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Zhang H, Dong X, Zhu L, Tang FS. Elafibranor: A promising treatment for alcoholic liver disease, metabolic-associated fatty liver disease, and cholestatic liver disease. World J Gastroenterol 2024; 30:4393-4398. [PMID: 39494094 PMCID: PMC11525860 DOI: 10.3748/wjg.v30.i40.4393] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/15/2024] [Accepted: 09/23/2024] [Indexed: 10/16/2024] Open
Abstract
Liver diseases pose a significant threat to human health. Although effective therapeutic agents exist for some liver diseases, there remains a critical need for advancements in research to address the gaps in treatment options and improve patient outcomes. This article reviews the assessment of Elafibranor's effects on liver fibrosis and intestinal barrier function in a mouse model of alcoholic liver disease (ALD), as reported by Koizumi et al in the World Journal of Gastroenterology. We summarize the impact and mechanisms of Elafibranor on ALD, metabolic-associated fatty liver disease, and cholestatic liver disease based on current research. We also explore its potential as a dual agonist of PPARα/δ, which is undergoing Phase III clinical trials for metabolic-associated steatohepatitis. Our goal is to stimulate further investigation into Elafibranor's use for preventing and treating these liver diseases and to provide insights for its clinical application.
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Affiliation(s)
- Hang Zhang
- Department of Clinical Pharmacy, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Clinical Pharmacy in Zunyi City, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
| | - Xuan Dong
- Department of Clinical Pharmacy, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Clinical Pharmacy in Zunyi City, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
| | - Lei Zhu
- Department of Clinical Pharmacy, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Clinical Pharmacy in Zunyi City, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
| | - Fu-Shan Tang
- Department of Clinical Pharmacy, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Clinical Pharmacy in Zunyi City, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
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Elblová P, Lunova M, Dejneka A, Jirsa M, Lunov O. Impact of mechanical cues on key cell functions and cell-nanoparticle interactions. DISCOVER NANO 2024; 19:106. [PMID: 38907808 PMCID: PMC11193707 DOI: 10.1186/s11671-024-04052-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 06/14/2024] [Indexed: 06/24/2024]
Abstract
In recent years, it has been recognized that mechanical forces play an important regulative role in living organisms and possess a direct impact on crucial cell functions, ranging from cell growth to maintenance of tissue homeostasis. Advancements in mechanobiology have revealed the profound impact of mechanical signals on diverse cellular responses that are cell type specific. Notably, numerous studies have elucidated the pivotal role of different mechanical cues as regulatory factors influencing various cellular processes, including cell spreading, locomotion, differentiation, and proliferation. Given these insights, it is unsurprising that the responses of cells regulated by physical forces are intricately linked to the modulation of nanoparticle uptake kinetics and processing. This complex interplay underscores the significance of understanding the mechanical microenvironment in shaping cellular behaviors and, consequently, influencing how cells interact with and process nanoparticles. Nevertheless, our knowledge on how localized physical forces affect the internalization and processing of nanoparticles by cells remains rather limited. A significant gap exists in the literature concerning a systematic analysis of how mechanical cues might bias the interactions between nanoparticles and cells. Hence, our aim in this review is to provide a comprehensive and critical analysis of the existing knowledge regarding the influence of mechanical cues on the complicated dynamics of cell-nanoparticle interactions. By addressing this gap, we would like to contribute to a detailed understanding of the role that mechanical forces play in shaping the complex interplay between cells and nanoparticles.
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Affiliation(s)
- Petra Elblová
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences, 18200, Prague, Czech Republic
- Faculty of Mathematics and Physics, Charles University, Ke Karlovu 3, 121 16, Prague 2, Czech Republic
| | - Mariia Lunova
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences, 18200, Prague, Czech Republic
- Institute for Clinical & Experimental Medicine (IKEM), 14021, Prague, Czech Republic
| | - Alexandr Dejneka
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences, 18200, Prague, Czech Republic
| | - Milan Jirsa
- Institute for Clinical & Experimental Medicine (IKEM), 14021, Prague, Czech Republic
| | - Oleg Lunov
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences, 18200, Prague, Czech Republic.
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Zhang C, Xi Y, Zhang Y, He P, Su X, Fan F, Wu M, Kong X, Shi Y. Genetic association analysis of dietary intake and idiopathic pulmonary fibrosis: a two-sample mendelian randomization study. BMC Pulm Med 2024; 24:15. [PMID: 38178024 PMCID: PMC10768076 DOI: 10.1186/s12890-023-02831-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 12/27/2023] [Indexed: 01/06/2024] Open
Abstract
BACKGROUND IPF is a complex lung disease whose aetiology is not fully understood, but diet may have an impact on its development and progression. Therefore, we investigated the potential causal connection between dietary intake and IPF through TSMR to offer insights for early disease prevention recommendations. METHODS The study incorporated 29 dietary exposure factors, oily fish intake, bacon intake, processed meat intake, poultry intake, beef intake, pork intake, lamb/mutton intake, non-oily fish intake, fresh fruit intake, cooked vegetable intake, baked bean intake, fresh tomato intake, tinned tomato intake, salad/raw vegetable intake, Fresh fruit intake, coffee intake, tea intake, water intake, red wine intake, average weekly beer plus cider intake, alcoholic drinks per week, cereal intake, bread intake, whole-wheat intake, whole-wheat cereal intake, cheese intake, yogurt intake, salt added to food and whole egg intake. The study explored the causal link between diet and IPF using TSMR analysis, predominantly the IVW method, and performed sensitivity analyses to validate the results. RESULT The study revealed that consuming oily fish, yogurt, and dried fruits had a protective effect against IPF, whereas the consumption of alcoholic beverages and beef was linked to an increased risk of IPF. CONCLUSION In this MR study, it was discovered that the consumption of oily fish, yogurt, and dried fruits exhibited a protective effect against IPF, whereas the intake of alcoholic beverages and beef was associated with an elevated risk of IPF. These findings underscore the significance of making informed and timely dietary decisions in IPF prevention.
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Affiliation(s)
- Chenwei Zhang
- Department of Respiratory and Critical Care Medicine, Shanxi Medical University Affiliated First Hospital, Taiyuan, 030000, China
| | - Yujia Xi
- Department of Urology, The Second Hospital of Shanxi Medical University, Taiyuan, 030000, China
| | - Yukai Zhang
- First School of Clinical Medicine, Shanxi Medical University, Taiyuan, 030000, China
| | - Peiyun He
- First School of Clinical Medicine, Shanxi Medical University, Taiyuan, 030000, China
| | - Xuesen Su
- First School of Clinical Medicine, Shanxi Medical University, Taiyuan, 030000, China
| | - Fangfang Fan
- Department of Respiratory and Critical Care Medicine, Shanxi Medical University Affiliated First Hospital, Taiyuan, 030000, China
| | - Min Wu
- Department of Respiratory and Critical Care Medicine, Shanxi Medical University Affiliated First Hospital, Taiyuan, 030000, China
| | - Xiaomei Kong
- Department of Respiratory and Critical Care Medicine, Shanxi Medical University Affiliated First Hospital, Taiyuan, 030000, China.
- NHC Key Laboratory of Pneumoconiosis, Taiyuan, 030000, China.
| | - Yiwei Shi
- Department of Respiratory and Critical Care Medicine, Shanxi Medical University Affiliated First Hospital, Taiyuan, 030000, China.
- NHC Key Laboratory of Pneumoconiosis, Taiyuan, 030000, China.
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Daucosterol Alleviates Alcohol-Induced Hepatic Injury and Inflammation through P38/NF-κB/NLRP3 Inflammasome Pathway. Nutrients 2023; 15:nu15010223. [PMID: 36615880 PMCID: PMC9823995 DOI: 10.3390/nu15010223] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/23/2022] [Accepted: 12/28/2022] [Indexed: 01/04/2023] Open
Abstract
Alcoholic liver disease (ALD) is caused by chronic excessive alcohol consumption, which leads to inflammation, oxidative stress, lipid accumulation, liver fibrosis/cirrhosis, and even liver cancer. However, there are currently no effective drugs for ALD. Herein, we report that a natural phytosterol Daucosterol (DAU) can effectively protect against liver injury caused by alcohol, which plays anti-inflammatory and antioxidative roles in many chronic inflammatory diseases. Our results demonstrate that DAU ameliorates liver inflammation induced by alcohol through p38/nuclear factor kappa B (NF-κB)/NOD-like receptor protein-3 (NLRP3) inflammasome pathway. Briefly, DAU decreases NF-κB nuclear translocation and inhibits NLRP3 activation by decreasing p38 phosphorylation. At the same time, DAU also protects against hepatic oxidative stress and lipid accumulation. In conclusion, our research provides a new clue about the protective effects of naturally active substances on ALD.
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The Effect of Alcohol Consumption in Unresectable Hepatocellular Carcinoma with Transarterial Chemoembolization. JOURNAL OF ONCOLOGY 2022; 2022:7062105. [PMID: 36618073 PMCID: PMC9822749 DOI: 10.1155/2022/7062105] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/28/2022] [Accepted: 12/12/2022] [Indexed: 01/01/2023]
Abstract
Background Alcohol consumption can increase the risk of developing hepatocellular carcinoma (HCC). However, whether continuous alcohol consumption can influence outcomes in patients with HCC who undergo transarterial chemoembolization (TACE) remains unclear. This study aimed to explore the effect of alcohol consumption in patients with unresectable HCC who underwent TACE. Methods The data used in the study were obtained from two centers and were retrospectively reviewed between January, 2014, and December, 2021. 254 patients with TACE were included in this study. Among them, 101 patients were continuous alcohol consumers and 153 patients had alcohol abstinence. Propensity score matching (PSM) and competing risk analysis were used to reduce the selection bias. Results The median overall survival (mOS) and median progression-free survival (mPFS) in the alcohol consumers' group were longer than those in the alcohol abstinence group, before and after PSM. Multivariate regression analysis showed that alcohol consumption increased all-cause mortality risk (HR: 1.486, 95% CI: 1.074-2.055; P=0.016) and tumor progression risk (HR: 1.434, 95% CI: 1.091-1.886; P=0.01) more than that with alcohol abstinence. In the competing risk analysis, after excluding deaths caused by other reasons, alcohol consumption increased cancer-specific mortality risk more than alcohol abstinence did before and after PSM. Adverse event analysis showed that alcohol consumption increased the risk of all grades of nausea and vomiting and grade III or IV nausea more than alcohol abstinence did after patients underwent TACE. Conclusion Alcohol consumption may lead to a poor prognosis and increase adverse events in patients receiving TACE compared to those with alcohol abstinence.
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Cao ZZ, Bao YY, Chen Z, Sheng LF, Zhou SH, Huang YP, Fan J. Fibroblast-epithelial metabolic coupling in laryngeal cancer. Pathol Res Pract 2022; 240:154177. [DOI: 10.1016/j.prp.2022.154177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/27/2022] [Accepted: 10/14/2022] [Indexed: 11/06/2022]
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Roy N, Nadda N, Kumar H, Prasad C, Kumar Jha J, Pandey HC, Vanamail P, Saraya A, Balhara YPS, Shalimar, Nayak B. Pattern recognition receptor CD14 gene polymorphisms in alcohol use disorder patients and its Influence on liver disease susceptibility. Front Immunol 2022; 13:975027. [PMID: 36238273 PMCID: PMC9551314 DOI: 10.3389/fimmu.2022.975027] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Background Alcohol use disorders (AUDs) leading to liver disease is major concern over other spectrum of disorder. Excessive alcohol consumption resulting in leaky gut syndrome is attributed to alcohol-induced liver injury through portal translocation of bacterial endotoxin. Susceptibility to alcoholic liver disease (ALD) in AUD patients could be dependent upon genes responsible for inflammation and alcohol metabolism. The pattern recognition receptor CD14 gene is a major player in endotoxin-mediated inflammation and susceptibility to ALD. This study investigated the genetic association of CD14 polymorphisms and other mechanisms relevant to altered inflammatory responses leading to ALD. Methods Patients with alcohol use disorder with ALD (n = 128) and without liver disease (ALC, n = 184) and controls without alcohol use disorder (NALC, n = 152) from North India were enrolled. The CD4 gene polymorphisms in the North Indian population were evaluated by RFLP and sequencing. Secretory CD14 (sCD14), LBP, TLR4, MD2, TNFα, IL1b, IFNγ, IL6, IL10, and IL4 levels in serum were measured by ELISA among groups. The influence of polymorphisms on CD14 gene promoter activity and circulatory bacterial DNA level was determined. Results The CD14 gene promoter and exonic region SNPs were found to be monomorphic, except for SNP rs2569190 for the North Indian population. The genetic association of SNP rs2569190(C/T) with the risk of developing ALD was found significant for TT genotype [ORTT, 95% CI = 2.19, 1.16–4.13 for ALD vs. ALC and OR, 2.09, 1.18–3.72 for ALD vs. NALC]. An increased sCD14 level was observed in AUD patients compared to NALC control. Increased levels of LBP, TLR4, TNFα, IL1β, IFNγ, and IL6 and reduced levels of MD2, IL10, and IL4 were observed among the ALD patients compared to the other two control groups. Elevated levels of pro-inflammatory and reduced levels of anti-inflammatory cytokines were observed in the risk genotype TT groups of ALD patients and the ALC group compared to NALC. Promoter activity was observed in the intronic region flanking SNPs and risk genotype can influence reporter activity, indicating CD14 gene expression. Conclusion Enhanced CD14 expression associated with inflammatory responses increases susceptibility to ALD in the TT genotype of AUD patients.
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Hyun JY, Kim SK, Yoon SJ, Lee SB, Jeong JJ, Gupta H, Sharma SP, Oh KK, Won SM, Kwon GH, Cha MG, Kim DJ, Ganesan R, Suk KT. Microbiome-Based Metabolic Therapeutic Approaches in Alcoholic Liver Disease. Int J Mol Sci 2022; 23:8749. [PMID: 35955885 PMCID: PMC9368757 DOI: 10.3390/ijms23158749] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/21/2022] [Accepted: 08/03/2022] [Indexed: 11/21/2022] Open
Abstract
Alcohol consumption is a global healthcare problem. Chronic alcohol consumption generates a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, fibrosis, and cirrhosis. Alcoholic liver diseases (ALD) refer to liver damage and metabolomic changes caused by excessive alcohol intake. ALD present several clinical stages of severity found in liver metabolisms. With increased alcohol consumption, the gut microbiome promotes a leaky gut, metabolic dysfunction, oxidative stress, liver inflammation, and hepatocellular injury. Much attention has focused on ALD, such as alcoholic fatty liver (AFL), alcoholic steatohepatitis (ASH), alcoholic cirrhosis (AC), hepatocellular carcinoma (HCC), a partnership that reflects the metabolomic significance. Here, we report on the global function of inflammation, inhibition, oxidative stress, and reactive oxygen species (ROS) mechanisms in the liver biology framework. In this tutorial review, we hypothetically revisit therapeutic gut microbiota-derived alcoholic oxidative stress, liver inflammation, inflammatory cytokines, and metabolic regulation. We summarize the perspective of microbial therapy of genes, gut microbes, and metabolic role in ALD. The end stage is liver transplantation or death. This review may inspire a summary of the gut microbial genes, critical inflammatory molecules, oxidative stress, and metabolic routes, which will offer future promising therapeutic compounds in ALD.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Raja Ganesan
- Institute for Liver and Digestive Disease, College of Medicine, Hallym University, Chuncheon 24253, Korea
| | - Ki Tae Suk
- Institute for Liver and Digestive Disease, College of Medicine, Hallym University, Chuncheon 24253, Korea
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Abstract
The liver is the major target organ of continued alcohol consumption at risk and resulting alcoholic liver disease (ALD) is the most common liver disease worldwide. The underlying molecular mechanisms are still poorly understood despite decades of scientific effort limiting our abilities to identify those individuals who are at risk to develop the disease, to develop appropriate screening strategies and, in addition, to develop targeted therapeutic approaches. ALD is predestined for the newly evolving translational medicine, as conventional clinical and health care structures seem to be constrained to fully appreciate this disease. This concept paper aims at summarizing the 15 years translational experience at the Center of Alcohol Research in Heidelberg, namely based on the long-term prospective and detailed characterization of heavy drinkers with mortality data. In addition, novel experimental findings will be presented. A special focus will be the long-known hepatic iron accumulation, the somewhat overlooked role of the hematopoietic system and novel insights into iron sensing and the role of hepcidin. Our preliminary work indicates that enhanced red blood cell (RBC) turnover is critical for survival in ALD patients. RBC turnover is not primarily due to vitamin deficiency but rather to ethanol toxicity directly targeted to erythrocytes but also to the bone marrow stem cell compartment. These novel insights also help to explain long-known aspects of ALD such as mean corpuscular volume of erythrocytes (MCV) and elevated aspartate transaminase (GOT/AST) levels. This work also aims at identifying future projects, naming unresolved observations, and presenting novel hypothetical concepts still requiring future validation.
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Wang X, Wang Y, Liu Y, Cong P, Xu J, Xue C. Hepatoprotective effects of sea cucumber ether-phospholipids against alcohol-induced lipid metabolic dysregulation and oxidative stress in mice. Food Funct 2022; 13:2791-2804. [PMID: 35174375 DOI: 10.1039/d1fo03833h] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Sea cucumber is widely consumed as food and folk medicine in Asia, and its phospholipids are rich sources of dietary eicosapentaenoic acid enriched ether-phospholipids (ether-PLs). Emerging evidence suggests that ether-PLs are associated with neurodegenerative disease and steatohepatitis. However, the function and mechanism of ether-PLs in alcoholic liver disease (ALD) are not well understood. To this end, the present study sought to investigate the hepatoprotective effects of sea cucumber ether-PLs, including plasmenyl phosphatidylethanolamine (PlsEtn) and plasmanyl phosphatidylcholine (PlsCho), and their underlying mechanisms. Our results showed that compared with EtOH-induced mice, ether-PL treated mice showed improved liver histology, decreased serum ALT and AST levels, and reduced alcohol metabolic enzyme (ALDH2 and ADH1) expressions. Mechanistic studies showed that ether-PLs attenuated "first-hit" hepatic steatosis and lipid accumulation evoked by alcohol administration. Moreover, PlsEtn more effectively restored endogenous plasmalogen levels than PlsCho, thereby enhancing hepatic antioxidation against "second-hit" reactive oxygen species (ROS) due to the damaged mitochondria and abnormal ethanol metabolism. Taken together, sea cucumber ether-PLs show great potential to become a natural functional food against chronic alcohol-induced hepatic steatosis and lipid metabolic dysregulation.
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Affiliation(s)
- Xiaoxu Wang
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, China.
| | - Yuliu Wang
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, China.
| | - Yanjun Liu
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, China. .,School of Food Science & Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China.
| | - Peixu Cong
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, China.
| | - Jie Xu
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, China.
| | - Changhu Xue
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, China. .,National Laboratory for Marine Science and Technology, Laboratory of Marine Drugs and Biological Products, Qingdao, 266237, Shandong, China
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BIOCHEMICAL CHANGES IN THE EXTRACELLULAR MATRIX OF RAT LIVER DURING CHRONIC ALCOHOL INTOXICATION. WORLD OF MEDICINE AND BIOLOGY 2022. [DOI: 10.26724/2079-8334-2022-4-82-221-225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Barré T, Fontaine H, Ramier C, Di Beo V, Pol S, Carrieri P, Marcellin F, Cagnot C, Dorival C, Zucman-Rossi J, Zoulim F, Carrat F, Protopopescu C. Elevated coffee consumption is associated with a lower risk of elevated liver fibrosis biomarkers in patients treated for chronic hepatitis B (ANRS CO22 Hepather cohort). Clin Nutr 2022; 41:610-619. [DOI: 10.1016/j.clnu.2022.01.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 01/04/2022] [Accepted: 01/15/2022] [Indexed: 11/03/2022]
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Seitz HK, Neuman MG. The History of Alcoholic Liver Disease: From an Unrecognized Disease to One of the Most Frequent Diseases in Hepatology. J Clin Med 2021; 10:858. [PMID: 33669694 PMCID: PMC7921942 DOI: 10.3390/jcm10040858] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/10/2021] [Accepted: 02/13/2021] [Indexed: 02/06/2023] Open
Abstract
This review describes the history of alcoholic liver disease from the beginning of the 1950s until now. It details how the hepatotoxicity of alcohol was discovered by epidemiology and basic research primarily by using new feeding techniques in rodents and primates. The article also recognizes the pioneering work of scientists who contributed to the understanding of the pathophysiology of alcoholic liver disease. In addition, clinical aspects, such as the development of diagnostics and treatment options for alcoholic liver disease, are discussed. Up-to-date knowledge of the mechanism of the disease in 2020 is presented.
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Affiliation(s)
- Helmut K. Seitz
- Centre of Liver and Alcohol Diseases, Ethianum Clinic, 69115 Heidelberg, Germany
- Faculty of Medicine, University of Heidelberg, 69117 Heidelberg, Germany
| | - Manuela G. Neuman
- In Vitro Drug Safety and Biotechnology and the Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L5, Canada;
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Li X, Liu Y, Yue W, Tan Y, Wang H, Zhang L, Chen J. A Compound of Chinese Herbs Protects against Alcoholic Liver Fibrosis in Rats via the TGF- β1/Smad Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2019; 2019:9121347. [PMID: 31118972 PMCID: PMC6500606 DOI: 10.1155/2019/9121347] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/11/2019] [Accepted: 03/31/2019] [Indexed: 02/06/2023]
Abstract
Alcoholic liver fibrosis (ALF) has become a major public health concern owing to its health impacts and the lack of effective treatment strategies for the disease. In this study, we investigated the effect of a compound composed of Chinese herbs Pueraria lobata (Willd.), Salvia miltiorrhiza, Schisandra chinensis, and Silybum marianum on ALF. An ALF model was established. Rats were fed with modified Lieber-Decarli alcohol liquid diet and injected with trace CCl4 at late stage. The rats were then treated with several doses of the compound. Biochemical and fibrosis-relevant parameters were measured from the sera obtained from the rats. Liver tissues were obtained for hematoxylin and eosin and Masson's trichrome staining. Matrix metalloproteinase-13 and tissue inhibitor of metalloproteinase-1 were determined by immunohistochemistry assays. The mRNA and protein expression levels of transforming growth factor-β1 (TGF-β1), Smad2, Smad3, and Smad7 on the livers were also measured by quantitative polymerase chain reaction and Western blot. Results showed that the compound treatment alleviated pathological lesions in the liver, decreased the serum levels of hyaluronan, laminin, and hydroxyproline, and diminished the expression of hepatic tissue inhibitor of metalloproteinase-1. Compound treatment also increased hepatic matrix metalloproteinase-13 expression and inhibited the TGF-β1/Smad signaling pathway. In conclusion, the compound has a protective effect against ALF in rats, and an underlying mechanism is involved in the TGF-β1/Smad signaling pathway.
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Affiliation(s)
- Xiaomeng Li
- West China School of Public Health and West China fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, China
| | - Yunjie Liu
- West China School of Public Health and West China fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, China
| | - Wuyang Yue
- West China School of Public Health and West China fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, China
| | - Yuefeng Tan
- West China School of Public Health and West China fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, China
| | - He Wang
- West China School of Public Health and West China fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, China
| | - Lishi Zhang
- West China School of Public Health and West China fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, China
| | - Jinyao Chen
- West China School of Public Health and West China fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, China
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Lamas-Paz A, Hao F, Nelson LJ, Vázquez MT, Canals S, Gómez del Moral M, Martínez-Naves E, Nevzorova YA, Cubero FJ. Alcoholic liver disease: Utility of animal models. World J Gastroenterol 2018; 24:5063-5075. [PMID: 30568384 PMCID: PMC6288648 DOI: 10.3748/wjg.v24.i45.5063] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/08/2018] [Accepted: 11/09/2018] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Experimental animal models of ALD, particularly rodents, have been used extensively to mimic human ALD. An ideal animal model should recapitulate all aspects of the ALD process, including significant steatosis, hepatic neutrophil infiltration, and liver injury. A better strategy against ALD depends on clear diagnostic biomarkers, accurate predictor(s) of its progression and new therapeutic approaches to modulate stop or even reverse the disease. Numerous models employing rodent animals have been established in the last decades to investigate the effects of acute and chronic alcohol exposure on the initiation and progression of ALD. Although significant progress has been made in gaining better knowledge on the mechanisms and pathology of ALD, many features of ALD are unknown, and require further investigation, ideally with improved animal models that more effectively mimic human ALD. Although differences in the degree and stages of alcoholic liver injury inevitably exist between animal models and human ALD, the acquisition and translational relevance will be greatly enhanced with the development of new and improved animal models of ALD.
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Affiliation(s)
- Arantza Lamas-Paz
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
- Yulia A Nevzovova, Francisco Javier Cubero, 12 de Octubre Health Research Institute (imas12), Madrid 28041, Spain
| | - Fengjie Hao
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
- Yulia A Nevzovova, Francisco Javier Cubero, 12 de Octubre Health Research Institute (imas12), Madrid 28041, Spain
| | - Leonard J Nelson
- Institute for Bioengineering (IBioE), School of Engineering, Faraday Building, The University of Edinburgh, Edinburgh EH9 3 JL, Scotland, United Kingdom
| | - Maria Teresa Vázquez
- Department of Human Anatomy and Embryology, Complutense University School of Medicine, Madrid 28040, Spain
| | - Santiago Canals
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, San Juan de Alicante 03550, Spain
| | - Manuel Gómez del Moral
- Department of Cell Biology, Complutense University School of Medicine, Madrid 28040, Spain
| | - Eduardo Martínez-Naves
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
- Yulia A Nevzovova, Francisco Javier Cubero, 12 de Octubre Health Research Institute (imas12), Madrid 28041, Spain
| | - Yulia A Nevzorova
- Department of Genetics, Physiology and Microbiology, Faculty of Biology, Universidad Complutense, Madrid 28040, Spain
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52062, Germany
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
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Ali H, Assiri MA, Shearn CT, Fritz KS. Lipid peroxidation derived reactive aldehydes in alcoholic liver disease. CURRENT OPINION IN TOXICOLOGY 2018; 13:110-117. [PMID: 31263795 DOI: 10.1016/j.cotox.2018.10.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Lipid peroxidation is a known consequence of oxidative stress and is thought to play a key role in numerous disease pathologies, including alcoholic liver disease (ALD). The overaccumulation of lipid peroxidation products during chronic alcohol consumption results in pathogenic lesions on protein, DNA, and lipids throughout the cell. Molecular adducts due to secondary end products of lipid peroxidation impact a host of biochemical processes, including inflammation, antioxidant defense, and metabolism. The aggregate burden of lipid peroxidation which occurs due to chronic alcohol metabolism, including downstream signaling events, contributes to the development and progression of ALD. In this current opinion we highlight recent studies and approaches relating cellular mechanisms of lipid peroxidation to the pathogenesis of alcoholic liver disease.
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Affiliation(s)
- Hadi Ali
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Mohammed A Assiri
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Colin T Shearn
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Kristofer S Fritz
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
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Mörs K, Kany S, Hörauf JA, Wagner N, Neunaber C, Perl M, Marzi I, Relja B. Suppression of the interleukin-1ß-induced inflammatory response of human Chang liver cells by acute and subacute exposure to alcohol: an in vitro study. Croat Med J 2018; 59:46-55. [PMID: 29740988 PMCID: PMC5941294 DOI: 10.3325/cmj.2018.59.46] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aim To evaluate protective immunosuppressive dose and time-dependent effects of ethanol in an in vitro model of acute inflammation in human Chang liver cells. Method The study was performed in 2016 and 2017 in the research laboratory of the Department of Trauma, Hand and Reconstructive Surgery, the University Hospital of the Goethe-University Frankfurt. Chang liver cells were stimulated with either interleukin (IL)-1β or IL-6 and subsequently treated with low-dose ethanol (85 mmol/L) or high-dose ethanol (170 mmol/L) for one hour (acute exposure) or 72 hours (subacute exposure). IL-6 and IL-1β release were determined by enzyme-linked immunosorbent assay. Neutrophil adhesion to Chang liver monolayers, production of reactive oxygen species, and apoptosis or necrosis were analyzed. Results Contrary to high-dose ethanol, acute low-dose ethanol exposure significantly reduced IL-1β-induced IL-6 and IL-6-induced IL-1β release (P < 0.05). Subacute ethanol exposure did not change proinflammatory cytokine release. Acute low-dose ethanol exposure significantly decreased inflammation-induced formation of reactive oxygen species (P < 0.05) and significantly improved cell survival (P < 0.05). Neither acute nor subacute high-dose ethanol exposure significantly changed inflammation-induced changes in reactive oxygen species or survival. Acute and subacute ethanol exposure, independently of the dose, significantly decreased neutrophil adhesion to inflamed Chang liver cells (P < 0.05). Conclusion Acute treatment of inflamed Chang liver cells with ethanol showed its immunosuppressive potential. However, the observed effects were limited to low-dose setting, indicating the relevance of ethanol dose in the modulation of inflammatory cell response.
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Affiliation(s)
| | | | | | | | | | | | | | - Borna Relja
- Borna Relja, Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt, Germany,
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Wang F, Tipoe GL, Yang C, Nanji AA, Hao X, So KF, Xiao J. Lycium barbarum Polysaccharide Supplementation Improves Alcoholic Liver Injury in Female Mice by Inhibiting Stearoyl-CoA Desaturase 1. Mol Nutr Food Res 2018; 62:e1800144. [PMID: 29797417 DOI: 10.1002/mnfr.201800144] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 05/04/2018] [Indexed: 01/21/2023]
Abstract
SCOPE Lycium barbarum polysaccharide (LBP) is a water fraction of wolfberry, which has been demonstrated to possess a hepatoprotective effect in several liver disease models. However, the anti-alcoholic liver disease (anti-ALD) mechanism of LBP has not been investigated thoroughly. Its protective effects on both male and femal mice are investigated in the current study. METHODS AND RESULTS A chronic ethanol-fed ALD in vivo model is applied to study the effect of LBP in both male and female mice. It is observed that ethanol causes more severe liver injury in female than male mice, and the ameliorative effects of LBP are also more significant in female mice, which are impaired after complete bilateral oophorectomy. The hepatic SCD1 expression is found to be positively correlated with the severity of the liver damage and the main mediator of LBP inducer of protection. The AMPK-CPT pathway is also activated by LBP to rebalance the dysregulated lipid metabolism during ALD development. By using concurrent sodium palmitate and an ethanol-induced in vitro cell damage model in AML-12 cell line, it is characterized that LBP directly interacts with ERα instead of ERβ to activate the SCD1-AMPK-CPT pathway. CONCLUSIONS LBP is an effective and safe hepatoprotective agent against ALD primarily through the SCD1-AMPK-CPT pathway after ERα agonist.
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Affiliation(s)
- Fei Wang
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Tongji Hospital, Tongji University School of Medicine, 389 Xin Cun Road, Shanghai, 200065, China
| | - George L Tipoe
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, 999077, Hong Kong
| | - Changqing Yang
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Tongji Hospital, Tongji University School of Medicine, 389 Xin Cun Road, Shanghai, 200065, China
| | - Amin A Nanji
- School of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H1V, Canada
| | - Xiangfeng Hao
- Yinchuan Bairuiyuan Biotechnology, Yinchuan, 750200, China
| | - Kwok-Fai So
- GMH Institute of CNS Regeneration, Guangdong Medical Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, 510632, China
| | - Jia Xiao
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Tongji Hospital, Tongji University School of Medicine, 389 Xin Cun Road, Shanghai, 200065, China.,School of Biomedical Sciences, The University of Hong Kong, Pokfulam, 999077, Hong Kong.,GMH Institute of CNS Regeneration, Guangdong Medical Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, 510632, China
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Hollenbach M. The Role of Glyoxalase-I (Glo-I), Advanced Glycation Endproducts (AGEs), and Their Receptor (RAGE) in Chronic Liver Disease and Hepatocellular Carcinoma (HCC). Int J Mol Sci 2017; 18:ijms18112466. [PMID: 29156655 PMCID: PMC5713432 DOI: 10.3390/ijms18112466] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 11/16/2017] [Accepted: 11/17/2017] [Indexed: 12/12/2022] Open
Abstract
Glyoxalase-I (Glo-I) and glyoxalase-II (Glo-II) comprise the glyoxalase system and are responsible for the detoxification of methylglyoxal (MGO). MGO is formed non-enzymatically as a by-product, mainly in glycolysis, and leads to the formation of advanced glycation endproducts (AGEs). AGEs bind to their receptor, RAGE, and activate intracellular transcription factors, resulting in the production of pro-inflammatory cytokines, oxidative stress, and inflammation. This review will focus on the implication of the Glo-I/AGE/RAGE system in liver injury and hepatocellular carcinoma (HCC). AGEs and RAGE are upregulated in liver fibrosis, and the silencing of RAGE reduced collagen deposition and the tumor growth of HCC. Nevertheless, data relating to Glo-I in fibrosis and cirrhosis are preliminary. Glo-I expression was found to be reduced in early and advanced cirrhosis with a subsequent increase of MGO-levels. On the other hand, pharmacological modulation of Glo-I resulted in the reduced activation of hepatic stellate cells and therefore reduced fibrosis in the CCl₄-model of cirrhosis. Thus, current research highlighted the Glo-I/AGE/RAGE system as an interesting therapeutic target in chronic liver diseases. These findings need further elucidation in preclinical and clinical studies.
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Affiliation(s)
- Marcus Hollenbach
- Department of Medicine, Neurology and Dermatology, Division of Gastroenterology and Rheumatology, University of Leipzig, Liebigstrasse 20, D-04103 Leipzig, Germany.
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Diethylcarbamazine attenuates the expression of pro-fibrogenic markers and hepatic stellate cells activation in carbon tetrachloride-induced liver fibrosis. Inflammopharmacology 2017; 26:599-609. [DOI: 10.1007/s10787-017-0329-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 02/17/2017] [Indexed: 01/26/2023]
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Hollenbach M, Thonig A, Pohl S, Ripoll C, Michel M, Zipprich A. Expression of glyoxalase-I is reduced in cirrhotic livers: A possible mechanism in the development of cirrhosis. PLoS One 2017; 12:e0171260. [PMID: 28231326 PMCID: PMC5322979 DOI: 10.1371/journal.pone.0171260] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 01/17/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND High concentrations of methylglyoxal (MGO) cause cytotoxiticy via formation of advanced glycation endproducts (AGEs) and inflammation. MGO is detoxificated enzymatically by glyoxalase-I (Glo-I). The aim of this study was to analyze the role of Glo-I during the development of cirrhosis. METHODS In primary hepatocytes, hepatic stellate cells (pHSC) and sinusoidal endothelial cells (pLSEC) from rats with early (CCl4 8wk) and advanced cirrhosis (CCl4 12wk) expression and activity of Glo-I were determined and compared to control. LPS stimulation (24h; 100ng/ml) of HSC was conducted in absence or presence of the partial Glo-I inhibitor ethyl pyruvate (EP) and the specific Glo-I inhibitor BrBzGSHCp2. MGO, inflammatory and fibrotic markers were measured by ELISA and Western blot. Additional rats were treated with CCl4 ± EP 40mg/kg b.w. i.p. from wk 8-12 and analyzed with sirius red staining and Western blot. RESULTS Expression of Glo-I was significantly reduced in cirrhosis in whole liver and primary liver cells accompanied by elevated levels of MGO. Activity of Glo-I was reduced in cirrhotic pHSC and pLSEC. LPS induced increases of TNF-α, Nrf2, collagen-I, α-SMA, NF-kB and pERK of HSC were blunted by EP and BrBzGSHCp2. Treatment with EP during development of cirrhosis significantly decreased the amount of fibrosis (12wk CCl4: 33.3±7.3%; EP wk 8-12: 20.7±6.2%; p<0.001) as well as levels of α-SMA, TGF-β and NF-κB in vivo. CONCLUSIONS Our results show the importance of Glo-I as major detoxifying enzyme for MGO in cirrhosis. The reduced expression of Glo-I in cirrhosis demonstrates a possible explanation for increased inflammatory injury and suggests a "vicious circle" in liver disease. Blunting of the Glo-I activity decrease the amount of fibrosis in established cirrhosis and constitutes a novel target for antifibrotic therapy.
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Affiliation(s)
- Marcus Hollenbach
- Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Antje Thonig
- Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Sabine Pohl
- Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Cristina Ripoll
- Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Maurice Michel
- Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Alexander Zipprich
- Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany
- * E-mail:
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Abstract
Alcoholic liver disease (ALD) is a leading cause of liver-related morbidity and mortality worldwide. ALD encompasses a spectrum of disorders including asymptomatic steatosis, steatohepatitis, fibrosis, cirrhosis and its related complications, and the acute-on-chronic state of alcoholic hepatitis. While multidisciplinary efforts continue to be aimed at curbing progression of this spectrum of disorders, there is an urgent need to focus our efforts on effective therapeutic interventions for alcoholic hepatitis (AH), the most severe form of ALD. AH is characterized by an abrupt development of jaundice and complications related to liver insufficiency and portal hypertension in patients with heavy alcohol intake. The mortality of patients with severe AH is very high (20-50 % at 3 months). The current therapeutic regimens are limited. The development of new therapies requires translational studies in human samples and suitable animal models that reproduce clinical and histological features of human AH. This review article summarizes the clinical syndrome, pre-clinical translational tools, and pathogenesis of AH at a molecular and cellular level, with the aim of identifying new targets of potential therapeutic intervention.
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Nevzorova YA, Cubero FJ, Hu W, Hao F, Haas U, Ramadori P, Gassler N, Hoss M, Strnad P, Zimmermann HW, Tacke F, Trautwein C, Liedtke C. Enhanced expression of c-myc in hepatocytes promotes initiation and progression of alcoholic liver disease. J Hepatol 2016; 64:628-640. [PMID: 26576483 DOI: 10.1016/j.jhep.2015.11.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 10/26/2015] [Accepted: 11/02/2015] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Progression of alcoholic liver disease (ALD) can be influenced by genetic factors, which potentially include specific oncogenes and tumor suppressors. In the present study, we tested the hypothesis that aberrant expression of the proto-oncogene c-myc might exert a crucial role in the development of ALD. METHODS Expression of c-myc was measured in biopsies of patients with ALD by quantitative real-time PCR and immunohistochemistry. Mice with transgenic expression of c-myc in hepatocytes (alb-myc(tg)) and wild-type (WT) controls were fed either control or ethanol (EtOH) containing Lieber-DeCarli diet for 4weeks to induce ALD. RESULTS Hepatic c-myc was strongly upregulated in human patients with advanced ALD and in EtOH-fed WT mice. Transcriptome analysis indicated deregulation of pathways involved in ER-stress, p53 signaling, hepatic fibrosis, cell cycle regulation, ribosomal synthesis and glucose homeostasis in EtOH-fed alb-myc(tg) mice. Transgenic expression of c-myc in hepatocytes with simultaneous EtOH-uptake led to early ballooning degeneration, increased liver collagen deposition and hepatic lipotoxicity, together with excessive CYP2E1-derived reactive oxygen species (ROS) production. Moreover, EtOH-fed alb-myc(tg) mice exhibited substantial changes in mitochondrial morphology associated with energy dysfunction. Pathway analysis revealed that elevated c-myc expression and ethanol uptake synergistically lead to strong AKT activation, Mdm2 phosphorylation and as a consequence to inhibition of p53. CONCLUSIONS Expression of c-myc and EtOH-uptake synergistically accelerate the progression of ALD most likely due to loss of p53-dependent protection. Thus, c-myc is a new potential marker for the early detection of ALD and identification of risk patients.
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Affiliation(s)
- Yulia A Nevzorova
- Department of Internal Medicine III, University Hospital RWTH Aachen, Germany.
| | - Francisco J Cubero
- Department of Internal Medicine III, University Hospital RWTH Aachen, Germany
| | - Wei Hu
- Department of Internal Medicine III, University Hospital RWTH Aachen, Germany
| | - Fengjie Hao
- Department of Internal Medicine III, University Hospital RWTH Aachen, Germany
| | - Ute Haas
- Department of Internal Medicine III, University Hospital RWTH Aachen, Germany
| | - Pierluigi Ramadori
- Department of Internal Medicine III, University Hospital RWTH Aachen, Germany
| | | | - Mareike Hoss
- Electron Microscopic Facility, Medical Faculty, University Hospital RWTH, Aachen, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, University Hospital RWTH Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF) Aachen, Germany
| | | | - Frank Tacke
- Department of Internal Medicine III, University Hospital RWTH Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, Germany
| | - Christian Liedtke
- Department of Internal Medicine III, University Hospital RWTH Aachen, Germany.
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Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism. World J Gastroenterol 2014; 20:17756-17772. [PMID: 25548474 PMCID: PMC4273126 DOI: 10.3748/wjg.v20.i47.17756] [Citation(s) in RCA: 347] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 05/22/2014] [Accepted: 08/28/2014] [Indexed: 02/06/2023] Open
Abstract
Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility.
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Yang AM, Wen LL, Yang CS, Wang SC, Chen CS, Bair MJ. Interleukin 10 promoter haplotype is associated with alcoholic liver cirrhosis in Taiwanese patients. Kaohsiung J Med Sci 2014; 30:291-8. [PMID: 24835349 DOI: 10.1016/j.kjms.2014.02.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 02/24/2014] [Accepted: 12/11/2013] [Indexed: 12/20/2022] Open
Abstract
Alcoholic liver cirrhosis is a severe form of alcohol-related liver damage. More than 95% of heavy drinkers develop a fatty liver, but only 35% of them develop cirrhosis. We postulate that genetic factors may play a role in this difference. Genetic polymorphisms of the cytokine genes may influence Kupffer cells cytokine genes expression. In this study, we evaluated the promoter polymorphisms of interleukin (IL) 1β, IL 6, IL 10, and tumor necrosis factor alpha (TNFα) and aimed to clarify the association between the polymorphisms and the disease. Forty alcoholic patients with liver cirrhosis and 64 healthy volunteers were included in our investigation. Genotyping on IL 1β -511 T>C, IL 6 -572 G>C, IL 10 -819 C>T, IL 10 -1082 G>A, and TNFα -308 G>A was done. Another 36 patients with recurrent alcoholic pancreatitis were included as an additional control group. Genotyping on IL 10 -819 C>T and IL 10 -1082 G>A was done. The polymorphisms on IL 1 and IL 6 showed no significant association. The p value for TNFα -308 G>A was 0.028 in comparison with healthy volunteers. Although the p value was less than 0.05, it did not reach significance after Bonferroni correction. The p values for IL 10 -819 C>T and IL 10 -1082 G>A were respectively 0.031 and 0.026 in healthy volunteers and 0.028 and 0.023 in the alcoholic pancreatitis group. The results also did not reach significance after Bonferroni correction. Among the participants with the GCC haplotype, healthy volunteers had p = 0.027 (p < 0.05) and an odds ratio (OR) of 0.124 [confidence interval (95%) CI, 0.015-0.997], whereas the alcoholic pancreatitis group had p = 0.023 (p < 0.05) and an OR of 0.106 (95% CI, 0.012-0.912). The odds ratio of people having one ATA haplotype was 6.233 (95% CI, 0.739-52.547) in healthy volunteers and 6.588 (95% CI, 0.727-59.679) in the alcoholic pancreatitis group; the corresponding rate was 10.521 (95% CI, 1.252-88.440) and 12.833 (95% CI 1.408-117.008) for people with two ATA haplotypes. The p values in these groups were 0.031 (p < 0.05) and 0.028 (p < 0.05), respectively. The presence of a GCC haplotype could have protective effect against alcoholic liver disease, whereas the presence of an ATA haplotype could predispose carriers to the disease. The IL 10 promoter haplotype is associated with alcoholic liver cirrhosis in Taiwanese patients.
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Affiliation(s)
- An-Ming Yang
- Department of Internal Medicine, En Chu Kong Hospital, New Taipei City, Taiwan; Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taiwan
| | - Li-Li Wen
- Department of Laboratory Medicine, En Chu Kong Hospital, New Taipei City, Taiwan
| | - Chang-Shyue Yang
- Department of Internal Medicine, En Chu Kong Hospital, New Taipei City, Taiwan
| | - Sun-Chong Wang
- Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taiwan
| | - Chien-Sheng Chen
- Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taiwan
| | - Ming-Jong Bair
- Department of Internal Medicine, Mackay Memorial Hospital, Taitung Branch, Taitung, Taiwan.
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Li J, Pan Y, Kan M, Xiao X, Wang Y, Guan F, Zhang X, Chen L. Hepatoprotective effects of berberine on liver fibrosis via activation of AMP-activated protein kinase. Life Sci 2014; 98:24-30. [DOI: 10.1016/j.lfs.2013.12.211] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 12/17/2013] [Accepted: 12/24/2013] [Indexed: 01/14/2023]
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Alcohol-related injury to peribiliary glands is a cause of peribiliary cysts: based on analysis of clinical and autopsy cases. J Clin Gastroenterol 2014; 48:153-9. [PMID: 23751840 DOI: 10.1097/mcg.0b013e318299c8c1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND AND GOAL Peribiliary cysts, which are known to be associated with various hepatobiliary diseases including alcoholic liver disease, have been reported to originate in the peribiliary glands along the biliary tree. The causal relationship between the peribiliary cysts and alcohol-related hepatic and pancreatic disease were examined in this study. METHODS AND RESULTS Peribiliary cysts were surveyed in the radiologic reports of out-patients and in-patients at our hospital (between 2007 and 2011), and a total of 31 patients with peribiliary cysts were found; 9 patients were associated with alcoholic liver disease and 2 patients with alcoholic pancreatitis. Among 202 consecutive autopsy cases with a history of heavy drinking (chronic alcoholics) at our Department (between 1990 and 2011), peribiliary cysts were found in 29 cases (14%), and the frequency of these cysts was correlated with the degree of alcohol-related hepatic fibrosis. Interestingly, peribiliary cysts were frequently associated with adenitis of the peribiliary glands (72%), and peribiliary adenitis and cyst formation correlated well with the degree of pancreatic fibrosis. CONCLUSIONS These results suggest that peribiliary cysts are more likely to occur in chronic alcoholics. The frequent association of peribiliary cysts with the degree of alcohol-related hepatic fibrosis suggests the involvement of the hepatic fibrogenetic process in peribiliary cyst formation. The frequent association of peribiliary adenitis and cyst formation with the degree of pancreatic fibrosis in chronic alcoholics suggests the involvement of alcoholic injuries in the pancreas, resulting in progressive fibrosis, and peribiliary glands, resulting in adenitis and cyst formation.
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Sung MT, Chen YC, Chi CW. Quercetin’s Potential to Prevent and Inhibit Oxidative Stress-Induced Liver Cancer. Cancer 2014. [DOI: 10.1016/b978-0-12-405205-5.00022-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Kim HG, Wang JH, Han JM, Hwang SY, Lee DS, Son CG. Chunggan extract (CGX), a traditional Korean herbal medicine, exerts hepatoprotective effects in a rat model of chronic alcohol consumption. Phytother Res 2013; 27:1854-1862. [PMID: 23460575 DOI: 10.1002/ptr.4935] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Revised: 12/27/2012] [Accepted: 01/07/2013] [Indexed: 12/25/2022]
Abstract
Chunggan extract, CGX, is a modification of a traditional herbal medicine that has been used for patients suffering from various liver disorders since 2001. Here, we investigated the hepatoprotective effects of CGX and its underlying mechanisms in a rat model of chronic alcohol consumption. Rats were orally administered 30% ethanol solution for 4 weeks with or without CGX (50, 100, 200 mg/kg). The histopathology, biochemistry, oxidative stress/antioxidant biomarkers, hepatofibrogenic cytokines, and serum endotoxin level were analyzed. Alcohol treatment markedly elevated the serum levels of aspartate transaminase, alkaline phosphatase, and total reactive oxygen species, and tissue levels of hydroxyproline and malondialdehyde (MDA), while reducing the total glutathione (GSH) contents and the activities of superoxide dismutase and catalase. These alterations were significantly attenuated by CGX treatment (mainly 100 and 200 mg/kg). CGX treatment normalized the elevation of fibrogenic cytokines, including transforming growth factor-β, platelet derived growth factor-β, and connective tissue growth factor in hepatic tissues and ameliorated the increase in serum endotoxin concentration. These results suggest that CGX protects liver tissue from alcohol injury through antioxidant actions and prevention of endotoxin reflux. .
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Affiliation(s)
- Hyeong Geug Kim
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical Collage of Daejeon University, 22-5 Daehung-dong, Jung-gu, Daejeon, 301-724, Republic of Korea
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Cordero-Pérez P, Torres-González L, Aguirre-Garza M, Camara-Lemarroy C, Guzmán-de la Garza F, Alarcón-Galván G, Zapata-Chavira H, de Jesús Sotelo-Gallegos M, Nadjedja Torres-Esquivel C, Sánchez-Fresno E, Cantú-Sepúlveda D, González-Saldivar G, Bernal-Ramirez J, E Muñoz-Espinosa L. Hepatoprotective effect of commercial herbal extracts on carbon tetrachloride-induced liver damage in Wistar rats. Pharmacognosy Res 2013; 5:150-6. [PMID: 23900881 PMCID: PMC3719254 DOI: 10.4103/0974-8490.112417] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Revised: 08/08/2012] [Accepted: 05/22/2013] [Indexed: 12/14/2022] Open
Abstract
Background: Various hepatoprotective herbal products from plants are available in Mexico, where up to 85% of patients with liver disease use some form of complementary and alternative medicine. However, only few studies have reported on the biological evaluation of these products. Objective: Using a model of carbon tetrachloride (CCl4)-induced hepatotoxicity in rats, we evaluated the effects of commercial herbal extracts used most commonly in the metropolitan area of Monterrey, Mexico. Materials and Methods: The commercial products were identified through surveys in public areas. The effect of these products given with or without CCl4 in rats was evaluated by measuring the serum concentrations of aspartate amino transferase (AST) and alanine amino transferase (ALT), and histopathological analysis. Legalon® was used as the standard drug. Results: The most commonly used herbal products were Hepatisan® capsules, Boldo capsules, Hepavida® capsules, Boldo infusion, and milk thistle herbal supplement (80% silymarin). None of the products tested was hepatotoxic according to transaminase and histological analyses. AST and ALT activities were significantly lower in the Hepavida+CCl4-treated group as compared with the CCl4-only group. AST and ALT activities in the silymarin, Hepatisan, and Boldo tea groups were similar to those in the CCl4 group. The CCl4 group displayed submassive confluent necrosis and mixed inflammatory infiltration. Both the Hepatisan+CCl4 and Boldo tea+CCl4 groups exhibited ballooning degeneration, inflammatory infiltration, and lytic necrosis. The silymarin+CCl4 group exhibited microvesicular steatosis. The Hepavida+CCl4- and Legalon+CCL4-treated groups had lower percentages of necrotic cells as compared with the CCl4-treated group; this treatment was hepatoprotective against necrosis. Conclusion: Only Hepavida had a hepatoprotective effect.
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Affiliation(s)
- Paula Cordero-Pérez
- Liver Unit, Gastroenterology Service from Department of Internal Medicine, Universidad Autónoma de Nuevo León, Av. Gonzalitos S/N Col. Mitras Centro C.P., Monterrey, Nuevo León, México
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Abe H, Aida Y, Ishiguro H, Yoshizawa K, Miyazaki T, Itagaki M, Sutoh S, Aizawa Y. Alcohol, postprandial plasma glucose, and prognosis of hepatocellular carcinoma. World J Gastroenterol 2013; 19:78-85. [PMID: 23326166 PMCID: PMC3542757 DOI: 10.3748/wjg.v19.i1.78] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Revised: 09/17/2012] [Accepted: 09/29/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To identify factors associated with prognosis of hepatocellular carcinoma (HCC) after initial therapy. METHODS A total of 377 HCC patients who were newly treated at Katsushika Medical Center, Japan from January 2000 to December 2009 and followed up for > 2 years, or died during follow-up, were enrolled. The factors related to survival were first analyzed in 377 patients with HCC tumor stage T1-T4 using multivariate Cox proportional hazards regression analysis. A similar analysis was performed in 282 patients with tumor stage T1-T3. Additionally, factors associated with the period between initial and subsequent therapy were examined in 144 patients who did not show local recurrence. Finally, 214 HCC stage T1-T3 patients who died during the observation period were classified into four groups according to their alcohol consumption and postprandial glucose levels, and differences in their causes of death were examined. RESULTS On multivariate Cox proportional hazards regression analysis, the following were significantly associated with survival: underlying liver disease stage [non-cirrhosis/Child-Pugh A vs B/C, hazard ratio (HR): 0.603, 95% CI: 0.417-0.874, P = 0.0079], HCC stage (T1/T2 vs T3/T4, HR: 0.447, 95% CI: 0.347-0.576, P < 0.0001), and mean postprandial plasma glucose after initial therapy (< 200 vs ≥ 200 mg/dL, HR: 0.181, 95% CI: 0.067-0.488, P = 0.0008). In T1-T3 patients, uninterrupted alcohol consumption after initial therapy (no vs yes, HR: 0.641, 95% CI: 0.469-0.877, P = 0.0055) was significant in addition to underlying liver disease stage (non-cirrhosis/Child-Pugh A vs B/C, HR: 0649, 95% CI: 0.476-0.885, P = 0.0068), HCC stage (T1 vs T2/T3, HR: 0.788, 95% CI: 0.653-0.945, P = 0.0108), and mean postprandial plasma glucose after initial therapy (< 200 mg/dL vs ≥ 200 mg/dL, HR: 0.502, 95% CI: 0.337-0.747, P = 0.0005). In patients without local recurrence, time from initial to subsequent therapy for newly emerging HCC was significantly longer in the "postprandial glucose within 200 mg/dL group" than the "postprandial glucose > 200 mg/dL group" (log-rank test, P < 0.05), whereas there was no difference in the period between the "non-alcohol group" (patients who did not drink regularly or those who could reduce their daily consumption to < 20 g) and the "continuation group" (drinkers who continued to drink > 20 g daily). Of 214 T1-T3 patients who died during the observation period, death caused by other than HCC progression was significantly more frequent in "group AL" (patients in the continuation and postprandial glucose within 200 mg/dL groups) than "group N" (patients in the non-alcohol and postprandial glucose within 200 mg/dL groups) (P = 0.0016). CONCLUSION This study found that abstinence from habitual alcohol consumption and intensive care for diabetes mellitus were related to improved prognosis in HCC patients.
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Chou CH, Chang YY, Tzang BS, Hsu CL, Lin YL, Lin HW, Chen YC. Effects of taurine on hepatic lipid metabolism and anti-inflammation in chronic alcohol-fed rats. Food Chem 2012. [DOI: 10.1016/j.foodchem.2012.04.036] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Roy N, Mukhopadhyay I, Das K, Pandit P, Majumder PP, Santra A, Datta S, Banerjee S, Chowdhury A. Genetic variants of TNFα, IL10, IL1β, CTLA4 and TGFβ1 modulate the indices of alcohol-induced liver injury in East Indian population. Gene 2012; 509:178-88. [PMID: 22902304 DOI: 10.1016/j.gene.2012.07.077] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Accepted: 07/31/2012] [Indexed: 02/06/2023]
Abstract
Alcohol induced liver disease or alcoholic liver disease (ALD), a complex trait, encompasses a gamut of pathophysiological alterations in the liver due to continuous exposure to a toxic amount of alcohol (more than 80 g per day). Of all chronic heavy drinkers, only 15-20% develops hepatitis or cirrhosis concomitantly or in succession. Several studies revealed that inter-individual as well as inter-ethnic genetic variation is one of the major factors that predispose to ALD. The role of genetic factors in ALD has long been sought for in ethnically distinct population groups. ALD is fast emerging as an important cause of chronic liver disease in India; even in populations such as "Bengalis" who were "culturally immune" earlier. While the genetic involvement in the pathogenesis of ALD is being sought for in different races, the complex pathophysiology of ALD as well as the knowledge of population level diversity of the relevant alcohol metabolizing and inflammatory pathways mandates the need for well designed studies of genetic factors in ethnically distinct population groups. An array of cytokines plays a critical role as mediators of injury, inflammation, fibrosis and cirrhosis in ALD. We, therefore, studied the association of polymorphisms in five relevant cytokine genes with "clinically significant" ALD in an ethnic "Bengali" population in Eastern India. Compared with "alcoholic" controls without liver disease (n=110), TNFα -238AA genotype, IL1β -511CC genotype, TGFβ1 -509CC genotype and IL10 -592AA genotype were significantly overrepresented in ALD patients (n=181; OR=2.4 and 95% CI 1.2-5.5, P(genotype)=0.042, P(allelic)=0.008; OR=2.7 and 95% CI 1.2-5.9, P(genotype)=0.018, P(allelic)=0.023; OR=4.7 and 95% CI 1.7-13.1, P(genotype)=0.003, P(allelic)=0.014; and OR=2.2 and 95% CI 1.1-4.8, P(genotype)=0.04, P(allelic)=0.039 respectively). Moreover a cumulative genetic risk analysis revealed a significant trend for developing ALD with an increase in the number of risk alleles on IL10 and TGFβ1 loci among alcoholics. The risk genotype of IL1β and TGFβ1 also influences the total bilirubin, albumin and alanine aminotransferase levels among alcoholic "Bengalis". The present study is the first case-control study from Eastern India that comprehensively identified polymorphic markers in TNFα, IL10, IL1β and TGFβ1 genes to be associated with ALD in the Bengali population, accentuating the significance of genetic factors in clinical expressions of ALD.
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Affiliation(s)
- Neelanjana Roy
- Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
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EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol 2012; 57:399-420. [PMID: 22633836 DOI: 10.1016/j.jhep.2012.04.004] [Citation(s) in RCA: 453] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Accepted: 04/04/2012] [Indexed: 12/12/2022]
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Grønbaek H, Sandahl TD, Mortensen C, Vilstrup H, Møller HJ, Møller S. Soluble CD163, a marker of Kupffer cell activation, is related to portal hypertension in patients with liver cirrhosis. Aliment Pharmacol Ther 2012; 36:173-80. [PMID: 22591184 DOI: 10.1111/j.1365-2036.2012.05134.x] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Revised: 04/05/2012] [Accepted: 04/25/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Activation of Kupffer cells may be involved in the pathogenesis of portal hypertension by release of vasoconstrictive substances and fibrosis due to co-activation of hepatic stellate cells. AIM To study soluble plasma (s) CD163, a specific marker of activated macrophages, as a biomarker for portal hypertension in patients with liver cirrhosis. METHODS We measured sCD163 concentration and the hepatic venous pressure gradient (HVPG) by liver vein catheterisation in 81 cirrhosis patients (Child-Pugh CP-A: n = 26, CP-B: n = 29, CP-C: n = 26) and 22 healthy subjects. We also measured their cardiac output (CO), cardiac index and systemic vascular resistance (SVR). Liver status was examined by Child-Pugh and MELD-score. RESULTS In cirrhosis, sCD163 concentration was nearly three times higher than in controls (4.7 ± 2.5 vs. 1.6 ± 0.5 mg/L, P < 0.001). sCD163 was also higher, as measured in steps by CP-score (P < 0.001). The HVPG rose steeply to an asymptote of 22 mmHg with sCD163 up to about 5 mg/L and not to higher values with higher sCD163. In a multivariate analysis, sCD163 was the only independent predictor of the HVPG but did not predict any of the systemic circulatory findings. sCD163 > 3.95 mg/L (upper normal limit) predicted HVPG ≥ 10 mmHg with a positive predictive value of 0.99. CONCLUSIONS Circulating sCD163 originating from activated Kupffer cells is increased in cirrhosis with increasing Child-Pugh score and with increasing HVPG, and it is an independent predictor for HVPG. These findings support a primary role of macrophage activation in portal hypertension, and may indicate a target for biological intervention.
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Affiliation(s)
- H Grønbaek
- Department of Medicine V, Aarhus University Hospital, Denmark
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Brown SD, Brown LAS. Ethanol (EtOH)-induced TGF-β1 and reactive oxygen species production are necessary for EtOH-induced alveolar macrophage dysfunction and induction of alternative activation. Alcohol Clin Exp Res 2012; 36:1952-62. [PMID: 22551312 DOI: 10.1111/j.1530-0277.2012.01825.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 02/26/2012] [Indexed: 01/17/2023]
Abstract
BACKGROUND Previous studies have shown that chronic ethanol (EtOH) ingestion results in impaired alveolar macrophage function, increased TGF-β(1) production, and decreased antioxidant availability. Similarly, alternative activation (M2 activation) of alveolar macrophages also induces TGF-β(1) production and impairs macrophage function. However, the potential links between EtOH-induced alveolar macrophage derangements, M2 activation, TGF-β(1) production signaling, and oxidant stress have yet to be examined. We hypothesized that EtOH-induced oxidant stress and induction of TGF-β(1) signaling result in alternative activation which subsequently impairs the phagocytic capacity of alveolar macrophages. METHODS Primary rat alveolar macrophages and the alveolar macrophages cell line NR8383 were treated with 0.08% EtOH ± the antioxidant glutathione (GSH) or a TGF-β(1) neutralizing antibody for 5 days. Outcome measures included TGF-β(1) production, reactive oxygen species (ROS) production, phagocytic capacity, and expression of markers of M2 activation. RESULTS Chronic EtOH treatment greatly decreased alveolar macrophage phagocytic function, increased ROS production, increased TGF-β(1) , and increased expression of markers of M2 activation. GSH supplementation and inhibition of TGF-β(1) signaling during EtOH treatment prevented these alterations. CONCLUSIONS EtOH treatment increased oxidant stress, TGF-β(1) production, and alternative activation in NR8383 cells. However, GSH supplementation and ablation of TGF-β(1) signaling prevented these effects. This suggested that the EtOH-induced switch to an M2 phenotype was a result of decreased antioxidant availability and increased TGF-β(1) signaling. Preventing EtOH-induced induction of alternative activation may improve alveolar macrophage function in alcoholic subjects and decrease the risk of respiratory infections.
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Affiliation(s)
- Sheena D Brown
- Department of Pediatrics, Emory University, and Center for Developmental Lung Biology, Children's Healthcare of Atlanta, Georgia 30322, USA
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Fang YJ, Chiu CH, Chang YY, Chou CH, Lin HW, Chen MF, Chen YC. Taurine ameliorates alcoholic steatohepatitis via enhancing self-antioxidant capacity and alcohol metabolism. Food Res Int 2011. [DOI: 10.1016/j.foodres.2011.08.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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GAO BIN, BATALLER RAMON. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011; 141:1572-85. [PMID: 21920463 PMCID: PMC3214974 DOI: 10.1053/j.gastro.2011.09.002] [Citation(s) in RCA: 1479] [Impact Index Per Article: 105.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2011] [Revised: 09/08/2011] [Accepted: 09/08/2011] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide and can lead to fibrosis and cirrhosis. The latest surveillance report published by the National Institute on Alcohol Abuse and Alcoholism showed that liver cirrhosis was the 12th leading cause of death in the United States, with a total of 29,925 deaths in 2007, 48% of which were alcohol related. The spectrum of ALD includes simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. Early work on the pathogenesis of the disease focused on ethanol metabolism-associated oxidative stress and glutathione depletion, abnormal methionine metabolism, malnutrition, and production of endotoxins that activate Kupffer cells. We review findings from recent studies that have characterized specific intracellular signaling pathways, transcriptional factors, aspects of innate immunity, chemokines, epigenetic features, microRNAs, and stem cells that are associated with ALD, improving our understanding of its pathogenesis. Despite this progress, no targeted therapies are available. The cornerstone of treatment for alcoholic hepatitis remains as it was 40 years ago: abstinence, nutritional support, and corticosteroids. There is an urgent need to develop new pathophysiology-oriented therapies. Recent translational studies of human samples and animal models have identified promising therapeutic targets.
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Affiliation(s)
- BIN GAO
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - RAMON BATALLER
- Liver Unit, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Catalonia, Spain
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Howarth DL, Vacaru AM, Tsedensodnom O, Mormone E, Nieto N, Costantini LM, Snapp EL, Sadler KC. Alcohol disrupts endoplasmic reticulum function and protein secretion in hepatocytes. Alcohol Clin Exp Res 2011; 36:14-23. [PMID: 21790674 DOI: 10.1111/j.1530-0277.2011.01602.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Many alcoholic patients have serum protein deficiency that contributes to their systemic problems. The unfolded protein response (UPR) is induced in response to disequilibrium in the protein folding capability of the endoplasmic reticulum (ER) and is implicated in hepatocyte lipid accumulation and apoptosis, which are associated with alcoholic liver disease (ALD). We investigated whether alcohol affects ER structure, function, and UPR activation in hepatocytes in vitro and in vivo. METHODS HepG2 cells expressing human cytochrome P450 2E1 and mouse alcohol dehydrogenase (VL-17A) were treated for up to 48 hours with 50 and 100 mM ethanol. Zebrafish larvae at 4 days postfertilization were exposed to 350 mM ethanol for 32 hours. ER morphology was visualized by fluorescence in cells and transmission electron microscopy in zebrafish. UPR target gene activation was assessed using quantitative PCR, in situ hybridization, and Western blotting. Mobility of the major ER chaperone, BIP, was monitored in cells by fluorescence recovery after photobleaching (FRAP). RESULTS VL-17A cells metabolized alcohol yet only had slight activation of some UPR target genes following ethanol treatment. However, ER fragmentation, crowding, and accumulation of unfolded proteins as detected by immunofluorescence and FRAP demonstrate that alcohol induced some ER dysfunction despite the lack of UPR activation. Zebrafish treated with alcohol, however, showed modest ER dilation, and several UPR targets were significantly induced. CONCLUSIONS Ethanol metabolism directly impairs ER structure and function in hepatocytes. Zebrafish are a novel in vivo system for studying ALD.
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Affiliation(s)
- Deanna L Howarth
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA
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Abstract
Obesity is a global epidemic with more than 1 billion overweight adults and at least 300 million obese patients worldwide. Diabetes is characterized by a defect in insulin secretion or a decrease in sensitivity to insulin, which results in elevated fasting blood glucose. Both obesity and elevated fasting glucose are risk factors for nonalcoholic fatty liver disease, a disease spectrum that includes hepatic steatosis (nonalcoholic fatty liver), nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from NASH to fibrosis through the development of a profibrotic mileau in the liver, including increased hepatocellular death, increased reactive oxygen species generation, and an altered adipokine/cytokine balance. This review will summarize recent advances in our understanding of the pathological interactions among excessive fat accumulation, insulin resistance, and hepatic fibrogenesis and discuss specific molecular pathways that may be of interest in the development of therapeutic interventions to prevent and/or reverse hepatic fibrosis.
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Affiliation(s)
- Dian J Chiang
- Dept. of Gastroenterology and Hepatology, Cleveland Clinic, OH 44195, USA.
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Miller AM, Horiguchi N, Jeong WIL, Radaeva S, Gao B. Molecular mechanisms of alcoholic liver disease: innate immunity and cytokines. Alcohol Clin Exp Res 2011; 35:787-93. [PMID: 21284667 PMCID: PMC3083482 DOI: 10.1111/j.1530-0277.2010.01399.x] [Citation(s) in RCA: 143] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases worldwide, causing fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma. In the past few decades, significant progress has been made in our understanding of the molecular mechanisms underlying alcoholic liver injury. Activation of innate immunity components such as Kupffer cells, LPS/TLR4, and complements in response to alcohol exposure plays a key role in the development and progression of alcoholic liver disease (ALD). LPS activation of Kupffer cells also produces IL-6 and IL-10 that may play a protective role in ameliorating ALD. IL-6 activates signal transducer and activator of transcription 3 (STAT3) in hepatocytes and sinusoidal endothelial cells, while IL-10 activates STAT3 in Kupffer cells/macrophages, subsequently protecting against ALD. In addition, alcohol consumption also inhibits some components of innate immunity such as natural killer (NK) cells, a type of cells that play key roles in anti-viral, anti-tumor, and anti-fibrotic defenses in the liver. Ethanol inhibition of NK cells likely contributes significantly to the pathogenesis of ALD. Understanding the roles of innate immunity and cytokines in alcoholic liver injury may provide insight into novel therapeutic targets in the treatment of alcoholic liver disease.
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Affiliation(s)
- Andrew M. Miller
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD20892, USA
| | - Norio Horiguchi
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD20892, USA
- Department of Medicine and Molecular Science, Gunma University School of Medicine, Japan
| | - Won-IL Jeong
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD20892, USA
- Laboratory of Liver Research, Korea Advanced Institute of Science and Technology, Korea
| | - Svetlana Radaeva
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD20892, USA
- Division of Metabolism and Health Effect, Extramural Program, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Bin Gao
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD20892, USA
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Yang H, Jeong EJ, Kim J, Sung SH, Kim YC. Antiproliferative triterpenes from the leaves and twigs of Juglans sinensis on HSC-T6 cells. JOURNAL OF NATURAL PRODUCTS 2011; 74:751-756. [PMID: 21309591 DOI: 10.1021/np1008202] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Bioassay-guided fractionation of an 80% MeOH extract of leaves and twigs of Juglan sinensis has resulted in the isolation of four new triterpenes (1-4) and 17 known triterpenes (5-21). The new compounds were determined to be 1-oxo-3β,23-dihydroxyolean-12-en-28-oic acid 28-O-β-D-glucopyranoside (1), 1-oxo-3β-hydroxyolean-18-ene (2), 3β,23-dihydroxyurs-12-en-28-oic acid 28-O-β-D-glucopyranoside (3), and 3β,22α-dihydroxyurs-12-en-28-oic acid 28-O-β-D-glucopyranoside (4) by spectroscopic analysis. Compounds 2, 13, 15, and 21 showed antiproliferative activities (14.2, 14.8, 15.6, and 11.0% at 100 μM, respectively) in HSC-T6 cells. Flow cytometry assays revealed that these compounds inhibited HSC-T6 proliferation by inducing apoptosis.
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Affiliation(s)
- Heejung Yang
- College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, Daehak-Dong, Gwanak-Gu, Seoul 151-742, Republic of Korea
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Bataller R, Rombouts K, Altamirano J, Marra F. Fibrosis in alcoholic and nonalcoholic steatohepatitis. Best Pract Res Clin Gastroenterol 2011; 25:231-44. [PMID: 21497741 DOI: 10.1016/j.bpg.2011.02.010] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2011] [Accepted: 02/18/2011] [Indexed: 01/31/2023]
Abstract
Both alcoholic and nonalcoholic steatohepatitis are relevant causes of cirrhosis and liver-related mortality. Alcohol abuse represents a major health problem in many countries, and liver disease is considered one of the most relevant causes of death related to this factor. Nonalcoholic fatty liver disease is the most common hepatic abnormality in the Western world, and progresses to cirrhosis and hepatocellular carcinoma in a significant portion of cases. Moreover, presence of NAFLD is associated with an increased risk of cardiovascular events. In this review, we discuss the characteristics of fibrosis in alcoholic and nonalcoholic steatohepatitis, focussing on the diagnostic issues and predictive factors. In addition, the pathogenetic mechanisms responsible for appearance and progression of fibrosis in the two conditions are briefly discussed.
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Affiliation(s)
- Ramon Bataller
- Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomèdica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.
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Gao B, Seki E, Brenner DA, Friedman S, Cohen JI, Nagy L, Szabo G, Zakhari S. Innate immunity in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 2011; 300:G516-25. [PMID: 21252049 PMCID: PMC3774265 DOI: 10.1152/ajpgi.00537.2010] [Citation(s) in RCA: 181] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2010] [Accepted: 01/12/2011] [Indexed: 02/06/2023]
Abstract
Excessive alcohol consumption is a leading cause of chronic liver disease in the Western world. Alcohol-induced hepatotoxicity and oxidative stress are important mechanisms contributing to the pathogenesis of alcoholic liver disease. However, emerging evidence suggests that activation of innate immunity involving TLR4 and complement also plays an important role in initiating alcoholic steatohepatitis and fibrosis, but the role of adaptive immunity in the pathogenesis of alcoholic liver disease remains obscure. Activation of a TLR4-mediated MyD88-independent (TRIF/IRF-3) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis, whereas activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis. Alcohol consumption activates the complement system in the liver by yet unidentified mechanisms, leading to alcoholic steatohepatitis. In contrast to activation of TLR4 and complement, alcohol consumption can inhibit natural killer cells, another important innate immunity component, contributing to alcohol-mediated acceleration of viral infection and liver fibrosis in patients with chronic viral hepatitis. Understanding of the role of innate immunity in the pathogenesis of alcoholic liver disease may help us identify novel therapeutic targets to treat this disease.
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Affiliation(s)
- Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA.
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Brocker C, Cantore M, Failli P, Vasiliou V. Aldehyde dehydrogenase 7A1 (ALDH7A1) attenuates reactive aldehyde and oxidative stress induced cytotoxicity. Chem Biol Interact 2011; 191:269-77. [PMID: 21338592 DOI: 10.1016/j.cbi.2011.02.016] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2010] [Revised: 02/12/2011] [Accepted: 02/13/2011] [Indexed: 11/20/2022]
Abstract
Mammalian aldehyde dehydrogenase 7A1 (ALDH7A1) is homologous to plant ALDH7B1 which protects against various forms of stress such as increased salinity, dehydration and treatment with oxidants or pesticides. Deleterious mutations in human ALDH7A1 are responsible for pyridoxine-dependent and folinic acid-responsive seizures. In previous studies, we have shown that human ALDH7A1 protects against hyperosmotic stress presumably through the generation of betaine, an important cellular osmolyte, formed from betaine aldehyde. Hyperosmotic stress is coupled to an increase in oxidative stress and lipid peroxidation (LPO). In this study, cell viability assays revealed that stable expression of mitochondrial ALDH7A1 in Chinese hamster ovary (CHO) cells provides significant protection against treatment with the LPO-derived aldehydes hexanal and 4-hydroxy-2-nonenal (4HNE) implicating a protective function for the enzyme during oxidative stress. A significant increase in cell survival was also observed in CHO cells expressing either mitochondrial or cytosolic ALDH7A1 treated with increasing concentrations of hydrogen peroxide (H(2)O(2)) or 4HNE, providing further evidence for anti-oxidant activity. In vitro enzyme activity assays indicate that human ALDH7A1 is sensitive to oxidation and that efficiency can be at least partially restored by incubating recombinant protein with the thiol reducing agent β-mercaptoethanol (BME). We also show that after reactivation with BME, recombinant ALDH7A1 is capable of metabolizing the reactive aldehyde 4HNE. In conclusion, ALDH7A1 mechanistically appears to provide cells protection through multiple pathways including the removal of toxic LPO-derived aldehydes in addition to osmolyte generation.
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Affiliation(s)
- Chad Brocker
- Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA
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Cubero FJ, Trautwein C. Oxidative Stress and Liver Injury. MOLECULAR PATHOLOGY LIBRARY 2011:427-435. [DOI: 10.1007/978-1-4419-7107-4_28] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Ha HL, Shin HJ, Feitelson MA, Yu DY. Oxidative stress and antioxidants in hepatic pathogenesis. World J Gastroenterol 2010; 16:6035-43. [PMID: 21182217 PMCID: PMC3012582 DOI: 10.3748/wjg.v16.i48.6035] [Citation(s) in RCA: 157] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2010] [Revised: 07/12/2010] [Accepted: 07/19/2010] [Indexed: 02/06/2023] Open
Abstract
Long term hepatitis B virus (HBV) infection is a major risk factor in pathogenesis of chronic liver diseases, including hepatocellular carcinoma (HCC). The HBV encoded proteins, hepatitis B virus X protein and preS, appear to contribute importantly to the pathogenesis of HCC. Both are associated with oxidative stress, which can damage cellular molecules like lipids, proteins, and DNA during chronic infection. Chronic alcohol use is another important factor that contributes to oxidative stress in the liver. Previous studies reported that treatment with antioxidants, such as curcumin, silymarin, green tea, and vitamins C and E, can protect DNA from damage and regulate liver pathogenesis-related cascades by reducing reactive oxygen species. This review summarizes some of the relationships between oxidative stress and liver pathogenesis, focusing upon HBV and alcohol, and suggests antioxidant therapeutic approaches.
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Gunzerath L, Hewitt BG, Li TK, Warren KR. Alcohol research: past, present, and future. Ann N Y Acad Sci 2010; 1216:1-23. [PMID: 21182533 DOI: 10.1111/j.1749-6632.2010.05832.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Created forty years ago, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) has played a major role in the great strides made in the understanding, treatment, prevention, and public acceptance of alcohol-use disorders. Throughout most of U.S. history "habitual drunkenness" was viewed as a problem of moral degeneracy or character flaw inherent in the individual. However, the wealth of scientific evidence amassed throughout NIAAA's history has established alcoholism as a medical condition, that is, as a disease for which affected individuals should feel no shame or be treated with disdain. We look at the developments in alcohol epidemiology, typology, etiology, prevention, and treatment research over the past 40 years. We also discuss how NIAAA addresses alcohol disorders from a life-course framework, affecting all stages of the lifespan, from fetus through child, adolescent, and young adult, to midlife/senior adult, with each stage involving different risks, consequences, prevention efforts, and treatment strategies.
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Affiliation(s)
- Lorraine Gunzerath
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20892, USA.
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Miranda-Mendez A, Lugo-Baruqui A, Armendariz-Borunda J. Molecular basis and current treatment for alcoholic liver disease. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2010; 7:1872-88. [PMID: 20622998 PMCID: PMC2898022 DOI: 10.3390/ijerph7051872] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2010] [Accepted: 03/05/2010] [Indexed: 12/12/2022]
Abstract
Alcohol use disorders and alcohol dependency affect millions of individuals worldwide. The impact of these facts lies in the elevated social and economic costs. Alcoholic liver disease is caused by acute and chronic exposure to ethanol which promotes oxidative stress and inflammatory response. Chronic consumption of ethanol implies liver steatosis, which is the first morphological change in the liver, followed by liver fibrosis and cirrhosis. This review comprises a broad approach of alcohol use disorders, and a more specific assessment of the pathophysiologic molecular basis, and genetics, as well as clinical presentation and current modalities of treatment for alcoholic liver disease.
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Affiliation(s)
- Alejandra Miranda-Mendez
- Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, Jalisco 44281, Mexico; E-Mails:
(A.M.M.);
(A.L.B.)
| | - Alejandro Lugo-Baruqui
- Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, Jalisco 44281, Mexico; E-Mails:
(A.M.M.);
(A.L.B.)
- OPD Hospital Civil de Guadalajara, Jalisco 44340, Mexico
| | - Juan Armendariz-Borunda
- Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, Jalisco 44281, Mexico; E-Mails:
(A.M.M.);
(A.L.B.)
- OPD Hospital Civil de Guadalajara, Jalisco 44340, Mexico
- Author to whom correspondence should be addressed; E-Mail:
; Tel.: +52-33-1058-5317; Fax: +52-33-1058-5318
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