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Cervelli R, Cencini M, Aringhieri G, Silvestrini B, Cacciato Insilla A, Campani D, Ghinolfi D, De Simone P, Tosetti M, Crocetti L. Ex-vivo 7T MRI of human explanted cirrhotic liver with HCC: quantitative and qualitative evaluation with radiological-pathological correlation. LA RADIOLOGIA MEDICA 2025; 130:567-576. [PMID: 39937367 DOI: 10.1007/s11547-025-01962-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 01/23/2025] [Indexed: 02/13/2025]
Abstract
INTRODUCTION Hepatocellular carcinoma's (HCC) pathological grading is a recognized factor influencing intrahepatic recurrence after treatment. Thus, understanding the HCC heterogeneity is crucial to select the best treatment option aiming at personalized medicine. 7T MRI can provide qualitative and quantitative data, potentially identifying imaging biomarkers for lesions characterization. MATERIALS AND METHODS From May 2019 to December 2019, all explanted livers of patients undergoing liver transplant were enrolled. All patients underwent whole body CT before liver transplant and all the explanted livers were evaluated (ex-vivo) by 7T MRI within 12 h from liver removal with qualitative and quantitative acquisitions, including 2D/3D magnetic resonance fingerprinting (MRF). First, two expert radiologists qualitatively and quantitatively evaluated the imaging data focusing on both lesions and surrounding tissue, comparing conventional and MRF sequences. Then, specimens were evaluated by an expert pathologist regarding both liver tissues and lesions, particularly focusing on HCC grading. CONCLUSIONS This work may represent the first step supporting the introduction of quantitative MR imaging (including MRF) in the clinical practice. Along with conventional protocol and dynamic contrast enhancement, the integration of quantitative MR imaging can provide imaging biomarkers useful to identify HCC lesions more prone to recurrence, leading to a better patient selection, according to a personalized medicine approach.
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Affiliation(s)
- Rosa Cervelli
- Diagnostic and Interventional Radiology, University of Pisa, Pisa, Italy
| | - Matteo Cencini
- Pisa Division, National Institute for Nuclear Physics (INFN), Pisa, Italy
| | - Giacomo Aringhieri
- Academic Radiology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
| | - Beatrice Silvestrini
- Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
| | | | | | - Davide Ghinolfi
- Hepatic Surgery and Liver Transplantation, University of Pisa, Pisa, Italy
| | - Paolo De Simone
- Hepatic Surgery and Liver Transplantation, University of Pisa, Pisa, Italy
| | | | - Laura Crocetti
- Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
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Xia N, Xue H, Li Y, Liu J, Lou Y, Li S, Wang Y, Lu J, Chen X. Potential Mechanisms and Effects of Dai Bai Jie Ethanol Extract in Preventing Acute Alcoholic Liver Injury. Curr Issues Mol Biol 2024; 47:3. [PMID: 39852118 PMCID: PMC11763393 DOI: 10.3390/cimb47010003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 12/17/2024] [Accepted: 12/20/2024] [Indexed: 01/26/2025] Open
Abstract
This study investigated the protective effect of Dai Bai Jie (DBJ) extract against acute alcoholic liver injury (AALI) and elucidated its potential mechanism. The total saponin level in the DBJ extracts was measured using vanillin-chloroform acid colorimetry. To observe the preventive and protective effects of DBJ on AML-12 cells in an ethanol environment, the effective components of DBJ were identified. An alcohol-induced AALI mouse model was used to evaluate the efficacy of DBJ against AALI. For this purpose, alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) levels were assessed, liver function indices and oxidative and inflammatory markers were determined, and histopathological examinations were performed. Mechanistic investigations were conducted using RT-qPCR assays and immunohistochemical analysis to determine the protective effects of DBJ. The samples (DBJ-1, DBJ-2, and DBJ-3) were obtained by extracting DBJ with water, 50% ethanol, and 95% ethanol, yielding total saponin contents of 5.35%, 6.64%, and 11.83%, respectively. DBJ-3 was isolated and purified, and its components were identified by Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). DBJ-3 had the greatest effect on cell viability in an ethanol environment. Moreover, DBJ-3 reduced inflammatory infiltration, liver cell degeneration, and hemorrhage, while increasing ADH and ALDH levels in liver tissues. Additionally, DBJ-3 considerably decreased the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), and triglyceride (TG) levels. DBJ-3 reduced malondialdehyde (MDA), reactive oxygen species (ROS), and inflammatory factors, such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin 6 (IL-6), while increasing superoxide dismutase (SOD) and glutathione S-transferase (GST) activities. Furthermore, DBJ-3 significantly increased alcohol dehydrogenase 1b (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) expression at the gene and protein levels within alcohol metabolism pathways and reduced the nuclear factor kappa-B (NF-κB) gene and protein levels. These findings suggest that DBJ-3 can prevent AALI by enhancing alcohol metabolism via the regulation of ADH1B and ALDH2 and the modulation of the NF-κB pathway to improve antioxidant and anti-inflammatory effects.
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Affiliation(s)
- Niantong Xia
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Hongwei Xue
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Yihang Li
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Jinghong 666100, China;
| | - Jia Liu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Yang Lou
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Shuyang Li
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Yutian Wang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Juan Lu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Xi Chen
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Jinghong 666100, China;
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Chaudhry H, Sohal A, Iqbal H, Roytman M. Alcohol-related hepatitis: A review article. World J Gastroenterol 2023; 29:2551-2570. [PMID: 37213401 PMCID: PMC10198060 DOI: 10.3748/wjg.v29.i17.2551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/10/2023] [Accepted: 04/13/2023] [Indexed: 05/23/2023] Open
Abstract
Alcohol-related hepatitis (ARH) is a unique type of alcohol-associated liver disease characterized by acute liver inflammation caused by significant alcohol use. It ranges in severity from mild to severe and carries significant morbidity and mortality. The refinement of scoring systems has enhanced prognostication and guidance of clinical decision-making in the treatment of this complex disease. Although treatment focuses on supportive care, steroids have shown benefit in select circumstances. There has been a recent interest in this disease process, as coronavirus disease 2019 pandemic led to substantial rise in cases. Although much is known regarding the pathogenesis, prognosis remains grim due to limited treatment options. This article summarizes the epidemiology, genetics, pathogenesis, diagnosis and treatment of ARH.
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Affiliation(s)
- Hunza Chaudhry
- Department of Internal Medicine, University of California, San Francisco, Fresno, CA 93701, United States
| | - Aalam Sohal
- Department of Hepatology, Liver Institute Northwest, Seattle, WA 98105, United States
| | - Humzah Iqbal
- Department of Internal Medicine, University of California, San Francisco, Fresno, CA 93701, United States
| | - Marina Roytman
- Department of Gastroenterology and Hepatology, University of California, San Francisco, Fresno, CA 93701, United States
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Xu R, He L, Vatsalya V, Ma X, Kim S, Mueller EG, Feng W, McClain CJ, Zhang X. Metabolomics analysis of urine from patients with alcohol-associated liver disease reveals dysregulated caffeine metabolism. Am J Physiol Gastrointest Liver Physiol 2023; 324:G142-G154. [PMID: 36513601 PMCID: PMC9870580 DOI: 10.1152/ajpgi.00228.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/28/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022]
Abstract
Excess alcohol intake causes millions of deaths annually worldwide. Asymptomatic early-stage, alcohol-associated liver disease (ALD) is easily overlooked, and ALD is usually only diagnosed in more advanced stages. We explored the possibility of using polar urine metabolites as biomarkers of ALD for early-stage diagnosis and functional assessment of disease severity by quantifying the abundance of polar metabolites in the urine samples of healthy controls (n = 18), patients with mild or moderate liver injury (n = 21), and patients with severe alcohol-associated hepatitis (n = 25). The polar metabolites in human urine were first analyzed by untargeted metabolomics, showing that 209 urine metabolites are significantly changed in patients, and 17 of these are highly correlated with patients' model for end-stage liver disease (MELD) score. Pathway enrichment analysis reveals that the caffeine metabolic pathway is the most affected in ALD. We then developed a targeted metabolomics method and measured the concentration of caffeine and its metabolites in urine using internal and external standard calibration, respectively. The described method can quantify caffeine and its 14 metabolites in 35 min. The results of targeted metabolomics analysis agree with the results of untargeted metabolomics, showing that 13 caffeine metabolites are significantly decreased in patients. In particular, the concentrations of 1-methylxanthine, paraxanthine, and 5-acetylamino-6-amino-3-methyluracil are markedly decreased with increased disease severity. We suggest that these three metabolites could serve as functional biomarkers for differentiating early-stage ALD from more advanced liver injury.NEW & NOTEWORTHY Our study using both untargeted and targeted metabolomics reveals the caffeine metabolic pathway is dysregulated in ALD. Three caffeine metabolites, 1-methylxanthine, paraxanthine, and 5-acetylamino-6-amino-3-methyluracil, can differentiate the severity of early-stage ALD.
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Affiliation(s)
- Raobo Xu
- Department of Chemistry, University of Louisville, Louisville, Kentucky
- Alcohol Research Center, University of Louisville School of Medicine, Louisville, Kentucky
- Hepatobiology and Toxicology Center of Biomedical Research Excellence, University of Louisville School of Medicine Louisville, Louisville, Kentucky
- Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, Kentucky
| | - Liqing He
- Department of Chemistry, University of Louisville, Louisville, Kentucky
- Alcohol Research Center, University of Louisville School of Medicine, Louisville, Kentucky
- Hepatobiology and Toxicology Center of Biomedical Research Excellence, University of Louisville School of Medicine Louisville, Louisville, Kentucky
- Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, Kentucky
| | - Vatsalya Vatsalya
- Alcohol Research Center, University of Louisville School of Medicine, Louisville, Kentucky
- Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Xipeng Ma
- Department of Chemistry, University of Louisville, Louisville, Kentucky
- Alcohol Research Center, University of Louisville School of Medicine, Louisville, Kentucky
- Hepatobiology and Toxicology Center of Biomedical Research Excellence, University of Louisville School of Medicine Louisville, Louisville, Kentucky
- Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, Kentucky
| | - Seongho Kim
- Department of Oncology, Wayne State University, Detroit, Michigan
- Biostatistics and Bioinformatics Core, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Eugene G Mueller
- Department of Chemistry, University of Louisville, Louisville, Kentucky
| | - Wenke Feng
- Alcohol Research Center, University of Louisville School of Medicine, Louisville, Kentucky
- Hepatobiology and Toxicology Center of Biomedical Research Excellence, University of Louisville School of Medicine Louisville, Louisville, Kentucky
- Department of Medicine, University of Louisville, Louisville, Kentucky
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky
| | - Craig J McClain
- Alcohol Research Center, University of Louisville School of Medicine, Louisville, Kentucky
- Hepatobiology and Toxicology Center of Biomedical Research Excellence, University of Louisville School of Medicine Louisville, Louisville, Kentucky
- Department of Medicine, University of Louisville, Louisville, Kentucky
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky
- Robley Rex Louisville Veterans Affairs Medical Center, Louisville, Kentucky
| | - Xiang Zhang
- Department of Chemistry, University of Louisville, Louisville, Kentucky
- Alcohol Research Center, University of Louisville School of Medicine, Louisville, Kentucky
- Hepatobiology and Toxicology Center of Biomedical Research Excellence, University of Louisville School of Medicine Louisville, Louisville, Kentucky
- Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, Kentucky
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky
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Mazzarella C, Spina A, Dallio M, Gravina AG, Romeo M, DI Mauro M, Loguercio C, Federico A. The analysis of alcohol consumption during the severe acute respiratory syndrome Coronavirus 2 Italian lockdown. Minerva Med 2022; 113:927-935. [PMID: 33949179 DOI: 10.23736/s0026-4806.21.07354-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND The SARS-CoV-2 lockdown resulted in deep changes of lifestyles, promoting in many people the onset of psychological symptoms generally associated with drug and alcohol abuse. The aim of this study was to assess the variation of alcohol drinking habits in a sample of Italian citizens during lockdown and to identify the psychosocial factors surrounding it. METHODS An online anonymous questionnaire was created and submitted from April 9 to April 28, 2020. Questions were related to personal psychosocial details and alcohol drinking habits during the lockdown, including Alcohol Use Disorders Identification Test (AUDIT C) questions. RESULTS On a total of 1234 surveys the increase of both anxiety and fear was largely detected (63% and 61% respectively). The 18% increased alcohol consumption during the lockdown and it showed a significant correlation with anxiety and fear experienced (both P<0.001). The relative risk for 7 to 9 and more than 10 drinks per day consumption were directly linked to these symptoms (P<0.001). The most involved categories of participants showed this harmful association were self-employed workers and participants who live alone, subject aged 30-50 with high level of instruction or students, and not occupied people in the age range 18-19 (all P<0.001). Additionally, the subset of the study population that showed low alcohol consumption before the lockdown has demonstrated the worsening of alcohol assumption during the quarantine (P<0.0001). CONCLUSIONS Several psychosocial factors are involved in determining the increase of alcohol consumption during lockdown and need the healthcare support to avoid awful impact on human life.
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Affiliation(s)
- Chiara Mazzarella
- Division of Hepatogastroenterology, Department of Precision Medicine, Luigi Vanvitelli University of Campania, Naples, Italy
| | - Annamaria Spina
- Division of Hepatogastroenterology, Department of Precision Medicine, Luigi Vanvitelli University of Campania, Naples, Italy
| | - Marcello Dallio
- Division of Hepatogastroenterology, Department of Precision Medicine, Luigi Vanvitelli University of Campania, Naples, Italy -
| | - Antonietta G Gravina
- Division of Hepatogastroenterology, Department of Precision Medicine, Luigi Vanvitelli University of Campania, Naples, Italy
| | - Mario Romeo
- Division of Hepatogastroenterology, Department of Precision Medicine, Luigi Vanvitelli University of Campania, Naples, Italy
| | | | - Carmelina Loguercio
- Division of Hepatogastroenterology, Department of Precision Medicine, Luigi Vanvitelli University of Campania, Naples, Italy
| | - Alessandro Federico
- Division of Hepatogastroenterology, Department of Precision Medicine, Luigi Vanvitelli University of Campania, Naples, Italy
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Centranthera grandiflore alleviates alcohol-induced oxidative stress and cell apoptosis. Chin J Nat Med 2022; 20:572-579. [DOI: 10.1016/s1875-5364(22)60181-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Indexed: 11/17/2022]
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Sangineto M, Grander C, Grabherr F, Mayr L, Enrich B, Schwärzler J, Dallio M, Bukke VN, Moola A, Moschetta A, Adolph TE, Sabbà C, Serviddio G, Tilg H. Recovery of Bacteroides thetaiotaomicron ameliorates hepatic steatosis in experimental alcohol-related liver disease. Gut Microbes 2022; 14:2089006. [PMID: 35786161 PMCID: PMC9255095 DOI: 10.1080/19490976.2022.2089006] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 06/06/2022] [Indexed: 02/04/2023] Open
Abstract
Alcohol-related liver disease (ALD) is a major cause of liver disease and represents a global burden, as treatment options are scarce. Whereas 90% of ethanol abusers develop alcoholic fatty liver disease (AFLD), only a minority evolves to steatohepatitis and cirrhosis. Alcohol increases lipogenesis and suppresses lipid-oxidation implying steatosis, although the key role of intestinal barrier integrity and microbiota in ALD has recently emerged. Bacteroides thetaiotaomicron (Bt) is a prominent member of human and murine intestinal microbiota, and plays important functions in metabolism, gut immunity, and mucosal barrier. We aimed to investigate the role of Bt in the genesis of ethanol-induced liver steatosis. Bt DNA was measured in feces of wild-type mice receiving a Lieber-DeCarli diet supplemented with an increase in alcohol concentration. In a second step, ethanol-fed mice were orally treated with living Bt, followed by analysis of intestinal homeostasis and histological and biochemical alterations in the liver. Alcohol feeding reduced Bt abundance, which was preserved by Bt oral supplementation. Bt-treated mice displayed lower hepatic steatosis and triglyceride content. Bt restored mucosal barrier and reduced LPS translocation by enhancing mucus thickness and production of Mucin2. Furthermore, Bt up-regulated Glucagon-like peptide-1 (GLP-1) expression and restored ethanol-induced Fibroblast growth factor 15 (FGF15) down-regulation. Lipid metabolism was consequently affected as Bt administration reduced fatty acid synthesis (FA) and improved FA oxidation and lipid exportation. Moreover, treatment with Bt preserved the mitochondrial fitness and redox state in alcohol-fed mice. In conclusion, recovery of ethanol-induced Bt depletion by oral supplementation was associated with restored intestinal homeostasis and ameliorated experimental ALD. Bt could serve as a novel probiotic to treat ALD in the future.
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Affiliation(s)
- Moris Sangineto
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
- C.U.R.E. (University Center for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Lisa Mayr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Barbara Enrich
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Marcello Dallio
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Vidyasagar Naik Bukke
- C.U.R.E. (University Center for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Archana Moola
- C.U.R.E. (University Center for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari, Bari, Italy
| | - Timon E. Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Carlo Sabbà
- Department of Interdisciplinary Medicine, University of Bari, Bari, Italy
| | - Gaetano Serviddio
- C.U.R.E. (University Center for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
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Kim HG, Cho JH, Kim J, Kim SJ. The Role of Epigenetic Changes in the Progression of Alcoholic Steatohepatitis. Front Physiol 2021; 12:691738. [PMID: 34335299 PMCID: PMC8323660 DOI: 10.3389/fphys.2021.691738] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022] Open
Abstract
Alcoholic steatohepatitis (ASH) is a progression hepatitis with severe fatty liver and its mortality rate for 30-days in patients are over 30%. Additionally, ASH is well known for one-fifth all alcoholic related liver diseases in the world. Excessive chronic alcohol consumption is one of the most common causes of the progression of ASH and is associated with poor prognosis and liver failure. Alcohol abuse dysregulates the lipid homeostasis and causes oxidative stress and inflammation in the liver. Consequently, metabolic pathways stimulating hepatic accumulation of excessive lipid droplets are induced. Recently, many studies have indicated a link between ASH and epigenetic changes, showing differential expression of alcohol-induced epigenetic genes in the liver. However, the specific mechanisms underlying the pathogenesis of ASH remain elusive. Thus, we here summarize the current knowledge about the roles of epigenetics in lipogenesis, inflammation, and apoptosis in the context of ASH pathophysiology. Especially, we highlight the latest findings on the roles of Sirtuins, a conserved family of class-III histone deacetylases, in ASH. Additionally, we discuss the involvement of DNA methylation, histone modifications, and miRNAs in ASH as well as the ongoing efforts for the clinical translation of the findings in ASH-related epigenetic changes.
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Affiliation(s)
- Hyeong Geug Kim
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Jung-Hyo Cho
- Department of East & West Cancer Center, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon, South Korea
| | - Jeongkyu Kim
- Department of Life Science, Chung-Ang University, Seoul, South Korea
| | - Seung-Jin Kim
- Kangwon Institute of Inclusive Technology, Kangwon National University, Chuncheon, South Korea
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Abdelhamid AM, Elsheakh AR, Suddek GM, Abdelaziz RR. Telmisartan alleviates alcohol-induced liver injury by activation of PPAR-γ/ Nrf-2 crosstalk in mice. Int Immunopharmacol 2021; 99:107963. [PMID: 34273638 DOI: 10.1016/j.intimp.2021.107963] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/01/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023]
Abstract
Excessive consumption of alcohol may induce severe liver damage, in part via oxidative stress and inflammatory responses, which implicates these processes as potential therapeutic approaches. Prior literature has shown that Telmisartan (TEL) may provide protective effects, presumably mediated by its anti-oxidant and anti-inflammatory activities. The purpose of this study was to determine TEL's hepatoprotective effects and to identify its possible curative mechanisms in alcoholic liver disease. A mouse chronic alcohol plus binge feedings model was used in the current study for induction of alcoholic liver disease (ALD). Our results showed that TEL (10 mg/kg/day) has the ability to reduce serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). TEL also increased the activity of superoxide dismutase (SOD) and glutathione (GSH) with concomitant reduction of nitric oxide (NO) malonaldehyde (MDA) in the liver homogenate. Moreover, TEL downregulated nuclear factor kappa B (NF-κB) expression and decreased liver content of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α). These anti-inflammatory and anti-oxidant activities were associated with a significant increase in the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), peroxisome proliferator-activated receptors -γ (PPAR-γ), and heme oxygenase-1 (Hmox-1). In conclusion, TEL's hepatoprotective effects against ALD may be attributable to its anti-inflammatory and anti-oxidant activities which may be in part via the modulation of PPAR-γ/ Nrf-2/ NF-κB crosstalk.
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Affiliation(s)
- Amir Mohamed Abdelhamid
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Egypt; Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Egypt
| | - Ahmed Ramadan Elsheakh
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Egypt
| | - Ghada Mohamed Suddek
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Egypt
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Aqueous Mulberry Leaf Extract Ameliorates Alcoholic Liver Injury Associating with Upregulation of Ethanol Metabolism and Suppression of Hepatic Lipogenesis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6658422. [PMID: 34035824 PMCID: PMC8124008 DOI: 10.1155/2021/6658422] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 04/28/2021] [Indexed: 12/20/2022]
Abstract
Excessive alcohol intake is a major cause of chronic liver damage and is highly associated with the development of a spectrum of hepatic disorders, including steatohepatitis, liver cirrhosis, and liver cancer. Thus, we aimed to explore the hepatoprotective effects of an aqueous mulberry leaf extract (AME) on alcoholic fatty liver disorder (AFLD) by using a mouse model fed with excessive ethanol. Compared with the normal diet, the ethanol diet significantly increased the body weight of the mice, while the AME supplement reduced the weight gain caused by the ethanol diet. The ethanol diet also attenuated the activity of alcohol dehydrogenase and antioxidant enzymes but increased lipid peroxidation in the liver, which were reversed by AME supplementation. Additionally, AME supplementation diminished the ethanol diet-induced hepatic leukocyte infiltration and expressions of IL-6 and TNFα. Moreover, AME supplementation also reduced the ethanol-diet-induced lipid accumulation and expression of 1-acylglycerol-3-phosphate acyltransferase, acetyl-CoA carboxylase, low-density lipoprotein receptor, and sterol regulatory element-binding protein-1/2 in the liver. Collectively, AME supplementation improved liver lipid accumulation and proinflammatory response in mice induced by the ethanol diet, which was associated with the upregulation of ethanol-metabolizing enzymes and the downregulation of lipogenesis components.
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Tighe SP, Akhtar D, Iqbal U, Ahmed A. Chronic Liver Disease and Silymarin: A Biochemical and Clinical Review. J Clin Transl Hepatol 2020; 8:454-458. [PMID: 33447529 PMCID: PMC7782115 DOI: 10.14218/jcth.2020.00012] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/20/2020] [Accepted: 09/08/2020] [Indexed: 02/07/2023] Open
Abstract
Chronic liver disease (CLD) is an under-recognized epidemic that continues to increase in prevalence and is a major health concern. Silymarin, the active compound of Silybum marianum (Milk thistle), has historically been used in CLD. A significant barrier to silymarin use is its poor bioavailability. Attempts at improving the bioavailability of silymarin have led to a better understanding of formulation methods, pharmacokinetics, dosing, and associated drug interactions. Clinically, silymarin exerts its hepatoprotective effects through antioxidative, antifibrotic, anti-inflammatory, antitoxin, and anticancerous mechanisms of actions. Despite the use of silymarin being extensively studied in alcoholic liver disease, metabolic-associated fatty liver disease, viral hepatitis, and drug-induced liver injury, the overall efficacy of silymarin remains unclear and more research is warranted to better elucidate the role of silymarin in CLD, specifically regarding its anti-inflammatory effects. Here, we review the current biochemical and clinical evidence regarding silymarin in CLD.
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Affiliation(s)
- Sean P. Tighe
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Daud Akhtar
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Umair Iqbal
- Department of Gastroenterology and Hepatology, Geisinger Commonwealth School of Medicine, Danville, PA, USA
- *Correspondence to: Umair Iqbal, Department of Gastroenterology and Hepatology, Geisinger Commonwealth School of Medicine, Danville, PA 17821, USA. Tel: +1-570-271-6211, E-mail:
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
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12
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Abdelhamid AM, Elsheakh AR, Abdelaziz RR, Suddek GM. Empagliflozin ameliorates ethanol-induced liver injury by modulating NF-κB/Nrf-2/PPAR-γ interplay in mice. Life Sci 2020; 256:117908. [PMID: 32512011 DOI: 10.1016/j.lfs.2020.117908] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/25/2020] [Accepted: 06/01/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Excessive alcohol intake contributes to severe liver damage involving oxidative stress and inflammatory responses, which make them promising therapeutic targets. Previous studies have demonstrated that empagliflozin (EMPA) showed cardiovascular, renal, and cerebral benefits potentially mediated through its antioxidant and anti-inflammatory actions. AIMS This experiment aimed to evaluate the hepatoprotective effect of EMPA on alcoholic liver disease (ALD) and the possible underlying mechanisms. MATERIALS AND METHODS Serum biochemical parameters and the liver contents of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Real-time qPCR was conducted to determine the gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (Hmox-1). In addition, ELISA was performed to measure tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, Nrf-2, and PPAR-γ. Nuclear factor-kappa B (NF-κB) was detected by immunohistochemical staining using an anti-NF-κB p65 antibody. KEY FINDINGS Our results revealed that the serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were significantly reduced by EMPA. EMPA also decreased the content of MDA and NO and increased the activities of SOD and GSH in liver homogenates. Moreover, EMPA inhibited the release of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, via the downregulation of NF-κB. These changes were associated with an improvement in histopathological deterioration. The protective effect of EMPA against oxidative stress and inflammation was associated with the upregulation of PPAR-γ, Nrf-2, and their target gene Hmox-1. SIGNIFICANCE EMPA showed protective activities against ethanol-induced liver injury by suppressing inflammation and oxidative stress via modulation of the NF-κB/Nrf-2/PPAR-γ axis.
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Affiliation(s)
- Amir Mohamed Abdelhamid
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science & Technology, Egypt.
| | - Ahmed Ramadan Elsheakh
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Egypt
| | | | - Ghada Mohamed Suddek
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Egypt
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Empagliflozin ameliorates ethanol-induced liver injury by modulating NF-κB/Nrf-2/PPAR-γ interplay in mice. Life Sci 2020. [DOI: 10.1016/j.lfs.2020.117908
expr 913773998 + 879574250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
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14
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Scarpellini E, Fagoonee S, Rinninella E, Rasetti C, Aquila I, Larussa T, Ricci P, Luzza F, Abenavoli L. Gut Microbiota and Liver Interaction through Immune System Cross-Talk: A Comprehensive Review at the Time of the SARS-CoV-2 Pandemic. J Clin Med 2020; 9:2488. [PMID: 32756323 PMCID: PMC7464500 DOI: 10.3390/jcm9082488] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/23/2020] [Accepted: 07/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIMS The gut microbiota is a complex ecosystem containing bacteria, viruses, fungi, yeasts and other single-celled organisms. It is involved in the development and maintenance of both innate and systemic immunity of the body. Emerging evidence has shown its role in liver diseases through the immune system cross-talk. We review herein literature data regarding the triangular interaction between gut microbiota, immune system and liver in health and disease. METHODS We conducted a search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials and case series using the following keywords and acronyms and their associations: gut microbiota, microbiome, gut virome, immunity, gastrointestinal-associated lymphoid tissue (GALT), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steato-hepatitis (NASH), alcoholic liver disease, liver cirrhosis, hepatocellular carcinoma. RESULTS The gut microbiota consists of microorganisms that educate our systemic immunity through GALT and non-GALT interactions. The latter maintain health but are also involved in the pathophysiology and in the outcome of several liver diseases, particularly those with metabolic, toxic or immune-mediated etiology. In this context, gut virome has an emerging role in liver diseases and needs to be further investigated, especially due to the link reported between severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and hepatic dysfunctions. CONCLUSIONS Changes in gut microbiota composition and alterations in the immune system response are involved in the pathogenesis of metabolic and immune-mediated liver diseases.
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Affiliation(s)
- Emidio Scarpellini
- Internal Medicine Unit, “Madonna del Soccorso” General Hospital, San Benedetto del, 63074 Tronto, Italy;
- Department of Biomedical Sciences, KU Leuven, Gasthuisberg University Hospital, TARGID, 3000 Leuven, Belgium
| | - Sharmila Fagoonee
- Institute for Biostructure and Bioimaging, National Research Council, Molecular Biotechnology Center, 10121 Turin, Italy;
| | - Emanuele Rinninella
- Nephrology and Urology Department, Gastroenterology, Endocrinology, Fondazione Policlinico A, Clinical Nutrition Unit, Gemelli IRCCS, 00168 Rome, Italy;
- Institute of Medical Pathology, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Carlo Rasetti
- Internal Medicine Unit, “Madonna del Soccorso” General Hospital, San Benedetto del, 63074 Tronto, Italy;
| | - Isabella Aquila
- Institute of Legal Medicine and Department of Surgical and Medical Sciences, University “Magna Graecia” of Catanzaro (UMG), 88100 Viale Europa, Italy; (I.A.); (P.R.)
| | - Tiziana Larussa
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
| | - Pietrantonio Ricci
- Institute of Legal Medicine and Department of Surgical and Medical Sciences, University “Magna Graecia” of Catanzaro (UMG), 88100 Viale Europa, Italy; (I.A.); (P.R.)
| | - Francesco Luzza
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
| | - Ludovico Abenavoli
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
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15
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Wang XK, Liao XW, Yang CK, Liu ZQ, Han QF, Zhou X, Zhang LB, Deng T, Gong YZ, Huang JL, Huang R, Han CY, Yu TD, Su H, Ye XP, Peng T, Zhu GZ. Oncogene PLCE1 may be a diagnostic biomarker and prognostic biomarker by influencing cell cycle, proliferation, migration, and invasion ability in hepatocellular carcinoma cell lines. J Cell Physiol 2020; 235:7003-7017. [PMID: 32037547 DOI: 10.1002/jcp.29596] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 01/09/2020] [Indexed: 12/21/2022]
Abstract
Hepatocellular carcinoma (HCC) is a lethal malignancy worldwide. HCC has traits of late diagnosis and high recurrence. This study explored potential diagnosis and prognosis significance of phospholipase C epsilon 1 (PLCE1) in HCC. The messenger RNA (mRNA) levels and diagnostic value of PLCE1 were determined by real-time polymerase chain reaction and online databases GEPIA, oncomine, and GSE14520 data set. Survival analysis used the Kaplan-Meier Plotter website. Cell cycle, proliferation, migration, and invasion assays were performed with downregulated PLCE1 expression in HCC-M and HepG2 cell lines. PLCE1 was differentially expressed and highly expressed in tumors and had low expression in nontumor tissues (all p < .05). The diagnostic value of PLCE1 was validated with the datasets (all p < .01, all areas under curves > 0.7). PLCE1 mRNA expression was associated with the overall and relapse-free survival (both p < .05). Functional experiments indicated that downregulation of PLCE1 expression led to increased G1 stage in cell cycle and decreased cell proliferation, migration, and invasion compared with a negative control group (all p ≤ .05). The oncogene PLCE1 was differentially expressed in HCC and non-HCC tissues. It is a candidate for diagnosis and serves as prognosis biomarker. PLCE1 influenced survival by affecting the cell cycle, proliferation, migration, and invasion ability.
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Affiliation(s)
- Xiang-Kun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Cheng-Kun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zheng-Qian Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Quan-Fa Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Lin-Bo Zhang
- Department of Health Management and Division of Physical Examination, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Teng Deng
- Department of Neurosurgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yi-Zhen Gong
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jian-Lu Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.,Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Rui Huang
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Chuang-Ye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Ting-Dong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Hao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xin-Ping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Guang-Zhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
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16
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Yu L, Xu F, Gao L. Predict New Therapeutic Drugs for Hepatocellular Carcinoma Based on Gene Mutation and Expression. Front Bioeng Biotechnol 2020; 8:8. [PMID: 32047745 PMCID: PMC6997129 DOI: 10.3389/fbioe.2020.00008] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 01/07/2020] [Indexed: 02/01/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common primary liver tumor and is an important medical problem worldwide. However, the use of current therapies for HCC is no possible to be cured, and despite numerous attempts and clinical trials, there are not so many approved targeted treatments for HCC. So, it is necessary to identify additional treatment strategies to prevent the growth of HCC tumors. We are looking for a systematic drug repositioning bioinformatics method to identify new drug candidates for the treatment of HCC, which considers not only aberrant genomic information, but also the changes of transcriptional landscapes. First, we screen the collection of HCC feature genes, i.e., kernel genes, which frequently mutated in most samples of HCC based on human mutation data. Then, the gene expression data of HCC in TCGA are combined to classify the kernel genes of HCC. Finally, the therapeutic score (TS) of each drug is calculated based on the kolmogorov-smirnov statistical method. Using this strategy, we identify five drugs that associated with HCC, including three drugs that could treat HCC and two drugs that might have side-effect on HCC. In addition, we also make Connectivity Map (CMap) profiles similarity analysis and KEGG enrichment analysis on drug targets. All these findings suggest that our approach is effective for accurate predicting novel therapeutic options for HCC and easily to be extended to other tumors.
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Affiliation(s)
- Liang Yu
- School of Computer Science and Technology, Xidian University, Xi'an, China
| | - Fengdan Xu
- School of Computer Science and Technology, Xidian University, Xi'an, China
| | - Lin Gao
- School of Computer Science and Technology, Xidian University, Xi'an, China
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17
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Mediterranean diet: the role of antioxidants in liver disease. Pathology 2020. [DOI: 10.1016/b978-0-12-815972-9.00025-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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18
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Affiliation(s)
- Ludovico Abenavoli
- Department of Health Sciences, University "Magna Graecia" Viale Europa, 88100, Catanzaro, Italy
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19
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Evaluation of AGP Fucosylation as a Marker for Hepatocellular Carcinoma of Three Different Etiologies. Sci Rep 2019; 9:11580. [PMID: 31399619 PMCID: PMC6689003 DOI: 10.1038/s41598-019-48043-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 07/26/2019] [Indexed: 02/08/2023] Open
Abstract
A mass spectrometric analysis platform has been developed to determine whether glycosylation patterns of alpha-1 acid glycoprotein (AGP) could be used as a marker for early detection of hepatocellular carcinoma (HCC) in different etiologies, i.e. non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALC), and hepatitis C virus (HCV). MALDI-MS profiling of N-glycans of AGP purified from 20 μL of patient serum in HCC (n = 72) and liver cirrhosis (n = 58) showed that a unique trifucosylated tetra-antennary glycan (m/z 3490.76) was predominantly identified in HCCs but was absent in healthy subjects and the majority of cirrhosis patients. Receiver operation characteristic (ROC) curve analysis showed that the trifucosylated N-glycan of AGP (triFc_AGP) could differentiate HCC from cirrhosis with an area under the curve (AUC) of 0.707, 0.726 and 0.751 for NASH, ALC and HCV, respectively. When combining triFc_AGP with INR and AFP, the panel had the greatest benefit in detection of NASH-related HCCs, with a significantly improved AUC of 0.882 for all NASH HCCs and 0.818 for early NASH HCCs compared to AFP alone (0.761 and 0.641, respectively). Moreover, triFc_AGP could serve as a potential marker for monitoring AFP-negative HCC patients.
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20
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Kong LZ, Chandimali N, Han YH, Lee DH, Kim JS, Kim SU, Kim TD, Jeong DK, Sun HN, Lee DS, Kwon T. Pathogenesis, Early Diagnosis, and Therapeutic Management of Alcoholic Liver Disease. Int J Mol Sci 2019; 20:ijms20112712. [PMID: 31159489 PMCID: PMC6600448 DOI: 10.3390/ijms20112712] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/30/2019] [Accepted: 05/31/2019] [Indexed: 02/08/2023] Open
Abstract
Alcoholic liver disease (ALD) refers to the damages to the liver and its functions due to alcohol overconsumption. It consists of fatty liver/steatosis, alcoholic hepatitis, steatohepatitis, chronic hepatitis with liver fibrosis or cirrhosis, and hepatocellular carcinoma. However, the mechanisms behind the pathogenesis of alcoholic liver disease are extremely complicated due to the involvement of immune cells, adipose tissues, and genetic diversity. Clinically, the diagnosis of ALD is not yet well developed. Therefore, the number of patients in advanced stages has increased due to the failure of proper early detection and treatment. At present, abstinence and nutritional therapy remain the conventional therapeutic interventions for ALD. Moreover, the therapies which target the TNF receptor superfamily, hormones, antioxidant signals, and MicroRNAs are used as treatments for ALD. In particular, mesenchymal stem cells (MSCs) are gaining attention as a potential therapeutic target of ALD. Therefore, in this review, we have summarized the current understandings of the pathogenesis and diagnosis of ALD. Moreover, we also discuss the various existing treatment strategies while focusing on promising therapeutic approaches for ALD.
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Affiliation(s)
- Ling-Zu Kong
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Advanced Convergence Technology and Science, Jeju National University, Jeju 63243, Korea.
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
| | - Nisansala Chandimali
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Advanced Convergence Technology and Science, Jeju National University, Jeju 63243, Korea.
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
| | - Ying-Hao Han
- Department of Disease Model Animal Research Center, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China.
| | - Dong-Ho Lee
- Primate Resources Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-si, Jeonbuk 56216, Korea.
| | - Ji-Su Kim
- Primate Resources Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-si, Jeonbuk 56216, Korea.
| | - Sun-Uk Kim
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju-si, Chungcheongbuk-do 28116, Korea.
| | - Tae-Don Kim
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
| | - Dong Kee Jeong
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Advanced Convergence Technology and Science, Jeju National University, Jeju 63243, Korea.
- Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea.
| | - Hu-Nan Sun
- Department of Disease Model Animal Research Center, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China.
- Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea.
| | - Dong Sun Lee
- Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea.
- Department of Biotechnology, College of Applied Life Science, Jeju National University, Jeju 63243, Korea.
| | - Taeho Kwon
- Primate Resources Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-si, Jeonbuk 56216, Korea.
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21
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Ružić M, Pellicano R, Fabri M, Luzza F, Boccuto L, Brkić S, Abenavoli L. Hepatitis C virus-induced hepatocellular carcinoma: a narrative review. Panminerva Med 2018; 60:185-191. [PMID: 29856183 DOI: 10.23736/s0031-0808.18.03472-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver carcinoma, accounting for about 80% of cases. In spite of advances in modern oncology, this neoplasia still holds the second place in overall cancer mortality. HCC is a multifactor disease: it results from accumulated oncogenic potentials made up of several groups of risk factors, the most significant of which is an infection with hepatotropic viruses. The hepatitis C virus (HCV) is one of the primary causes of morbidity and mortality across the world and affects 1.1% of worldwide population. It has been calculated that on average 2.5% of patients affected by chronic HCV infection develops HCC. Hepatocarcinogenesis is the result of the combination of superposing virus specific factors, immunological mechanisms, environmental factors and factors related to the individuals genetic background. Host-related factors include male gender, age of at least 50 years, family predisposition, obesity, advanced liver fibrosis or cirrhosis and coinfection with other hepatotropic viruses and human immunodeficiency virus. Environmental factors include heavy alcohol abuse, cigarette smoking, and exposure to aflatoxin. In the era of interferon (IFN)-based therapy, the risk of HCC development after established sustained virological response (SVR) was 1% yearly. Data reported in patients with SVR about the increase of HCC prevalence have appeared, after the initial enthusiasm on the efficacy of HCV direct acting antiviral drugs (DAA) protocols. Actually, these data are controversial, but they certainly suggest the need to undertake large, multicenter studies and caution in everyday clinical practice.
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Affiliation(s)
- Maja Ružić
- Clinic for Infectious Diseases, Clinical Centre of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | | | - Milotka Fabri
- Clinic for Infectious Diseases, Clinical Centre of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Francesco Luzza
- Department of Health Sciences, University "Magna Graecia", Catanzaro, Italy
| | - Luigi Boccuto
- Greenwood Genetic Center, Greenwood, SC, USA
- Clemson University School of Health Research, Clemson, SC, USA
| | - Snežana Brkić
- Clinic for Infectious Diseases, Clinical Centre of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Ludovico Abenavoli
- Department of Health Sciences, University "Magna Graecia", Catanzaro, Italy -
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22
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Abenavoli L, Izzo AA, Milić N, Cicala C, Santini A, Capasso R. Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phytother Res 2018; 32:2202-2213. [PMID: 30080294 DOI: 10.1002/ptr.6171] [Citation(s) in RCA: 253] [Impact Index Per Article: 36.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 07/06/2018] [Accepted: 07/09/2018] [Indexed: 12/17/2022]
Abstract
Milk thistle (MT; Silybum marianum), a member of the Asteraceae family, is a therapeutic herb with a 2,000-year history of use. MT fruits contain a mixture of flavonolignans collectively known as silymarin, being silybin (also named silibinin) the main component. This article reviews the chemistry of MT, the pharmacokinetics and bioavailability, the pharmacologically relevant actions for liver diseases (e.g., anti-inflammatory, immunomodulating, antifibrotic, antioxidant, and liver-regenerating properties) as well as the clinical potential in patients with alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, drug-induced liver injury, and mushroom poisoning. Overall, literature data suggest that, despite encouraging preclinical data, further well-designed randomized clinical trials are needed to fully substantiate the real value of MT preparations in liver diseases.
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Affiliation(s)
- Ludovico Abenavoli
- Department of Health Sciences, University Magna Graecia, Catanzaro, Italy
| | - Angelo A Izzo
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Natasa Milić
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Carla Cicala
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Antonello Santini
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Raffaele Capasso
- Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy
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23
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Savić Ž, Vračarić V, Milić N, Nićiforović D, Damjanov D, Pellicano R, Medić-Stojanoska M, Abenavoli L. Vitamin D supplementation in patients with alcoholic liver cirrhosis: a prospective study. Minerva Med 2018; 109:352-357. [PMID: 29963831 DOI: 10.23736/s0026-4806.18.05723-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The liver is involved in the metabolism of vitamin D. The prevalence of osteopenia in alcoholic liver disease (ALD) patients is 34-48%, and the prevalence of osteoporosis is 11-36%. Advanced liver disease is considered a risk factor for the development of osteoporosis. The aim of this study was to establish the relationship between vitamin D level and Child-Pugh score in patients with alcoholic liver cirrhosis (ALC), and to evaluate the effects of oral vitamin D supplementation. METHODS Seventy male ALC patients in the absence of active alcohol intake were enrolled and their clinical and laboratory data were recorded. A supplementation of cholecalciferol 1000 IU/day was administered. The vitamin D status was analyzed during the study, in patients stratified by Child-Pugh score. RESULTS The study was completed by fifty patients. At the enrollment, the mean level of vitamin D was 60.73±28.02, 50.53±39.52 and 26.71±12.81 nmol/L, respectively for Child-Pugh score class A, B and C. During vitamin D supplementation it was found in all the patients a significant increase of its levels during the first six months (P<0.05). However, in class C the improvement was consistent also after year (P<0.05). At the end of the study, two of seven patients initially in class C changed in class A, four from class C to B, and one remained in class C (P=0.012). Out of seventeen patients initially in class B, eleven changed to class A, and six remained in class B. CONCLUSIONS In patients with ALC, higher level of vitamin D level is related with lower Child-Pugh score. The supplementation of 1000 IU/day of vitamin D in these patients was optimal for a period of at least six months. A decrease in the Child-Pugh score was also found, with a redistribution of the patients in different classes.
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Affiliation(s)
- Željka Savić
- Clinic of Gastroenterology and Hepatology, Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Vladimir Vračarić
- Clinic of Gastroenterology and Hepatology, Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Nataša Milić
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Dijana Nićiforović
- Clinic of Radiology, Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Dragomir Damjanov
- Clinic of Gastroenterology and Hepatology, Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | | | - Milica Medić-Stojanoska
- Clinic for Endocrinology, Diabetes, and Metabolic Diseases, Clinical Center of Vojvodina, University of Novi Sad, Novi Sad, Serbia
| | - Ludovico Abenavoli
- Department of Health Sciences, Magna Græcia University, Catanzaro, Italy -
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24
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Jovel J, Lin Z, O'keefe S, Willows S, Wang W, Zhang G, Patterson J, Moctezuma-Velázquez C, Kelvin DJ, Ka-Shu Wong G, Mason AL. A Survey of Molecular Heterogeneity in Hepatocellular Carcinoma. Hepatol Commun 2018; 2:941-955. [PMID: 30094405 PMCID: PMC6078210 DOI: 10.1002/hep4.1197] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 04/11/2018] [Accepted: 04/17/2018] [Indexed: 12/24/2022] Open
Abstract
Understanding the heterogeneity of dysregulated pathways associated with the development of hepatocellular carcinoma (HCC) may provide prognostic and therapeutic avenues for disease management. As HCC involves a complex process of genetic and epigenetic modifications, we evaluated expression of both polyadenylated transcripts and microRNAs from HCC and liver samples derived from two cohorts of patients undergoing either partial hepatic resection or liver transplantation. Copy number variants were inferred from whole genome low‐pass sequencing data, and a set of 56 cancer‐related genes were screened using an oncology panel assay. HCC was associated with marked transcriptional deregulation of hundreds of protein‐coding genes. In the partially resected livers, diminished transcriptional activity was observed in genes associated with drug catabolism and increased expression in genes related to inflammatory responses and cell proliferation. Moreover, several long noncoding RNAs and microRNAs not previously linked with HCC were found to be deregulated. In liver transplant recipients, down‐regulation of genes involved in energy production and up‐regulation of genes associated with glycolysis were detected. Numerous copy number variants events were observed, with hotspots on chromosomes 1 and 17. Amplifications were more common than deletions and spanned regions containing genes potentially involved in tumorigenesis. Colony stimulating factor 1 receptor (CSF1R), fibroblast growth factor receptor 3 (FGFR3), fms‐like tyrosine kinase 3 (FLT3), nucleolar phosphoprotein B23 (NPM1), platelet‐derived growth factor receptor alpha polypeptide (PDGFRA), phosphatase and tensin homolog (PTEN), G‐protein‐coupled receptors‐like receptor Smoothened (SMO), and tumor protein P53 (TP53) were mutated in all tumors; another 26 cancer‐related genes were mutated with variable penetrance. Conclusion: Our results underscore the marked molecular heterogeneity between HCC tumors and reinforce the notion that precision medicine approaches are needed for management of individual HCC. These data will serve as a resource to generate hypotheses for further research to improve our understanding of HCC biology. (Hepatology Communications 2018; 00:000‐000)
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Affiliation(s)
- Juan Jovel
- Department of Medicine University of Alberta Edmonton Canada
| | - Zhen Lin
- Department of Medicine University of Alberta Edmonton Canada
| | - Sandra O'keefe
- Department of Medicine University of Alberta Edmonton Canada
| | - Steven Willows
- Department of Medicine University of Alberta Edmonton Canada
| | - Weiwei Wang
- Department of Medicine University of Alberta Edmonton Canada
| | - Guangzhi Zhang
- Department of Medicine University of Alberta Edmonton Canada
| | | | | | - David J Kelvin
- Division of Experimental Therapeutics University Health Network Toronto Canada
| | - Gane Ka-Shu Wong
- Department of Medicine University of Alberta Edmonton Canada.,Department of Biological Sciences University of Alberta Edmonton Canada.,BGI-Shenzhen Shenzhen China
| | - Andrew L Mason
- Department of Medicine University of Alberta Edmonton Canada
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25
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Abstract
Alcoholic liver disease (ALD) is a definition encompassing a spectrum of disorders ranging from simple steatosis to cirrhosis and hepatocellular carcinoma. Excessive alcohol consumption triggers a series of metabolic reactions that affect the liver by inducing lipogenesis, increasing oxidative stress, and causing abnormal inflammatory responses. The metabolic pathways regulating lipids, reactive oxygen species (ROS), and immune system are closely related and in some cases cross-regulate each other. Therefore, it must be taken into account that major genetic and epigenetic abnormalities affecting enzymes involved in one of such pathways can play a pivotal role in ALD pathogenesis. However, recent studies have pointed out how a significant predisposition can also be determined by minor variants, such as relatively common polymorphisms, epigenetic modifications, and microRNA abnormalities. Genetic and epigenetic factors can also affect the progression of liver diseases, promoting fibrogenesis, cirrhosis, and ultimately hepatocellular carcinoma. It is noteworthy that some of these factors, such as some of the cytokines involved in the abnormal inflammatory responses, are shared with non-alcoholic liver disease, while other factors are unique to ALD. The study of the genetic and epigenetic components involved in the liver damages caused by alcohol is crucial to identify individuals with high risk of developing ALD, design personalized protocols for prevention and/or treatment, and select the best molecular targets for new therapies.
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Affiliation(s)
- Luigi Boccuto
- Greenwood Genetic Center, Greenwood, SC, USA. Clemson University School of Health Research, Clemson, SC, USA
| | - Ludovico Abenavoli
- Department of Health Sciences, University "Magna Græcia", Catanzaro, Italy
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26
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Nutrition and Liver Disease. Nutrients 2017; 10:nu10010009. [PMID: 29295475 PMCID: PMC5793237 DOI: 10.3390/nu10010009] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 12/20/2017] [Accepted: 12/20/2017] [Indexed: 12/13/2022] Open
Abstract
Malnutrition in children and adults with advanced liver disease represents a tremendous challenge as the nutritional problems are multifactorial. This Editorial comments the articles appearing in this special issue of Nutrients, “Nutrition and Liver disease” dealing with multiple diagnostic and therapeutic features that relate the outcomes of liver disease to nutrition. To improve quality of life and prevent nutrition-related medical complications, patients diagnosed with advanced liver disease should have their nutritional status promptly assessed and be supported by appropriate dietary interventions. Furthermore specific food supplements and/or restriction diets are often necessary for those with hepatic conditions associated with an underlying metabolic or nutritional or intestinal disease.
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