

Deficiencies in vitamins or other factors(B6,B12,folic acid, betaine)and genetic disorders for the metabolism of the non-protein amino acid-homocysteine(Hcy)lead to hyperhomocysteinemia(HHcy).HHcy is an integral component of several disorders including cardiovascular disease,neurodegeneration,diabetes and alcoholic liver *** unleashes mediators of inflammation such as NFκB,IL-1β,IL-6,and IL-8,increases production of intracellular superoxide anion causing oxidative stress and reducing intracellular level of nitric oxide(NO),and induces endoplasrnic reticulum(ER)stress which can explain many processes of Hcy-promoted cell injury such as apoptosis, fat accumulation,and *** models have played an important role in determining the biological effects of *** stress may also be involved in other liver diseases such as α_1-antitrypsin(α_1-AT)deficiency and hepatitis C and/or B virus *** research should evaluate the possible potentiative effects of alcohol and hepatic virus infection on ER stress-induced liver injury,study potentially beneficial effects of lowering Hcy and preventing ER stress in alcoholic humans,and examine polymorphisrn of Hcy metabolizing enzymes as potential risk-factors for the development of HHcy and liver disease.

关键词： Animals Endoplasmic Reticulum Humans Hyperhomocysteinemia Liver Diseases, Alcoholic Oxidative Stress

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Herb-Induced Liver Injury: A Global Concern

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Chinese Journal of Integrative Medicine 2018年第9期24卷 643-644页

作者： neil kaplowitz USC Research Center for Liver Disease USC Keck School of Medicine

Chinese medicine and herb medicine though used to treat liver diseases are an important cause of liver injury. Many phytochemicals have the potential to injure the liver, some in a dose-related fashion and more often in an idiosyncratic fashion, meaning occurrence is uncommon to rare in the population using these treatments. As is the case with pharmaceuticals, the phytochemicals are usually tolerated despite either no or mild transient subclinical injury but rarely in some susceptible patients cause moderate to severe liver injury which is likely mediated by the adaptive immune system.

关键词： herb-induced liver injury diagnosis and management guideline Chinese medicine

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Current concepts and controversies in the treatment of alcoholic hepatitis

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World Journal of Gastroenterology 2006年第43期12卷 6909-6921页

作者： Catherine Rongey neil kaplowitz Robert Wood Johnson Clinical Scholars Program University of California at Los Angeles 911 Broxton Avenue Los Angeles CA 90024 United States Department of Gastroenterology and Hepatology University of Southern California 2011 Zonal Avenue Los Angeles CA 90033 United States

The treatment of alcoholic hepatitis remains one of the most debated topics in medicine and a field of continued research. In this review, we discuss the evolution of scoring systems, including the recent development of the Glasgow alcoholic hepatitis score, role of liver biopsy and current treatment interventions. Studies of treatment interventions with glucocorticoids, pentoxifylline, infliximab, s-adenosyl-methionine, and colchicine are reviewed with discussion on quality. Glucocorticoids currently remain the mainstay of treatment for severe alcoholic hepatitis.

关键词： Alcoholic hepatitis Treatment Glucocorticoid Biopsy Scoring system

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The gut microbial metabolite, 3,4-dihydroxyphenylpropionic acid, alleviates hepatic ischemia/reperfusion injury via mitigation of macrophage pro-inflammatory activity in mice

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Acta Pharmaceutica Sinica B 2022年第1期12卷 182-196页

作者： Rui Li Li Xie Lei Li Xiaojiao Chen Tong Yao Yuanxin Tian Qingping Li Kai Wang Chenyang Huang Cui Li Yifan Li Hongwei Zhou neil kaplowitz Yong Jiang Peng Chen Department of Pathophysiology Guangdong Provincial Key Laboratory of ProteomicsSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical ScienceSouthern Medical UniversityGuangzhou 510515China Division of Hepatobiliopancreatic Surgery Department of General SurgeryNanfang HospitalSouthern Medical UniversityGuangzhou 510515China USC Research Center for Liver Disease Department of MedicineKeck School of Medicine of USCLos AngelesCA 90089USA Microbiome Medicine Center Zhujiang HospitalSouthern Medical UniversityGuangzhou 510280China

Hepatic ischemia/reperfusion injury(HIRI) is a serious complication that occurs following shock and/or liver surgery. Gut microbiota and their metabolites are key upstream modulators of development of liver injury. Herein, we investigated the potential contribution of gut microbes to ***/reperfusion surgery was performed to establish a murine model of HIRI. 16 S r RNA gene sequencing and metabolomics were used for microbial analysis. Transcriptomics and proteomics analysis were employed to study the host cell responses. Our results establish HIRI was significantly increased when surgery occurred in the evening(ZT12, 20:00) when compared with the morning(ZT0, 08:00);however, antibiotic pretreatment reduced this diurnal variation. The abundance of a microbial metabolite3,4-dihydroxyphenylpropionic acid was significantly higher in ZT0 when compared with ZT12 in the gut and this compound significantly protected mice against HIRI. Furthermore, 3,4-dihydroxyphenylpropionic acid suppressed the macrophage pro-inflammatory response in vivo and in vitro. This metabolite inhibits histone deacetylase activity by reducing its phosphorylation. Histone deacetylase inhibition suppressed macrophage pro-inflammatory activation and diminished the diurnal variation of HIRI. Our findings revealed a novel protective microbial metabolite against HIRI in mice. The potential underlying mechanism was at least in part, via 3,4-dihydroxyphenylpropionic acid-dependent immune regulation and histone deacetylase(HDAC) inhibition in macrophages.

关键词： Hepatic ischemia/reperfusion injury Diurnal variation 3,4-Dihydroxy phenylpropionic acid Gut microbiota

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