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1
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Anouti A, Kerr TA, Mitchell MC, Cotter TG. Advances in the management of alcohol-associated liver disease. Gastroenterol Rep (Oxf) 2024; 12:goae097. [PMID: 39502523 PMCID: PMC11537353 DOI: 10.1093/gastro/goae097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 09/29/2024] [Accepted: 10/08/2024] [Indexed: 11/08/2024] Open
Abstract
Alcohol-associated liver disease (ALD) is a significant global health challenge, encompassing a spectrum from steatotic liver disease to cirrhosis and alcohol-associated hepatitis, and contributed to 25% of global cirrhosis deaths in 2019. The identification of both modifiable (e.g. heavy drinking, metabolic syndromes) and non-modifiable risk factors (e.g. genetic predispositions) is crucial for effective disease management. Alcohol use assessment and treatment, by using both behavioral therapy and pharmacotherapeutic modalities, nutrition support, and optimization of liver disease modifiers, form the cornerstone of management. Advances in medical therapies, such as fecal microbiota transplantation and novel agents such as IL-22, are being explored for their therapeutic potential. A unifying theme in ALD care is the need for a personalized approach to management, accounting for the spectrum of the disease and individual patient characteristics, to tailor interventions effectively. Finally, it is essential to address the challenges to effective ALD treatment, including socioeconomic, logistical, and stigma-related barriers, to improve patient outcomes. This review discusses the current knowledge on ALD, including epidemiology, pathophysiology, risk factors, and management strategies, highlighting the critical role of integrated care models.
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Affiliation(s)
- Ahmad Anouti
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Thomas A Kerr
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Mack C Mitchell
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Thomas G Cotter
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
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Baden KER, McClain H, Craig E, Gibson N, Draime JA, Chen AMH. S-Adenosylmethionine (SAMe) for Liver Health: A Systematic Review. Nutrients 2024; 16:3668. [PMID: 39519500 PMCID: PMC11547595 DOI: 10.3390/nu16213668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 10/24/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND/OBJECTIVES S-adenosylmethionine (SAMe) is a natural compound implicated in the treatment of liver dysfunction. In this systematic review, our objective was to determine the efficacy, safety, and optimal dose of SAMe in liver diseases. METHODS Using the PRISMA methodology, we searched PubMed, CINAHL, and Web of Science using key MeSH search terms. For title/abstract screening, full-text review, and data extraction, two independent researchers reviewed articles, and a third researcher resolved conflicts. Data extraction also included a quality assessment of included articles. RESULTS Of the 1881 non-duplicated studies, 15 articles focusing on SAMe use in the liver were included. All included studies (n = 15) scored a 4 or 5 out of 5 points on the quality assessment, which indicated high study quality. Overall, SAMe was effective in improving liver-related parameters with few adverse events, which were primarily mild, transient gastrointestinal complaints. CONCLUSIONS The most common doses were SAMe 1000 mg or 1200 mg per day with or without another treatment or natural supplement. Future studies are needed to assess long-term efficacy and safety data of SAMe and the optimal route of administration in liver diseases.
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Affiliation(s)
| | - Halley McClain
- School of Pharmacy, Cedarville University, Cedarville, OH 45314, USA
| | - Eliya Craig
- School of Pharmacy, Cedarville University, Cedarville, OH 45314, USA
| | - Nathan Gibson
- School of Pharmacy, Cedarville University, Cedarville, OH 45314, USA
| | - Juanita A Draime
- School of Pharmacy, Cedarville University, Cedarville, OH 45314, USA
| | - Aleda M H Chen
- School of Pharmacy, Cedarville University, Cedarville, OH 45314, USA
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Lai W, Zhang J, Sun J, Min T, Bai Y, He J, Cao H, Che Q, Guo J, Su Z. Oxidative stress in alcoholic liver disease, focusing on proteins, nucleic acids, and lipids: A review. Int J Biol Macromol 2024; 278:134809. [PMID: 39154692 DOI: 10.1016/j.ijbiomac.2024.134809] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 08/11/2024] [Accepted: 08/14/2024] [Indexed: 08/20/2024]
Abstract
Oxidative stress is one of the important factors in the development of alcoholic liver disease. The production of reactive oxygen species and other free radicals is an important feature of alcohol metabolism in the liver and an important substance in liver injury. When large amounts of ROS are produced, the homeostasis of the liver REDOX system will be disrupted and liver injury will be caused. Oxidative stress can damage proteins, nucleic acids and lipids, liver dysfunction. In addition, damaging factors produced by oxidative damage to liver tissue can induce the occurrence of inflammation, thereby aggravating the development of ALD. This article reviews the oxidative damage of alcohol on liver proteins, nucleic acids, and lipids, and provides new insights and summaries of the oxidative stress process. We also discussed the relationship between oxidative stress and inflammation in alcoholic liver disease from different perspectives. Finally, the research status of antioxidant therapy in alcoholic liver disease was summarized, hoping to provide better help for learning and developing the understanding of alcoholic liver disease.
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Affiliation(s)
- Weiwen Lai
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jiahua Zhang
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jiawei Sun
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Tianqi Min
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Jincan He
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd, Science City, Guangzhou 510663, China
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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4
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Hoang LD, Aoyama E, Hiasa M, Omote H, Kubota S, Kuboki T, Takigawa M. Positive Regulation of S-Adenosylmethionine on Chondrocytic Differentiation via Stimulation of Polyamine Production and the Gene Expression of Chondrogenic Differentiation Factors. Int J Mol Sci 2023; 24:17294. [PMID: 38139122 PMCID: PMC10743985 DOI: 10.3390/ijms242417294] [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: 11/03/2023] [Revised: 11/30/2023] [Accepted: 12/04/2023] [Indexed: 12/24/2023] Open
Abstract
S-adenosylmethionine (SAM) is considered to be a useful therapeutic agent for degenerative cartilage diseases, although its mechanism is not clear. We previously found that polyamines stimulate the expression of differentiated phenotype of chondrocytes. We also found that the cellular communication network factor 2 (CCN2) played a huge role in the proliferation and differentiation of chondrocytes. Therefore, we hypothesized that polyamines and CCN2 could be involved in the chondroprotective action of SAM. In this study, we initially found that exogenous SAM enhanced proteoglycan production but not cell proliferation in human chondrocyte-like cell line-2/8 (HCS-2/8) cells. Moreover, SAM enhanced gene expression of cartilage-specific matrix (aggrecan and type II collagen), Sry-Box transcription factor 9 (SOX9), CCN2, and chondroitin sulfate biosynthetic enzymes. The blockade of the methionine adenosyltransferase 2A (MAT2A) enzyme catalyzing intracellular SAM biosynthesis restrained the effect of SAM on chondrocytes. The polyamine level in chondrocytes was higher in SAM-treated culture than control culture. Additionally, Alcian blue staining and RT-qPCR indicated that the effects of SAM on the production and gene expression of aggrecan were reduced by the inhibition of polyamine synthesis. These results suggest that the stimulation of polyamine synthesis and gene expression of chondrogenic differentiation factors, such as CCN2, account for the mechanism underlying the action of SAM on chondrocytes.
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Affiliation(s)
- Loc Dinh Hoang
- Advanced Research Center for Oral and Craniofacial Sciences (ARCOCS), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan;
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan;
| | - Eriko Aoyama
- Advanced Research Center for Oral and Craniofacial Sciences (ARCOCS), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan;
| | - Miki Hiasa
- Laboratory of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-0082, Japan; (M.H.); (H.O.)
| | - Hiroshi Omote
- Laboratory of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-0082, Japan; (M.H.); (H.O.)
| | - Satoshi Kubota
- Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan;
| | - Takuo Kuboki
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan;
| | - Masaharu Takigawa
- Advanced Research Center for Oral and Craniofacial Sciences (ARCOCS), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan;
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Aghara H, Chadha P, Zala D, Mandal P. Stress mechanism involved in the progression of alcoholic liver disease and the therapeutic efficacy of nanoparticles. Front Immunol 2023; 14:1205821. [PMID: 37841267 PMCID: PMC10570533 DOI: 10.3389/fimmu.2023.1205821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 09/07/2023] [Indexed: 10/17/2023] Open
Abstract
Alcoholic liver disease (ALD) poses a significant threat to human health, with excessive alcohol intake disrupting the immunotolerant environment of the liver and initiating a cascade of pathological events. This progressive disease unfolds through fat deposition, proinflammatory cytokine upregulation, activation of hepatic stellate cells, and eventual development of end-stage liver disease, known as hepatocellular carcinoma (HCC). ALD is intricately intertwined with stress mechanisms such as oxidative stress mediated by reactive oxygen species, endoplasmic reticulum stress, and alcohol-induced gut dysbiosis, culminating in increased inflammation. While the initial stages of ALD can be reversible with diligent care and abstinence, further progression necessitates alternative treatment approaches. Herbal medicines have shown promise, albeit limited by their poor water solubility and subsequent lack of extensive exploration. Consequently, researchers have embarked on a quest to overcome these challenges by delving into the potential of nanoparticle-mediated therapy. Nanoparticle-based treatments are being explored for liver diseases that share similar mechanisms with alcoholic liver disease. It underscores the potential of these innovative approaches to counteract the complex pathogenesis of ALD, providing new avenues for therapeutic intervention. Nevertheless, further investigations are imperative to fully unravel the therapeutic potential and unlock the promise of nanoparticle-mediated therapy specifically tailored for ALD treatment.
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Affiliation(s)
| | | | | | - Palash Mandal
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology, Anand, Gujarat, India
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6
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Aghara H, Chadha P, Zala D, Mandal P. Stress mechanism involved in the progression of alcoholic liver disease and the therapeutic efficacy of nanoparticles. Front Immunol 2023; 14. [DOI: https:/doi.org/10.3389/fimmu.2023.1205821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023] Open
Abstract
Alcoholic liver disease (ALD) poses a significant threat to human health, with excessive alcohol intake disrupting the immunotolerant environment of the liver and initiating a cascade of pathological events. This progressive disease unfolds through fat deposition, proinflammatory cytokine upregulation, activation of hepatic stellate cells, and eventual development of end-stage liver disease, known as hepatocellular carcinoma (HCC). ALD is intricately intertwined with stress mechanisms such as oxidative stress mediated by reactive oxygen species, endoplasmic reticulum stress, and alcohol-induced gut dysbiosis, culminating in increased inflammation. While the initial stages of ALD can be reversible with diligent care and abstinence, further progression necessitates alternative treatment approaches. Herbal medicines have shown promise, albeit limited by their poor water solubility and subsequent lack of extensive exploration. Consequently, researchers have embarked on a quest to overcome these challenges by delving into the potential of nanoparticle-mediated therapy. Nanoparticle-based treatments are being explored for liver diseases that share similar mechanisms with alcoholic liver disease. It underscores the potential of these innovative approaches to counteract the complex pathogenesis of ALD, providing new avenues for therapeutic intervention. Nevertheless, further investigations are imperative to fully unravel the therapeutic potential and unlock the promise of nanoparticle-mediated therapy specifically tailored for ALD treatment.
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Cuevas-López B, Romero-Ramirez EI, García-Arroyo FE, Tapia E, León-Contreras JC, Silva-Palacios A, Roldán FJ, Campos ONM, Hernandez-Esquivel L, Marín-Hernández A, Gonzaga-Sánchez JG, Hernández-Pando R, Pedraza-Chaverri J, Sánchez-Lozada LG, Aparicio-Trejo OE. NAC Pre-Administration Prevents Cardiac Mitochondrial Bioenergetics, Dynamics, Biogenesis, and Redox Alteration in Folic Acid-AKI-Induced Cardio-Renal Syndrome Type 3. Antioxidants (Basel) 2023; 12:1592. [PMID: 37627587 PMCID: PMC10451243 DOI: 10.3390/antiox12081592] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/05/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
The incidence of kidney disease is increasing worldwide. Acute kidney injury (AKI) can strongly favor cardio-renal syndrome (CRS) type 3 development. However, the mechanism involved in CRS development is not entirely understood. In this sense, mitochondrial impairment in both organs has become a central axis in CRS physiopathology. This study aimed to elucidate the molecular mechanisms associated with cardiac mitochondrial impairment and its role in CRS development in the folic acid-induced AKI (FA-AKI) model. Our results showed that 48 h after FA-AKI, the administration of N-acetyl-cysteine (NAC), a mitochondrial glutathione regulator, prevented the early increase in inflammatory and cell death markers and oxidative stress in the heart. This was associated with the ability of NAC to protect heart mitochondrial bioenergetics, principally oxidative phosphorylation (OXPHOS) and membrane potential, through complex I activity and the preservation of glutathione balance, thus preventing mitochondrial dynamics shifting to fission and the decreases in mitochondrial biogenesis and mass. Our data show, for the first time, that mitochondrial bioenergetics impairment plays a critical role in the mechanism that leads to heart damage. Furthermore, NAC heart mitochondrial preservation during an AKI event can be a valuable strategy to prevent CRS type 3 development.
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Affiliation(s)
- Belén Cuevas-López
- Department of Cardio-Renal Physiology, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico; (B.C.-L.); (E.I.R.-R.); (F.E.G.-A.); (E.T.); (J.G.G.-S.); (L.G.S.-L.)
| | - Edgar Ignacio Romero-Ramirez
- Department of Cardio-Renal Physiology, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico; (B.C.-L.); (E.I.R.-R.); (F.E.G.-A.); (E.T.); (J.G.G.-S.); (L.G.S.-L.)
| | - Fernando E. García-Arroyo
- Department of Cardio-Renal Physiology, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico; (B.C.-L.); (E.I.R.-R.); (F.E.G.-A.); (E.T.); (J.G.G.-S.); (L.G.S.-L.)
| | - Edilia Tapia
- Department of Cardio-Renal Physiology, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico; (B.C.-L.); (E.I.R.-R.); (F.E.G.-A.); (E.T.); (J.G.G.-S.); (L.G.S.-L.)
| | - Juan Carlos León-Contreras
- Experimental Pathology Section, National Institute of Medical Sciences and Nutrition “Salvador Zubirán”, Mexico City 14000, Mexico; (J.C.L.-C.); (R.H.-P.)
| | - Alejandro Silva-Palacios
- Department of Cardiovascular Biomedicine, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico;
| | - Francisco-Javier Roldán
- Outpatient Department, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico;
| | - Omar Noel Medina Campos
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico; (O.N.M.C.); (J.P.-C.)
| | - Luz Hernandez-Esquivel
- Department of Biochemistry, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico; (L.H.-E.); (A.M.-H.)
| | - Alvaro Marín-Hernández
- Department of Biochemistry, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico; (L.H.-E.); (A.M.-H.)
| | - José Guillermo Gonzaga-Sánchez
- Department of Cardio-Renal Physiology, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico; (B.C.-L.); (E.I.R.-R.); (F.E.G.-A.); (E.T.); (J.G.G.-S.); (L.G.S.-L.)
| | - Rogelio Hernández-Pando
- Experimental Pathology Section, National Institute of Medical Sciences and Nutrition “Salvador Zubirán”, Mexico City 14000, Mexico; (J.C.L.-C.); (R.H.-P.)
| | - José Pedraza-Chaverri
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico; (O.N.M.C.); (J.P.-C.)
| | - Laura Gabriela Sánchez-Lozada
- Department of Cardio-Renal Physiology, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico; (B.C.-L.); (E.I.R.-R.); (F.E.G.-A.); (E.T.); (J.G.G.-S.); (L.G.S.-L.)
| | - Omar Emiliano Aparicio-Trejo
- Department of Cardio-Renal Physiology, National Institute of Cardiology Ignacio Chávez, Mexico City 14080, Mexico; (B.C.-L.); (E.I.R.-R.); (F.E.G.-A.); (E.T.); (J.G.G.-S.); (L.G.S.-L.)
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Raikhelson KL, Kondrashina EA, Pazenko EV. Principles of treatment of different forms of alcoholic liver disease: A review. TERAPEVT ARKH 2023; 95:187-192. [PMID: 37167136 DOI: 10.26442/00403660.2023.02.202071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 03/30/2023] [Indexed: 04/03/2023]
Abstract
The review considers the principles of treatment of various forms of alcoholic liver disease from the point of view of the evidence base and clinical recommendations. The main therapy for severe alcoholic hepatitis is systemic glucocorticosteroids, their effect on survival is increased by the addition of antioxidants (N-acetylcysteine, ademethionine). The effect of ademetionine on the life expectancy of patients with alcoholic cirrhosis of ChildPugh class A and B has been proven. The treatment of patients with mild forms of alcoholic liver disease is not well developed, and the evidence base for most of the drugs used is modest.
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Ryu T, Kim K, Choi SE, Chung KPS, Jeong WI. New insights in the pathogenesis of alcohol-related liver disease: The metabolic, immunologic, and neurologic pathways ☆. LIVER RESEARCH 2023; 7:1-8. [PMID: 39959703 PMCID: PMC11791844 DOI: 10.1016/j.livres.2022.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 07/04/2022] [Accepted: 09/28/2022] [Indexed: 02/16/2023]
Abstract
Alcohol-related liver disease (ALD) became an important health issue worldwide. Following chronic alcohol consumption, the development of ALD might be caused by metabolic and immunologic factors, such as reactive oxygen species (ROS) and pro-inflammatory cytokines. For example, hepatic cytochrome P450 2E1 enzyme increases ROS production and stimulates de novo lipogenesis after alcohol exposure. In addition, damage- and pathogen-associated molecular patterns stimulate their specific receptors in non-parenchymal cells, including Kupffer cells, hepatic stellate cells (HSCs), and lymphocytes, which result in hepatocyte death and infiltration of pro-inflammatory cells (e.g., neutrophils and macrophages) in the liver. Moreover, our studies have suggested the novel involvement of neurologic signaling pathways (e.g., endocannabinoid and glutamate) through the metabolic synapse between hepatocytes and HSCs in the development of alcohol-related hepatic steatosis. Additionally, agouti-related protein and beta2-adrenergic receptors aggravate hepatic steatosis. Furthermore, organ-crosstalk has emerged as a critical issue in ALD. Chronic alcohol consumption induces dysbiosis and barrier disruption in the gut, leading to endotoxin leakage into the portal circulation, or lipolysis-mediated transport of triglycerides from the adipose tissue to the liver. In summary, this review addresses multiple pathogeneses of ALD, provides novel neurologic signaling pathways, and emphasizes the importance of organ-crosstalk in the development of ALD.
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Affiliation(s)
- Tom Ryu
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Kyurae Kim
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Sung Eun Choi
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Katherine Po Sin Chung
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Won-Il Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
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Adekunle AD, Adejumo A, Singal AK. Therapeutic targets in alcohol-associated liver disease: progress and challenges. Therap Adv Gastroenterol 2023; 16:17562848231170946. [PMID: 37187673 PMCID: PMC10176580 DOI: 10.1177/17562848231170946] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 04/04/2023] [Indexed: 05/17/2023] Open
Abstract
Alcohol-associated liver disease (ALD) is a complex disease with rapidly increasing prevalence. Although there are promising therapeutic targets on the horizon, none of the newer targets is currently close to an Food and Drug Administration approval. Strategies are needed to overcome challenges in study designs and conducting clinical trials and provide impetus to the field of drug development in the landscape of ALD and alcoholic hepatitis. Management of ALD is complex and should include therapies to achieve and maintain alcohol abstinence, preferably delivered by a multidisciplinary team. Although associated with clear mortality benefit in select patients, the use of early liver transplantation still requires refinement to create uniformity in selection protocols across transplant centers. There is also a need for reliable noninvasive biomarkers for prognostication. Last but not the least, strategies are urgently needed to implement integrated multidisciplinary care models for treating the dual pathology of alcohol use disorder and of liver disease for improving the long-term outcomes of patients with ALD.
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Affiliation(s)
- Ayooluwatomiwa Deborah Adekunle
- Department of Internal Medicine, St. Luke’s
Hospital, Chesterfield, Missouri, USA
- Division of Hepatology, University of
Pittsburgh Medical Center, Pittsburgh, PA, USA
- Division of Transplant Hepatology, University
of South Dakota Sanford Medical School, Sioux Falls, SD
| | - Adeyinka Adejumo
- Department of Internal Medicine, St. Luke’s
Hospital, Chesterfield, Missouri, USA
- Division of Hepatology, University of
Pittsburgh Medical Center, Pittsburgh, PA, USA
- Division of Transplant Hepatology, University
of South Dakota Sanford Medical School, Sioux Falls, SD
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11
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A liver secretome gene signature-based approach for determining circulating biomarkers of NAFLD severity. PLoS One 2022; 17:e0275901. [PMID: 36260611 PMCID: PMC9581378 DOI: 10.1371/journal.pone.0275901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 09/25/2022] [Indexed: 11/08/2022] Open
Abstract
Non-invasive biomarkers of non-alcoholic fatty liver disease (NAFLD) supporting diagnosis and monitoring disease progression are urgently needed. The present study aimed to establish a bioinformatics pipeline capable of defining and validating NAFLD biomarker candidates based on paired hepatic global gene expression and plasma bioanalysis from individuals representing different stages of histologically confirmed NAFLD (no/mild, moderate, more advanced NAFLD). Liver secretome gene signatures were generated in a patient cohort of 26 severely obese individuals with the majority having no or mild fibrosis. To this end, global gene expression changes were compared between individuals with no/mild NAFLD and moderate/advanced NAFLD with subsequent filtering for candidate gene products with liver-selective expression and secretion. Four candidate genes, including LPA (lipoprotein A), IGFBP-1 (insulin-like growth factor-binding protein 1), SERPINF2 (serpin family F member 2) and MAT1A (methionine adenosyltransferase 1A), were differentially expressed in moderate/advanced NAFLD, which was confirmed in three independent RNA sequencing datasets from large, publicly available NAFLD studies. The corresponding gene products were quantified in plasma samples but could not discriminate among different grades of NAFLD based on NAFLD activity score. Conclusion: We demonstrate a novel approach based on the liver transcriptome allowing for identification of secreted hepatic gene products as potential circulating diagnostic biomarkers of NAFLD. Using this approach in larger NAFLD patient cohorts may yield potential circulating biomarkers for NAFLD severity.
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12
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Li LX, Guo FF, Liu H, Zeng T. Iron overload in alcoholic liver disease: underlying mechanisms, detrimental effects, and potential therapeutic targets. Cell Mol Life Sci 2022; 79:201. [PMID: 35325321 PMCID: PMC11071846 DOI: 10.1007/s00018-022-04239-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/04/2022] [Accepted: 03/09/2022] [Indexed: 02/06/2023]
Abstract
Alcoholic liver disease (ALD) is a global public health challenge due to the high incidence and lack of effective therapeutics. Evidence from animal studies and ALD patients has demonstrated that iron overload is a hallmark of ALD. Ethanol exposure can promote iron absorption by downregulating the hepcidin expression, which is probably mediated by inducing oxidative stress and promoting erythropoietin (EPO) production. In addition, ethanol may enhance iron uptake in hepatocytes by upregulating the expression of transferrin receptor (TfR). Iron overload in the liver can aggravate ethanol-elicited liver damage by potentiating oxidative stress via Fenton reaction, promoting activation of Kupffer cells (KCs) and hepatic stellate cells (HSCs), and inducing a recently discovered programmed iron-dependent cell death, ferroptosis. This article reviews the current knowledge of iron metabolism, regulators of iron homeostasis, the mechanism of ethanol-induced iron overload, detrimental effects of iron overload in the liver, and potential therapeutic targets.
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Affiliation(s)
- Long-Xia Li
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Fang-Fang Guo
- Department of Pharmacy, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Hong Liu
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
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13
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Pascale RM, Simile MM, Calvisi DF, Feo CF, Feo F. S-Adenosylmethionine: From the Discovery of Its Inhibition of Tumorigenesis to Its Use as a Therapeutic Agent. Cells 2022; 11:409. [PMID: 35159219 PMCID: PMC8834208 DOI: 10.3390/cells11030409] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 01/10/2022] [Accepted: 01/14/2022] [Indexed: 02/07/2023] Open
Abstract
Alterations of methionine cycle in steatohepatitis, cirrhosis, and hepatocellular carcinoma induce MAT1A decrease and MAT2A increase expressions with the consequent decrease of S-adenosyl-L-methionine (SAM). This causes non-alcoholic fatty liver disease (NAFLD). SAM administration antagonizes pathological conditions, including galactosamine, acetaminophen, and ethanol intoxications, characterized by decreased intracellular SAM. Positive therapeutic effects of SAM/vitamin E or SAM/ursodeoxycholic acid in animal models with NAFLD and intrahepatic cholestasis were not confirmed in humans. In in vitro experiments, SAM and betaine potentiate PegIFN-alpha-2a/2b plus ribavirin antiviral effects. SAM plus betaine improves early viral kinetics and increases interferon-stimulated gene expression in patients with viral hepatitis non-responders to pegIFNα/ribavirin. SAM prevents hepatic cirrhosis, induced by CCl4, inhibits experimental tumors growth and is proapoptotic for hepatocellular carcinoma and MCF-7 breast cancer cells. SAM plus Decitabine arrest cancer growth and potentiate doxorubicin effects on breast, head, and neck cancers. Furthermore, SAM enhances the antitumor effect of gemcitabine against pancreatic cancer cells, inhibits growth of human prostate cancer PC-3, colorectal cancer, and osteosarcoma LM-7 and MG-63 cell lines; increases genomic stability of SW480 cells. SAM reduces colorectal cancer progression and inhibits the proliferation of preneoplastic rat liver cells in vivo. The discrepancy between positive results of SAM treatment of experimental tumors and modest effects against human disease may depend on more advanced human disease stage at moment of diagnosis.
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Affiliation(s)
- Rosa M. Pascale
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
| | - Maria M. Simile
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
| | - Diego F. Calvisi
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
| | - Claudio F. Feo
- Department of Medical, Surgical and Experimental Sciences, Division of Surgery, University of Sassari, 07100 Sassari, Italy;
| | - Francesco Feo
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
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14
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Crosstalk between Oxidative Stress and Inflammatory Liver Injury in the Pathogenesis of Alcoholic Liver Disease. Int J Mol Sci 2022; 23:ijms23020774. [PMID: 35054960 PMCID: PMC8775426 DOI: 10.3390/ijms23020774] [Citation(s) in RCA: 107] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/04/2022] [Accepted: 01/07/2022] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) is characterized by the injury, inflammation, and scarring in the liver owing to excessive alcohol consumption. Currently, ALD is a leading cause for liver transplantation. Therefore, extensive studies (in vitro, in experimental ALD models and in humans) are needed to elucidate pathological features and pathogenic mechanisms underlying ALD. Notably, oxidative changes in the liver have been recognized as a signature trait of ALD. Progression of ALD is linked to the generation of highly reactive free radicals by reactions involving ethanol and its metabolites. Furthermore, hepatic oxidative stress promotes tissue injury and, in turn, stimulates inflammatory responses in the liver, forming a pathological loop that promotes the progression of ALD. Accordingly, accumulating further knowledge on the relationship between oxidative stress and inflammation may help establish a viable therapeutic approach for treating ALD.
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15
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Petagine L, Zariwala MG, Patel VB. Alcoholic liver disease: Current insights into cellular mechanisms. World J Biol Chem 2021; 12:87-103. [PMID: 34630912 PMCID: PMC8473419 DOI: 10.4331/wjbc.v12.i5.87] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/20/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) due to chronic alcohol consumption is a significant global disease burden and a leading cause of mortality. Alcohol abuse induces a myriad of aberrant changes in hepatocytes at both the cellular and molecular level. Although the disease spectrum of ALD is widely recognized, the precise triggers for disease progression are still to be fully elucidated. Oxidative stress, mitochondrial dysfunction, gut dysbiosis and altered immune system response plays an important role in disease pathogenesis, triggering the activation of inflammatory pathways and apoptosis. Despite many recent clinical studies treatment options for ALD are limited, especially at the alcoholic hepatitis stage. We have therefore reviewed some of the key pathways involved in the pathogenesis of ALD and highlighted current trials for treating patients.
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Affiliation(s)
- Lucy Petagine
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
| | - Mohammed Gulrez Zariwala
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
| | - Vinood B Patel
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
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16
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Nicoll R, Gerasimidis K, Forrest E. The Role of Micronutrients in the Pathogenesis of Alcohol-Related Liver Disease. Alcohol Alcohol 2021; 57:275-282. [PMID: 34491307 DOI: 10.1093/alcalc/agab060] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/27/2021] [Accepted: 08/03/2021] [Indexed: 11/13/2022] Open
Abstract
AIMS Chronic alcohol consumption may result in liver injury and chronic liver disease, but other factors are likely to influence disease progression. Malnutrition, specifically micronutrient deficiency, is frequently associated with both alcohol use disorder and chronic liver disease. We hypothesize that micronutrient deficiencies may affect the progression of liver disease in this population. METHODS Systematic integrative review of the medical literature; electronic search of MEDLINE 1950-2021; studies investigating role of any micronutrient in the acceleration of alcohol-related liver injury in humans or animals. Studies which specifically related to alcoholic hepatitis were excluded. Outcomes were extracted and recorded in tabulated form and discussed narratively. RESULTS We identified 46 studies investigating the role of micronutrient deficiencies in the pathogenesis of alcohol-related liver disease. Specific micronutrients which were identified included folic acid or related B vitamins (n = 9 studies), Vitamin D (n = 9 studies), magnesium (n = 8 studies), zinc (n = 8 studies) and selenium (n = 12 including one systematic review). Observational evidence suggests a potential role of magnesium deficiency in accelerating alcohol-related liver injury with weak or negative evidence for other micronutrients. CONCLUSIONS Magnesium deficiency may increase the risk of alcohol-related liver injury and adverse liver outcomes. However, currently, there is insufficient evidence to support magnesium supplementation except for clinically relevant magnesium deficiency. Long-term prospective cohort studies assessing the impact of micronutrients on liver disease progression in patients with alcohol use disorder are lacking and may help determine whether there is a causal role for micronutrient deficiencies in alcohol-related liver injury.
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Affiliation(s)
- Ruairidh Nicoll
- Department of Gastroenterology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK
| | - Konstantinos Gerasimidis
- Department of Human Nutrition, School of Medicine, College of Medicine, Veterinary and Life Sciences, University of Glasgow, New Lister Building, Glasgow Royal Infirmary, Glasgow G31 2ER, UK
| | - Ewan Forrest
- Department of Gastroenterology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK
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17
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Park JH, Bok MK, Kim J, Maeng S, Kim SH, Jung JH, Lee HJ, Lim H. Effect of an extract of Pinus koraiensis leaves, Lycium chinense fruit, and Saururus chinensis (Lour.) Baill. leaves on liver function in excessive drinkers: A randomized, double-blind, placebo-controlled trial. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104535] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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18
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Middleton P, Vergis N. Mitochondrial dysfunction and liver disease: role, relevance, and potential for therapeutic modulation. Therap Adv Gastroenterol 2021; 14:17562848211031394. [PMID: 34377148 PMCID: PMC8320552 DOI: 10.1177/17562848211031394] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 06/18/2021] [Indexed: 02/04/2023] Open
Abstract
Mitochondria are key organelles involved in energy production as well as numerous metabolic processes. There is a growing interest in the role of mitochondrial dysfunction in the pathogenesis of common chronic diseases as well as in cancer development. This review will examine the role mitochondria play in the pathophysiology of common liver diseases, including alcohol-related liver disease, non-alcoholic fatty liver disease, chronic hepatitis B and hepatocellular carcinoma. Mitochondrial dysfunction is described widely in the literature in studies examining patient tissue and in disease models. Despite significant differences in pathophysiology between chronic liver diseases, common mitochondrial defects are described, including increased mitochondrial reactive oxygen species production and impaired oxidative phosphorylation. We review the current literature on mitochondrial-targeted therapies, which have the potential to open new therapeutic avenues in the management of patients with chronic liver disease.
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Affiliation(s)
| | - Nikhil Vergis
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
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19
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Michalak A, Lach T, Cichoż-Lach H. Oxidative Stress-A Key Player in the Course of Alcohol-Related Liver Disease. J Clin Med 2021; 10:3011. [PMID: 34300175 PMCID: PMC8303854 DOI: 10.3390/jcm10143011] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress is known to be an inseparable factor involved in the presentation of liver disorders. Free radicals interfere with DNA, proteins, and lipids, which are crucial in liver metabolism, changing their expression and biological functions. Additionally, oxidative stress modifies the function of micro-RNAs, impairing the metabolism of hepatocytes. Free radicals have also been proven to influence the function of certain transcriptional factors and to alter the cell cycle. The pathological appearance of alcohol-related liver disease (ALD) constitutes an ideal example of harmful effects due to the redox state. Finally, ethanol-induced toxicity and overproduction of free radicals provoke irreversible changes within liver parenchyma. Understanding the underlying mechanisms associated with the redox state in the course of ALD creates new possibilities of treatment for patients. The future of hepatology may become directly dependent on the effective action against reactive oxygen species. This review summarizes current data on the redox state in the natural history of ALD, highlighting the newest reports on this topic.
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Affiliation(s)
- Agata Michalak
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
| | - Tomasz Lach
- Department of Orthopedics and Traumatology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
| | - Halina Cichoż-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
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20
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Syed Javid Hasan SAH, Pawirotaroeno RAO, Syed Javid Hasan SAH, Abzianidze E. Role of Chronic Alcoholism Causing Cancer in Omnivores and Vegetarians through Epigenetic Modifications. Glob Med Genet 2021; 7:80-86. [PMID: 33392610 PMCID: PMC7772008 DOI: 10.1055/s-0040-1721814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
One of the significant consequences of alcohol consumption is cancer formation via several contributing factors such as action of alcohol metabolites, vitamin deficiencies, and oxidative stress. All these factors have been shown to cause epigenetic modifications via DNA hypomethylation, thus forming a basis for cancer development. Several published reviews and studies were systematically reviewed. Omnivores and vegetarians differ in terms of nutritional intake and deficiencies. As folate deficiency was found to be common among the omnivores, chronic alcoholism could possibly cause damage and eventually cancer in an omnivorous individual via DNA hypomethylation due to folate deficiency. Furthermore, as niacin was found to be deficient among vegetarians, damage in vegetarian chronic alcoholics could be due to increased NADH/NAD
+
ratio, thus slowing alcohol metabolism in liver leading to increased alcohol and acetaldehyde which inhibit methyltransferase enzymes, eventually leading to DNA hypomethylation. Hence correcting the concerned deficiency and supplementation with S-adenosyl methionine could prove to be protective in chronic alcohol use.
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Affiliation(s)
| | | | | | - Elene Abzianidze
- Department of Molecular and Medical Genetics, Tbilisi State Medical University, Tbilisi, Georgia
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21
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Asgharpour A, Dinani A, Friedman SL. Basic science to clinical trials in non-alcoholic fatty liver disease and alcohol-related liver disease: collaboration with industry. Transl Gastroenterol Hepatol 2021; 6:5. [PMID: 33409399 PMCID: PMC7724182 DOI: 10.21037/tgh.2020.01.04] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 01/17/2020] [Indexed: 12/19/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) are highly prevalent forms of chronic liver diseases globally, associated with rising all-cause morbidity and mortality. While distinct diseases, NAFLD and ALD share several similarities; both can result in fatty liver disease, steatohepatitis, associated hepatic fibrosis and cirrhosis-related complications, including hepatocellular carcinoma (HCC). Our understanding of the pathophysiology and manifestations of these diseases has advanced significantly, which has established a new foundation to identify therapeutic targets and test new treatments. This review underscores emerging pathogenic pathways that establish a template for target identification and clinical trials. Success is critically dependent upon productive interactions between academic investigators and industry to address unmet therapeutic needs in NAFLD and ALD.
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Affiliation(s)
- Amon Asgharpour
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Amreen Dinani
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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22
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Ramos-Lopez O, Milagro FI, Riezu-Boj JI, Martinez JA. Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition. Inflamm Res 2021; 70:29-49. [PMID: 33231704 PMCID: PMC7684853 DOI: 10.1007/s00011-020-01425-y] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/26/2020] [Accepted: 11/12/2020] [Indexed: 12/12/2022] Open
Abstract
AIM AND OBJECTIVE Emerging translational evidence suggests that epigenetic alterations (DNA methylation, miRNA expression, and histone modifications) occur after external stimuli and may contribute to exacerbated inflammation and the risk of suffering several diseases including diabetes, cardiovascular diseases, cancer, and neurological disorders. This review summarizes the current knowledge about the harmful effects of high-fat/high-sugar diets, micronutrient deficiencies (folate, manganese, and carotenoids), obesity and associated complications, bacterial/viral infections, smoking, excessive alcohol consumption, sleep deprivation, chronic stress, air pollution, and chemical exposure on inflammation through epigenetic mechanisms. Additionally, the epigenetic phenomena underlying the anti-inflammatory potential of caloric restriction, n-3 PUFA, Mediterranean diet, vitamin D, zinc, polyphenols (i.e., resveratrol, gallic acid, epicatechin, luteolin, curcumin), and the role of systematic exercise are discussed. METHODS Original and review articles encompassing epigenetics and inflammation were screened from major databases (including PubMed, Medline, Science Direct, Scopus, etc.) and analyzed for the writing of the review paper. CONCLUSION Although caution should be exercised, research on epigenetic mechanisms is contributing to understand pathological processes involving inflammatory responses, the prediction of disease risk based on the epigenotype, as well as the putative design of therapeutic interventions targeting the epigenome.
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Affiliation(s)
- Omar Ramos-Lopez
- Medicine and Psychology School, Autonomous University of Baja California, Tijuana, Baja California, Mexico
| | - Fermin I Milagro
- Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, University of Navarra, 1 Irunlarrea Street, 31008, Pamplona, Spain.
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
- CIBERobn, Fisiopatología de la Obesidad y la Nutrición, Carlos III Health Institute, Madrid, Spain.
| | - Jose I Riezu-Boj
- Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, University of Navarra, 1 Irunlarrea Street, 31008, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| | - J Alfredo Martinez
- Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, University of Navarra, 1 Irunlarrea Street, 31008, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
- CIBERobn, Fisiopatología de la Obesidad y la Nutrición, Carlos III Health Institute, Madrid, Spain
- Precision Nutrition and Cardiometabolic Health, IMDEA-Food Institute (Madrid Institute for Advanced Studies), Madrid, Spain
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23
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Stabler SP. Alterations in Sulfur Amino Acids as Biomarkers of Disease. J Nutr 2020; 150:2532S-2537S. [PMID: 33000156 DOI: 10.1093/jn/nxaa118] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 03/31/2020] [Accepted: 04/02/2020] [Indexed: 01/30/2023] Open
Abstract
Homocysteine (Hcy) is methylated by methionine synthase to form methionine with methyl-cobalamin as a cofactor. The reaction demethylates 5-methyltetrahydrofolate to tetrahydrofolate, which is required for DNA and RNA synthesis. Deficiency of either of the cobalamin (Cbl) and/or folate cofactors results in elevated Hcy and megaloblastic anemia. Elevated Hcy is a sensitive biomarker of Cbl and/or folate status and more specific than serum vitamin assays. Elevated Hcy normalizes when the correct vitamin is given. Elevated Hcy is associated with alcohol use disorder and drugs that target folate or Cbl metabolism, and is a risk factor for thrombotic vascular disease. Elevated methionine and cystathionine are associated with liver disease. Elevated Hcy, cystathionine, and cysteine, but not methionine, are common in patients with chronic renal failure. Higher cysteine predicts obesity and future weight gain. Serum S-adenosylhomocysteine (AdoHcy) is elevated in Cbl deficiency and chronic renal failure. Drugs that require methylation for catabolism may deplete liver S-adenosylmethionine and raise AdoHcy and Hcy. Deficiency of Cbl or folate or perturbations of their metabolism cause major changes in sulfur amino acids.
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Affiliation(s)
- Sally P Stabler
- Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO, USA
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24
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Oxidative stress in alcohol-related liver disease. World J Hepatol 2020. [DOI: 10.4254/wjh.v12.i7.333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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25
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Tan HK, Yates E, Lilly K, Dhanda AD. Oxidative stress in alcohol-related liver disease. World J Hepatol 2020; 12:332-349. [PMID: 32821333 PMCID: PMC7407918 DOI: 10.4254/wjh.v12.i7.332] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/06/2020] [Accepted: 05/17/2020] [Indexed: 02/06/2023] Open
Abstract
Alcohol consumption is one of the leading causes of the global burden of disease and results in high healthcare and economic costs. Heavy alcohol misuse leads to alcohol-related liver disease, which is responsible for a significant proportion of alcohol-attributable deaths globally. Other than reducing alcohol consumption, there are currently no effective treatments for alcohol-related liver disease. Oxidative stress refers to an imbalance in the production and elimination of reactive oxygen species and antioxidants. It plays important roles in several aspects of alcohol-related liver disease pathogenesis. Here, we review how chronic alcohol use results in oxidative stress through increased metabolism via the cytochrome P450 2E1 system producing reactive oxygen species, acetaldehyde and protein and DNA adducts. These trigger inflammatory signaling pathways within the liver leading to expression of pro-inflammatory mediators causing hepatocyte apoptosis and necrosis. Reactive oxygen species exposure also results in mitochondrial stress within hepatocytes causing structural and functional dysregulation of mitochondria and upregulating apoptotic signaling. There is also evidence that oxidative stress as well as the direct effect of alcohol influences epigenetic regulation. Increased global histone methylation and acetylation and specific histone acetylation inhibits antioxidant responses and promotes expression of key pro-inflammatory genes. This review highlights aspects of the role of oxidative stress in disease pathogenesis that warrant further study including mitochondrial stress and epigenetic regulation. Improved understanding of these processes may identify novel targets for therapy.
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Affiliation(s)
- Huey K Tan
- Hepatology Research Group, Institute of Translational and Stratified Medicine, Faculty of Health, University of Plymouth, Plymouth PL6 8BU, United Kingdom
- South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth PL6 8DH, United Kingdom
| | - Euan Yates
- Hepatology Research Group, Institute of Translational and Stratified Medicine, Faculty of Health, University of Plymouth, Plymouth PL6 8BU, United Kingdom
| | - Kristen Lilly
- Hepatology Research Group, Institute of Translational and Stratified Medicine, Faculty of Health, University of Plymouth, Plymouth PL6 8BU, United Kingdom
- Department of Clinical Immunology, University Hospitals Plymouth NHS Trust, Plymouth PL6 8DH, United Kingdom
| | - Ashwin D Dhanda
- Hepatology Research Group, Institute of Translational and Stratified Medicine, Faculty of Health, University of Plymouth, Plymouth PL6 8BU, United Kingdom
- South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth PL6 8DH, United Kingdom
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26
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Cheng H, Zhu J, Shan J, Ouyang X, Yang H, Wei R, Zeng J. Involvement of toll-like receptor 2/myeloid differentiation factor 88/nuclear factor kappa B/NLR family pyrin domain-containing 3 signaling pathways in the hepatoprotective effect of Lagotis brachystachys in rats with alcoholic liver disease. Pharmacogn Mag 2020. [DOI: 10.4103/pm.pm_557_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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27
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Brzački V, Mladenović B, Dimić D, Jeremić L, Živanović D, Djukić D, Stojanović NM, Sokolović DT. Comparison between the effects of selenomethionine and S-adenosylmethionine in preventing cholestasis-induced rat liver damage. Amino Acids 2019; 51:795-803. [DOI: 10.1007/s00726-019-02716-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 02/28/2019] [Indexed: 01/09/2023]
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28
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Abstract
Alcohol consumption is one of the main risks to public health. Alcohol use disorders (AUDs) cause 80% of hepatotoxic deaths, and approximately 50% of cirrhosis is alcohol-related. The acceptable daily intake (ADI) for ethanol is 2.6 g/day, deduced from morbidity and mortality rates due to liver fibrosis. The relative risk of cirrhosis increases significantly for doses above 60 g/day for men and 20 g/day for women over a period of around 10 years. Twenty to 40% of steatosis cases will evolve into steatohepatitis/steatofibrosis, and 8 to 20% will evolve directly into liver cirrhosis. About 20 to 40% of steatohepatitis cases will evolve into cirrhosis, and 4 to 5% into hepatocellular carcinoma. This cascade of events evolves in 5 to 40 years, with the temporal variability caused by the subjects' genetic patterns and associated risk/comorbidity factors. Steatohepatitis should be considered "the rate limiting step:" usually, it can be resolved through abstinence, although for some patients, once this situation develops, it is not substantially modified by abstention and there is a risk of fibrotic evolution. Early detection of fibrosis, obtained by hepatic elastography, is a crucial step in patients with AUDs. Such strategy allows patients to be included in a detoxification program in order to achieve abstention. Drugs such as silybin, metadoxine, and adenosylmethionine can be used. Other drugs, with promising antifibrotic effects, are currently under study. In this review, we discuss clinical and pathogenetic aspects of alcohol-related liver fibrosis and present and future strategies to prevent cirrhosis.
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Affiliation(s)
- Gianni Testino
- Alcohological Regional Center, Ligurian Region, ASL3, San Martino Hospital, Genoa, Italy -
| | - Silvia Leone
- Alcohological Regional Center, Ligurian Region, ASL3, San Martino Hospital, Genoa, Italy
| | - Sharmila Fagoonee
- Institute for Biostructure and Bioimaging (CNR), Molecular Biotechnology Center, Turin, Italy
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Ohashi K, Pimienta M, Seki E. Alcoholic liver disease: A current molecular and clinical perspective. LIVER RESEARCH 2018; 2:161-172. [PMID: 31214376 PMCID: PMC6581514 DOI: 10.1016/j.livres.2018.11.002] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Heavy alcohol use is the cause of alcoholic liver disease (ALD). The ALD spectrum ranges from alcoholic steatosis to steatohepatitis, fibrosis, and cirrhosis. In Western countries, approximately 50% of cirrhosis-related deaths are due to alcohol use. While alcoholic cirrhosis is no longer considered a completely irreversible condition, no effective anti-fibrotic therapies are currently available. Another significant clinical aspect of ALD is alcoholic hepatitis (AH). AH is an acute inflammatory condition that is often comorbid with cirrhosis, and severe AH has a high mortality rate. Therapeutic options for ALD are limited. The established treatment for AH is corticosteroids, which improve short-term survival but do not affect long-term survival. Liver transplantation is a curative treatment option for alcoholic cirrhosis and AH, but patients must abstain from alcohol use for 6 months to qualify. Additional effective therapies are needed. The molecular mechanisms underlying ALD are complex and have not been fully elucidated. Various molecules, signaling pathways, and crosstalk between multiple hepatic and extrahepatic cells contribute to ALD progression. This review highlights established and emerging concepts in ALD clinicopathology, their underlying molecular mechanisms, and current and future ALD treatment options.
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Affiliation(s)
- Koichiro Ohashi
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Michael Pimienta
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA,University of California San Diego, School of Medicine, La Jolla, CA, USA
| | - Ekihiro Seki
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA,University of California San Diego, School of Medicine, La Jolla, CA, USA,Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Department of Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA,Corresponding author. Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA., (E. Seki)
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Zhao N, Guo FF, Xie KQ, Zeng T. Targeting Nrf-2 is a promising intervention approach for the prevention of ethanol-induced liver disease. Cell Mol Life Sci 2018; 75:3143-3157. [PMID: 29947925 PMCID: PMC11105722 DOI: 10.1007/s00018-018-2852-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 05/18/2018] [Accepted: 06/06/2018] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) remains to be a worldwide health problem. It is generally accepted that oxidative stress plays critical roles in the pathogenesis of ALD, and antioxidant therapy represents a logical strategy for the prevention and treatment of ALD. Nuclear factor erythroid-derived 2-like 2 (NFE2L2 or Nrf-2) is essential for the antioxidant responsive element (ARE)-mediated induction of endogenous antioxidant enzymes such as heme oxygenase 1 (HO-1) and glutamate-cysteine ligase [GCL, the rate-limiting enzyme in the synthesis of glutathione (GSH)]. Activation of Nrf-2 pathway by genetic manipulation or pharmacological agents has been demonstrated to provide protection against ALD, which suggests that targeting Nrf-2 may be a promising approach for the prevention and treatment of ALD. Herein, we review the relevant literature about the potential hepatoprotective roles of Nrf-2 activation against ALD.
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Affiliation(s)
- Ning Zhao
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan, 250012, Shandong, China
| | - Fang-Fang Guo
- Department of Pharmacy, Qilu Hospital of Shandong University, 107 Wenhua West Road, Jinan, 250012, Shandong, China
| | - Ke-Qin Xie
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan, 250012, Shandong, China
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan, 250012, Shandong, China.
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Chronic liver diseases and the potential use of S-adenosyl-L-methionine as a hepatoprotector. Eur J Gastroenterol Hepatol 2018; 30:893-900. [PMID: 29683981 DOI: 10.1097/meg.0000000000001141] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chronic liver diseases result in overall deterioration of health status and changes in metabolism. The search for strategies to control and combat these hepatic diseases has witnessed a great boom in the last decades. Nutritional therapy for controlling and managing liver diseases may be a positive influence as it improves the function of the liver. In this review, we focus mainly on describing liver conditions such as nonalcoholic fatty liver disease, and intrahepatic cholestasis as well as using S-adenosyl-L-methionine as a dietary supplement and its potential alternative therapeutic effect to correct the hepatic dysfunction associated with these conditions.
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Tumor-suppressive effect of S-adenosylmethionine supplementation in a murine model of inflammation-mediated hepatocarcinogenesis is dependent on treatment longevity. Oncotarget 2017; 8:104772-104784. [PMID: 29285212 PMCID: PMC5739599 DOI: 10.18632/oncotarget.18300] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 04/03/2017] [Indexed: 12/27/2022] Open
Abstract
Chronic inflammation precedes the majority of hepatocellular carcinoma (HCC) cases. We investigated the chemopreventive potential of S-adenosylmethionine (SAM), an essential donor for all methylation reactions in the cell, at the late precancerous stage of HCC development using the Mdr2-knockout (Mdr2-KO, Abcb4−/−) mice, a model of inflammation-mediated hepatocarcinogenesis. Previously, we revealed down-regulation of the genes regulating SAM metabolism in the liver of these mice at the precancerous stages. Now, we have supplied Mdr2-KO mice at the late precancerous stage with SAM during either a short-term (17 days) or a long-term (51 days) period and explored the effects of such supplementation on tumor development, DNA methylation and gene expression in the liver. The short-term SAM supplementation significantly decreased the number of small tumor nodules, proliferating hepatocytes and the total DNA methylation level, while it increased expression of the tumor suppressor proteins Mat1a and p21. Surprisingly, the long-term SAM supplementation did not affect tumor growth and hepatocyte proliferation, while it increased the total liver DNA methylation. Our results demonstrate that the short-term SAM supplementation in the Mdr2-KO mice inhibited liver tumor development potentially by increasing multiple tumor suppressor mechanisms resulting in cell cycle arrest. The long-term SAM supplementation resulted in a bypass of the cell cycle arrest in this HCC model by a yet unknown mechanism.
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Buzzetti E, Kalafateli M, Thorburn D, Davidson BR, Thiele M, Gluud LL, Del Giovane C, Askgaard G, Krag A, Tsochatzis E, Gurusamy KS, Cochrane Hepato‐Biliary Group. Pharmacological interventions for alcoholic liver disease (alcohol-related liver disease): an attempted network meta-analysis. Cochrane Database Syst Rev 2017; 3:CD011646. [PMID: 28368093 PMCID: PMC6464309 DOI: 10.1002/14651858.cd011646.pub2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Alcohol-related liver disease is due to excessive alcohol consumption. It includes a spectrum of liver diseases such as alcohol-related fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Mortality associated with alcoholic hepatitis is high. The optimal pharmacological treatment of alcoholic hepatitis and other alcohol-related liver disease remains controversial. OBJECTIVES To assess the comparative benefits and harms of different pharmacological interventions in the management of alcohol-related liver disease through a network meta-analysis and to generate rankings of the available pharmacological interventions according to their safety and efficacy in order to identify potential treatments. However, even in the subgroup of participants when the potential effect modifiers appeared reasonably similar across comparisons, there was evidence of inconsistency by one or more methods of assessment of inconsistency. Therefore, we did not report the results of the network meta-analysis and reported the comparative benefits and harms of different interventions using standard Cochrane methodology. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform and randomised controlled trials registers until February 2017 to identify randomised clinical trials on pharmacological treatments for alcohol-related liver diseases. SELECTION CRITERIA Randomised clinical trials (irrespective of language, blinding, or publication status) including participants with alcohol-related liver disease. We excluded trials that included participants who had previously undergone liver transplantation and those with co-existing chronic viral diseases. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention. DATA COLLECTION AND ANALYSIS Two review authors independently identified trials and independently extracted data. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CIs) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS We identified a total of 81 randomised clinical trials. All the trials were at high risk of bias, and the overall quality of the evidence was low or very low for all outcomes. Alcoholic hepatitisFifty randomised clinical trials included 4484 participants with alcoholic hepatitis. The period of follow-up ranged from one to 12 months. Because of concerns about transitivity assumption, we did not perform the network meta-analysis. None of the active interventions showed any improvement in any of the clinical outcomes reported in the trials, which includes mortality (at various time points), cirrhosis, decompensated cirrhosis, liver transplantation. None of the trials reported health-related quality of life or incidence of hepatocellular carcinoma. Severe alcoholic hepatitisOf the trials on alcoholic hepatitis, 19 trials (2545 participants) included exclusively participants with severe alcoholic hepatitis (Maddrey Discriminat Function > 32). The period of follow-up ranged from one to 12 months. There was no alteration in the conclusions when only people with severe alcoholic hepatitis were included in the analysis. SOURCE OF FUNDING Eleven trials were funded by parties with vested interest in the results. Sixteen trials were funded by parties without vested interest in the results. The source of funding was not reported in 23 trials. Other alcohol-related liver diseasesThirty-one randomised clinical trials included 3695 participants with other alcohol-related liver diseases (with a wide spectrum of alcohol-related liver diseases). The period of follow-up ranged from one to 48 months. The mortality at maximal follow-up was lower in the propylthiouracil group versus the no intervention group (OR 0.45, 95% CI 0.26 to 0.78; 423 participants; 2 trials; low-quality evidence). However, this result is based on two small trials at high risk of bias and further confirmation in larger trials of low risk of bias is necessary to recommend propylthiouracil routinely in people with other alcohol-related liver diseases. The mortality at maximal follow-up was higher in the ursodeoxycholic acid group versus the no intervention group (OR 2.09, 95% CI 1.12 to 3.90; 226 participants; 1 trial; low-quality evidence). SOURCE OF FUNDING Twelve trials were funded by parties with vested interest in the results. Three trials were funded by parties without vested interest in the results. The source of funding was not reported in 16 trials. AUTHORS' CONCLUSIONS Because of very low-quality evidence, there is uncertainty in the effectiveness of any pharmacological intervention versus no intervention in people with alcoholic hepatitis or severe alcoholic hepatitis. Based on low-quality evidence, propylthiouracil may decrease mortality in people with other alcohol-related liver diseases. However, these results must be confirmed by adequately powered trials with low risk of bias before propylthiouracil can be considered effective.Future randomised clinical trials should be conducted with approximately 200 participants in each group and follow-up of one to two years in order to compare the benefits and harms of different treatments in people with alcoholic hepatitis. Randomised clinical trials should include health-related quality of life and report serious adverse events separately from adverse events. Future randomised clinical trials should have a low risk of bias and low risk of random errors.
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Affiliation(s)
- Elena Buzzetti
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Maria Kalafateli
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryPond StreetLondonUKNW3 2QG
| | - Maja Thiele
- Odense University HospitalDepartment of Gastroenterology and HepatologySdr. Boulevard 29, Entrance 126OdenseDenmark5000
| | - Lise Lotte Gluud
- Copenhagen University Hospital HvidovreGastrounit, Medical DivisionKettegaards AlleHvidovreDenmark2650
| | - Cinzia Del Giovane
- University of Modena and Reggio EmiliaCochrane Italy, Department of Diagnostic, Clinical and Public Health MedicineVia del Pozzo 71ModenaItaly41124
| | - Gro Askgaard
- RigshospitaletDepartment of HepatologyBlegdamsvej 9København ØDenmark2100
| | - Aleksander Krag
- Odense University HospitalDepartment of Gastroenterology and HepatologySdr. Boulevard 29, indgang 126Odense CDenmark5000
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
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King AL, Mantena SK, Andringa KK, Millender-Swain T, Dunham-Snary KJ, Oliva CR, Griguer CE, Bailey SM. The methyl donor S-adenosylmethionine prevents liver hypoxia and dysregulation of mitochondrial bioenergetic function in a rat model of alcohol-induced fatty liver disease. Redox Biol 2016; 9:188-197. [PMID: 27566282 PMCID: PMC5007436 DOI: 10.1016/j.redox.2016.08.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 08/15/2016] [Accepted: 08/16/2016] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Mitochondrial dysfunction and bioenergetic stress play an important role in the etiology of alcoholic liver disease. Previous studies from our laboratory show that the primary methyl donor S-Adenosylmethionine (SAM) minimizes alcohol-induced disruptions in several mitochondrial functions in the liver. Herein, we expand on these earlier observations to determine whether the beneficial actions of SAM against alcohol toxicity extend to changes in the responsiveness of mitochondrial respiration to inhibition by nitric oxide (NO), induction of the mitochondrial permeability transition (MPT) pore, and the hypoxic state of the liver. METHODS For this, male Sprague-Dawley rats were pair-fed control and alcohol-containing liquid diets with and without SAM for 5 weeks and liver hypoxia, mitochondrial respiration, MPT pore induction, and NO-dependent control of respiration were examined. RESULTS Chronic alcohol feeding significantly enhanced liver hypoxia, whereas SAM supplementation attenuated hypoxia in livers of alcohol-fed rats. SAM supplementation prevented alcohol-mediated decreases in mitochondrial state 3 respiration and cytochrome c oxidase activity. Mitochondria isolated from livers of alcohol-fed rats were more sensitive to calcium-mediated MPT pore induction (i.e., mitochondrial swelling) than mitochondria from pair-fed controls, whereas SAM treatment normalized sensitivity for calcium-induced swelling in mitochondria from alcohol-fed rats. Liver mitochondria from alcohol-fed rats showed increased sensitivity to NO-dependent inhibition of respiration compared with pair-fed controls. In contrast, mitochondria isolated from the livers of SAM treated alcohol-fed rats showed no change in the sensitivity to NO-mediated inhibition of respiration. CONCLUSION Collectively, these findings indicate that the hepato-protective effects of SAM against alcohol toxicity are mediated, in part, through a mitochondrial mechanism involving preservation of key mitochondrial bioenergetic parameters and the attenuation of hypoxic stress.
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Affiliation(s)
- Adrienne L King
- Departments of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
| | - Sudheer K Mantena
- Departments of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
| | - Kelly K Andringa
- Departments of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
| | - Telisha Millender-Swain
- Departments of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Departments of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
| | - Kimberly J Dunham-Snary
- Departments of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
| | - Claudia R Oliva
- Departments of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
| | - Corinne E Griguer
- Departments of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
| | - Shannon M Bailey
- Departments of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Departments of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
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Ghorbani Z, Hajizadeh M, Hekmatdoost A. Dietary supplementation in patients with alcoholic liver disease: a review on current evidence. Hepatobiliary Pancreat Dis Int 2016; 15:348-360. [PMID: 27498574 DOI: 10.1016/s1499-3872(16)60096-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Alcoholic liver disease (ALD) is one of the main causes of liver disease worldwide. Although the pathogenesis of ALD has not yet been well elucidated, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species play a pivotal role in the clinical and pathological spectrum of the disease. This review summarizes the existing evidences on dietary supplements considered to have antioxidant, and/or anti-inflammatory properties, and their role in the management of ALD and the proposed mechanisms. DATA SOURCES The present study reviewed all studies published in PubMed, ScienceDirect and Scopus, from 1959 to 2015, indicating the role of different dietary supplementation in attenuation of many pathophysiological processes involved in development and progression of ALD. Full-texts of citations were used except for those that were published in languages other than English. RESULTS Significant progress has been made to understand the key events and molecular players for the onset and progression of ALD from both experimental and clinical studies; however, there is no successful treatment currently available. The present review discussed the role of a variety of dietary supplements (e.g. vitamin A, carotenoids, vitamins B3, C and E, in addition to antioxidants and anti-inflammatory agents) in treating ALD. It has been shown that supplementation with some carotenoids, vitamin B3, vitamin C, silymarin, curcumin, probiotics, zinc, S-adenosylmethionine and garlic may have potential beneficial effects in animal models of ALD; however, the number of clinical studies is very limited. In addition, supplementation should be accompanied with alcohol cessation. CONCLUSIONS Since oxidative stress and inflammation are involved in the pathogenesis of ALD, dietary supplements that can modulate these pathologies could be useful in the treatment of ALD. In addition to alcohol cessation, these supplements have shown beneficial effects on animal models of ALD. Clinical trials are needed to validate the beneficiary role of these supplements in patients with ALD.
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Affiliation(s)
- Zeinab Ghorbani
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology, Research Institute Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Abstract
Alcoholic liver disease includes a broad clinical-histological spectrum from simple steatosis, cirrhosis, acute alcoholic hepatitis with or without cirrhosis to hepatocellular carcinoma as a complication of cirrhosis. The pathogenesis of alcoholic liver disease can be conceptually divided into (1) ethanol-mediated liver injury, (2) inflammatory immune response to injury, (3) intestinal permeability and microbiome changes. Corticosteroids may improve outcomes, but this is controversial and probably only impacts short-term survival. New pathophysiology-based therapies are under study, including antibiotics, caspase inhibition, interleukin-22, anakinra, FXR agonist and others. These studies provide hope for better future outcomes for this difficult disease.
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Affiliation(s)
- Winston Dunn
- Gastroenterology & Hepatology, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS USA
| | - Vijay H. Shah
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN USA
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Zhang F, Gu JX, Zou XP, Zhuge YZ. Protective effects of S-adenosylmethionine against CCl4- and ethanol-induced experimental hepatic fibrosis. Mol Biol 2016; 50:246-251. [DOI: 10.1134/s0026893316020278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/19/2025]
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Rosato V, Abenavoli L, Federico A, Masarone M, Persico M. Pharmacotherapy of alcoholic liver disease in clinical practice. Int J Clin Pract 2016; 70:119-31. [PMID: 26709723 DOI: 10.1111/ijcp.12764] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
AIMS Alcohol is the most commonly used addictive substance and alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide, responsible for 47.9% of all liver chronic deaths. Despite ALD has a significant burden on the health, few therapeutic advances have been made in the last 40 years, particularly in the long-term management of these patients. METHODS we searched in PubMed, Scopus, Google Scholar, and MEDLINE databases to identify relevant English language publications focused on long-term therapy of ALD. RESULTS From the huge literature on this topic, including about 755 studies, 75 were selected as eligible including clinical trials and meta-analysis. CONCLUSIONS Abstinence remains the cornerstone of ALD therapy but it is also the most difficult therapeutic target to achieve and the risk of recidivism is very high at any time. Several drugs (disulfiram, naltrexone, acamprosate, sodium oxybate) have proven to be effective to prevent alcohol relapse and increase the abstinence, although the psychotherapeutic support remains crucial. Baclofen seems to be effective to improve abstinence, showing an excellent safety and tolerability. ALD is often complicated by a state of malnutrition, which is related to a worst mortality. A nutritional therapy may improve survival in cirrhotic patients, reversing muscle wasting, weight loss and specific nutritional deficiencies. While in aggressive forms of alcoholic hepatitis are recommended specific drug treatments, including glucocorticoids or pentoxifylline, for the long-term treatment of ALD, specific treatments aimed at stopping the progression of fibrosis are not yet approved, but there are some future perspective in this field, including probiotics and antibiotics, caspase inhibitors, osteopontin and endocannabinoids.
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Affiliation(s)
- V Rosato
- Internal Medicine and Hepatology Department, Second University of Naples, Naples, Italy
| | - L Abenavoli
- Department of Health Science, University Magna Graecia, Catanzaro, Italy
| | - A Federico
- Gastroenterology and Endoscopy Unit, Second University of Naples, Naples, Italy
| | - M Masarone
- Internal Medicine and Hepatology Unit, University of Salerno, Baronissi, Italy
| | - M Persico
- Internal Medicine and Hepatology Unit, University of Salerno, Baronissi, Italy
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Kim MS, Ong M, Qu X. Optimal management for alcoholic liver disease: Conventional medications, natural therapy or combination? World J Gastroenterol 2016; 22:8-23. [PMID: 26755857 PMCID: PMC4698510 DOI: 10.3748/wjg.v22.i1.8] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/07/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Alcohol consumption is the principal factor in the pathogenesis of chronic liver diseases. Alcoholic liver disease (ALD) is defined by histological lesions on the liver that can range from simple hepatic steatosis to more advanced stages such as alcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma and liver failure. As one of the oldest forms of liver injury known to humans, ALD is still a leading cause of liver-related morbidity and mortality and the burden is exerting on medical systems with hospitalization and management costs rising constantly worldwide. Although the biological mechanisms, including increasing of acetaldehyde, oxidative stress with induction of cytochrome p450 2E1, inflammatory cytokine release, abnormal lipid metabolism and induction of hepatocyte apoptosis, by which chronic alcohol consumption triggers serious complex progression of ALD is well established, there is no universally accepted therapy to prevent or reverse. In this article, we have briefly reviewed the pathogenesis of ALD and the molecular targets for development of novel therapies. This review is focused on current therapeutic strategies for ALD, including lifestyle modification with nutrition supplements, available pharmacological drugs and new agents that are under development, liver transplantation, application of complementary medicines, and their combination. The relevant molecular mechanisms of each conventional medication and natural agent have been reviewed according to current available knowledge in the literature. We also summarized efficacy vs safety on conventional and herbal medicines which are specifically used for the prevention and treatment of ALD. Through a system review, this article highlighted that the combination of pharmaceutical drugs with naturally occurring agents may offer an optimal management for ALD and its complications. It is worthwhile to conduct large-scale, multiple centre clinical trials to further prove the safety and benefits for the integrative therapy on ALD.
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Pavlov CS, Casazza G, Nikolova D, Tikhonov I, Tsochatzis E, Gluud C. S-adenosyl-L-methionine for people with alcoholic liver disease. Hippokratia 2015. [DOI: 10.1002/14651858.cd011949] [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]
Affiliation(s)
- Chavdar S Pavlov
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital; The Cochrane Hepato-Biliary Group; Blegdamsvej 9 Copenhagen Denmark DK-2100
- I.M. Sechenov First Moscow State Medical University; Clinic of Internal Diseases Propedeutics; Pogodinskaja 1 Moscow Russian Federation 119991
| | - Giovanni Casazza
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital; The Cochrane Hepato-Biliary Group; Blegdamsvej 9 Copenhagen Denmark DK-2100
- Università degli Studi di Milano; Dipartimento di Scienze Biomediche e Cliniche "L. Sacco"; via GB Grassi 74 Milan Italy 20157
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital; The Cochrane Hepato-Biliary Group; Blegdamsvej 9 Copenhagen Denmark DK-2100
| | - Igor Tikhonov
- I.M. Sechenov First Moscow State Medical University; Department of Hepatology; Pogodinskaja 1 Moscow Russian Federation 119991
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive Health; Sheila Sherlock Liver Centre; Pond Street London UK NW3 2QG
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital; The Cochrane Hepato-Biliary Group; Blegdamsvej 9 Copenhagen Denmark DK-2100
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Rossi RE, Conte D, Massironi S. Diagnosis and treatment of nutritional deficiencies in alcoholic liver disease: Overview of available evidence and open issues. Dig Liver Dis 2015; 47:819-825. [PMID: 26164399 DOI: 10.1016/j.dld.2015.05.021] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 04/28/2015] [Accepted: 05/30/2015] [Indexed: 02/08/2023]
Abstract
Malnutrition is common in alcoholic liver disease and is associated with high rates of complications and mortality. In this article, the current literature was reviewed to highlight the relevance of proper nutritional management providing levels of evidence, when available. A PubMed search was performed for English-language publications from 1980 through 2014 with the keywords: alcoholic liver disease, nutritional deficiencies, nutritional support, enteral nutrition, parenteral nutrition, and protein-energy malnutrition. Manuscripts focused on nutritional approach in patients with alcoholic liver disease were selected. Although nutritional support for malnourished patients improves the outcome of hospitalization, surgery, transplantation and reduces the complications of liver disease and the length of hospital stay, specific guidelines are scanty. Both enteral and parenteral nutrition appear to improve nutritional parameters and liver function; however data on survival is often conflicting. As micronutrient depletion is common in alcoholic liver disease and each deficiency produces specific sequelae, all cirrhotic patients should be screened at baseline for deficiencies of micronutrient and supplemented as needed. In summary, protein-energy malnutrition and micronutrient depletion are clinical concerns in alcoholic liver disease. Nutritional therapy, including enteral nutrition, parenteral nutrition and micronutrient supplementation should be part of the multidisciplinary management of these patients.
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Affiliation(s)
- Roberta Elisa Rossi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
| | - Dario Conte
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Sara Massironi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Italy
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Tong S, Guo J, Song H, Lv S, Zhu Y, Ma J, Zheng Y. Effect of ademetionine on cytochrome P450 isoforms activity in rats. Int J Clin Exp Med 2015; 8:9716-9722. [PMID: 26309647 PMCID: PMC4538182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 06/07/2015] [Indexed: 06/04/2023]
Abstract
Cocktail method was used to evaluate the influence of ademetionine on the activities of CYP450 isoforms CYP1A2, CYP2D6, CYP3A4, CYP2C19, CYP2C9 and CYP2B6, which were reflected by the changes of pharmacokinetic parameters of six specific probe drugs phenacetin, metroprolol, midazolam, omeprazole, tolbutamide and bupropion, respectively. The experimental rats were randomly divided into two group, control group and ademetionine group. The ademetionine group rats were given 50 mg/kg ademetionine by continuous oral administration for 7 days. The mixture of six probes was given to rats through oral administration and the blood samples were obtained at a series of time-points through the caudal vein. The concentrations of probe drugs in rat plasma were measured by UPLC-MS/MS. In the experiment for ademetionine and control group, there was statistical pharmacokinetics difference for phenacetin, metroprolol, midazolam, omeprazole, tolbutamide and bupropion. Continuous oral administration for 7 days could induce the activities of CYP450 isoforms CYP1A2 of rats, while it may inhibit the activities of CYP2D6, CYP3A4, CYP2C19 and CYP2C9.
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Affiliation(s)
- Shuhua Tong
- Department of Clinical Pharmacy, Jinhua Central HospitalJinhua 321000, China
| | - Jiayi Guo
- Department of Clinical Pharmacy, Jinhua Central HospitalJinhua 321000, China
| | - Huanchun Song
- Department of Clinical Pharmacy, Jinhua Central HospitalJinhua 321000, China
| | - Shiwen Lv
- Department of Clinical Pharmacy, Jinhua Central HospitalJinhua 321000, China
| | - Yalan Zhu
- Department of Clinical Pharmacy, Jinhua Central HospitalJinhua 321000, China
| | - Jianshe Ma
- Function Experiment Teaching Center of Wenzhou Medical UniversityWenzhou 325000, China
| | - Yuancai Zheng
- The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000, China
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Noureddin M, Mato JM, Lu SC. Nonalcoholic fatty liver disease: update on pathogenesis, diagnosis, treatment and the role of S-adenosylmethionine. Exp Biol Med (Maywood) 2015; 240:809-20. [PMID: 25873078 PMCID: PMC4818965 DOI: 10.1177/1535370215579161] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide affecting over one-third of the population in the U.S. It has been associated with obesity, type 2 diabetes, hyperlipidemia, and insulin resistance and is initiated by the accumulation of triglycerides in hepatocytes. Isolated hepatic steatosis (IHS) remains a benign process, while a subset develops superimposed inflammatory activity and progression to nonalcoholic steatohepatitis (NASH) with or without fibrosis. However, the molecular mechanisms underlying NAFLD progression are not completely understood. Liver biopsy is still required to differentiate IHS from NASH as easily accessible noninvasive biomarkers are lacking. In terms of treatments for NASH, pioglitazone, vitamin E, and obeticholic acid have shown some benefit. All of these agents have potential complications associated with long-term use. Nowadays, a complex hypothesis suggests that multiple parallel hits are involved in NASH development. However, the 'key switch' between IHS and NASH remains to be discovered. We have recently shown that knocking out enzymes involved in S-adenosylmethionine (SAMe) metabolism, the main biological methyl donor in humans that is abundant in the liver, will lead to NASH development in mice. This could be due to the fact that a normal SAMe level is required to establish the proper ratio of phosphatidylethanolamine to phosphatidylcholine that has been found to be important in NAFLD progression. New data from humans have also suggested that these enzymes play a role in the pathogenesis of NAFLD and that some of SAMe cycle metabolites may serve as noninvasive biomarkers of NASH. In this review, we discuss the evidence of the role of SAMe in animal models and humans with NAFLD and how studying this area may lead to the discovery of new noninvasive biomarkers and possibly personalized treatment for NASH.
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Affiliation(s)
| | - José M Mato
- Ibaizabal Kalea, 101, 48170 Zamudio, Bizkaia, Spain
| | - Shelly C Lu
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Strategies to prevent and reverse liver fibrosis in humans and laboratory animals. Arch Toxicol 2015; 89:1727-50. [PMID: 25963329 DOI: 10.1007/s00204-015-1525-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 04/28/2015] [Indexed: 02/07/2023]
Abstract
Liver fibrosis results from chronic damage to the liver in conjunction with various pathways and is mediated by a complex microenvironment. Based on clinical observations, it is now evident that fibrosis is a dynamic, bidirectional process with an inherent capacity for recovery and remodeling. The major mechanisms involved in liver fibrosis include the repetitive injury of hepatocytes, the activation of the inflammatory response after injury stimulation, and the activation and proliferation of hepatic stellate cells (HSCs), which represents the major extracellular matrix (ECM)-producing cells, stimulated by hepatocyte injury and inflammation. The microenvironment in the liver is synergistically regulated abnormal ECM deposition, scar formation, angiogenesis, and fibrogenesis. Moreover, recent studies have clarified novel mechanism in fibrosis such as epigenetic regulation of HSCs, the leptin and PPARγ pathways, the coagulation system, and even autophagy. Uncovering the mechanisms of liver fibrogenesis provides a basis to develop potential therapies to reverse and treat the fibrotic response, thereby improving the outcomes of patients with chronic liver disease. Although both scientific and clinical challenges remain, emerging studies attempt to reveal the ideal anti-fibrotic drug that could be easily delivered to the liver with high specificity and low toxicity. This review highlights the mechanisms, including novel pathways underlying fibrogenesis that may be translated into preventive and treatment strategies, reviews both current and novel agents that target specific pathways or multiple targets, and discusses novel drug delivery systems such as nanotechnology that can be applied in the treatment of liver fibrosis. In addition, we also discuss some current treatment strategies that are being applied in animal models and in clinical trials.
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Abstract
Betaine supplements of alcoholic beverages are proposed to prevent the development of alcoholic liver disease in patients that abuse alcohol. This recommendation is based on the observation of studies where it has been shown in binge drinking and chronic ethanol feeding animal models that betaine prevents liver injury resulting from high blood alcohol levels. The basic observation is that betaine added to ethanol being ingested increases the elimination rate of blood alcohol, which prevents the blood alcohol levels (BALs) from reaching high levels. The mechanism of how betaine does this is postulated to be that betaine causes the increase in the elimination rate by increasing the metabolic rate which generates NAD the rate limiting cofactor of alcohol oxidation by ADH. Betaine does this most likely by supporting the methylation of norepinephrine to form epinephrine by phenylethanolamine N-methyltransferase. Epinephrine is 5 to 10-fold more active than norepinephrine in increasing the metabolic rate.
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Affiliation(s)
- S W French
- Harbor-UCLA Medical Center, Torrance, CA 90509, United States.
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Guo T, Chang L, Xiao Y, Liu Q. S-adenosyl-L-methionine for the treatment of chronic liver disease: a systematic review and meta-analysis. PLoS One 2015; 10:e0122124. [PMID: 25774783 PMCID: PMC4361566 DOI: 10.1371/journal.pone.0122124] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 02/07/2015] [Indexed: 12/13/2022] Open
Abstract
It has been well established that S-adenosyl-L-methionine (SAMe) is the principal methyl donor in methyltransferase reactions and that SAMe supplementation restores hepatic glutathione (GSH) deposits and attenuates liver injury. However, the effectiveness of SAMe therapy in chronic liver disease has not been adequately addressed. We searched globally recognized electronic databases, including PubMed, the Cochrane Database and EMBASE, to retrieve relevant randomized controlled trials (RCTs) of chronic liver disease published in the past 20 years. We then performed a systematic review and meta-analysis of the enrolled trials that met the inclusion criteria.The results showed that twelve RCTs from 11 studies, which examined 705 patients, were included in this research. For liver function, certain results obtained from data synthesis and independent comparisons demonstrated significant differences between the levels of total bilirubin (TBIL) and aspartate transaminase (AST). However, no studies identified significant differences regarding alanine transaminase (ALT) levels. An analysis of the adverse events and long-term prognosis also indicated no significant differences between the SAMe and the placebo groups. In a subgroup analysis of gravidas and children, several of the included data indicated that there was a significant difference in the pruritus score. Furthermore, the results regarding ursodeoxycholic acid (UDCA) and stronger neo-minophagen C (SNMC) indicated that both treatments were more effective than SAMe was in certain chronic liver diseases. These findings suggest that SAMe could be used as the basis of a medication regimen for liver function improvement because of its safety. However, SAMe also demonstrated limited clinical value in the treatment of certain chronic liver diseases.
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Affiliation(s)
- Tao Guo
- Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University, Wuhan 430071, P.R. China
| | - Lei Chang
- Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University, Wuhan 430071, P.R. China
| | - Yusha Xiao
- Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University, Wuhan 430071, P.R. China
| | - Quanyan Liu
- Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University, Wuhan 430071, P.R. China
- * E-mail:
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Williams JA, Manley S, Ding WX. New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases. World J Gastroenterol 2014; 20:12908-12933. [PMID: 25278688 PMCID: PMC4177473 DOI: 10.3748/wjg.v20.i36.12908] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 03/07/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has been made to understand key events and molecular players for the onset and progression of alcoholic liver disease from both experimental and clinical alcohol studies. No successful treatments are currently available for treating alcoholic liver disease; therefore, development of novel pathophysiological-targeted therapies is urgently needed. This review summarizes the recent progress on animal models used to study alcoholic liver disease and the detrimental factors that contribute to alcoholic liver disease pathogenesis including miRNAs, S-adenosylmethionine, Zinc deficiency, cytosolic lipin-1β, IRF3-mediated apoptosis, RIP3-mediated necrosis and hepcidin. In addition, we summarize emerging adaptive protective effects induced by alcohol to attenuate alcohol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1α.
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Park BJ, Lee YJ, Lee HR. Chronic liver inflammation: Clinical implications beyond alcoholic liver disease. World J Gastroenterol 2014; 20:2168-2175. [PMID: 24605015 PMCID: PMC3942821 DOI: 10.3748/wjg.v20.i9.2168] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Revised: 12/21/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic alcohol exposure can lead to alcoholic liver disease, including hepatitis, cirrhosis and hepatocellular carcinoma, and chronic inflammation can simultaneously cause systemic medical illness. Recent evidence suggests that alcoholic liver disease is a predictor for liver-related diseases, cardiovascular disease, immunologic disease, and bone disease. Chronic inflammation in alcoholic liver disease is mediated by a direct inflammatory cascade from the alcohol detoxification process and an indirect inflammatory cascade in response to gut microflora-derived lipopolysaccharides (LPS). The pathophysiology of alcoholic liver disease and its related systemic illness is characterized by oxidative stress, activation of the immune cascade, and gut-liver interactions. Integrative therapeutic strategies for alcoholic liver disease include abstaining from alcohol consumption; general anti-inflammatories such as glucocorticoid, pentoxifylline, and tumour necrosis factor-α antagonist; antioxidants such as N- acetylcysteine; gut microflora and LPS modulators such as rifaximin and/or probiotics. This review focuses on the impact of chronic liver inflammation on systemic health problems and several potential therapeutic targets.
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Abenavoli L, Milic N, Rouabhia S, Addolorato G. Pharmacotherapy of acute alcoholic hepatitis in clinical practice. World J Gastroenterol 2014; 20:2159-67. [PMID: 24605014 PMCID: PMC3942820 DOI: 10.3748/wjg.v20.i9.2159] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 01/02/2014] [Accepted: 01/14/2014] [Indexed: 02/06/2023] Open
Abstract
Severe alcoholic hepatitis (AH) is an acute form of alcohol induced liver disease with a poor prognosis that is seen in the patients who consume large quantities of alcohol. The diagnosis of AH is based on the appropriate alcohol intake history and is supported with clinical and histological features, and several scoring systems. Glucocorticoids are the mainstay for treating severe AH with pentoxifylline used as an alternative to steroids in addition to total alcohol abstinence. Liver transplantation is a possible therapeutic option for severe AH. Among the anti-craving medications able to improve abstinence rate, baclofen seems to be effective and safe in the alcoholic patients affected by severe liver damage.
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Neuman MG, French SW, Casey CA, Kharbanda KK, Nanau RM, Rasineni K, McVicker BL, Kong V, Donohue TM. Changes in the pathogenesis of alcohol-induced liver disease — Preclinical studies. Exp Mol Pathol 2013; 95:376-84. [PMID: 24161955 DOI: 10.1016/j.yexmp.2013.10.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2013] [Accepted: 10/15/2013] [Indexed: 12/14/2022]
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