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Yildiz E, Zaffar D, Ozturk NB, Gurakar M, Donmez AE, Toruner MD, Simsek C, Gurakar A. Liver transplantation for alcohol-associated liver disease: The changing landscape. HEPATOLOGY FORUM 2025; 6:77-86. [PMID: 40248677 PMCID: PMC11999900 DOI: 10.14744/hf.2024.2024.0057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 01/14/2025] [Accepted: 02/11/2025] [Indexed: 04/19/2025]
Abstract
Alcoholic liver disease(ALD) is considered as a growing public health issue with universally increasing disease burden. Various genetic and environmental factors play role in its etiology. ALD recently has become the major indication for Liver Transplantation (LT). Most LT programs select their candidates by adhering to six months of alcohol abstinence policy. Nevertheless, early liver transplantation (ELT) has become a subject of research, both in Europe and the United States, as an effective and lifesaving option among highly selected severe alcohol-associated hepatitis (SAH) patients. ELT is a promising way in the management of ALD, perhaps changing clinical practice for carefully selected patient groups.
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Affiliation(s)
- Eda Yildiz
- Department of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Duha Zaffar
- Department of Internal Medicine, University of Maryland Midtown Campus, Baltimore, Maryland, USA
| | - N. Begum Ozturk
- Department of Internal Medicine, Beaumont Hospital, Royal Oak, Michigan, USA
| | - Merve Gurakar
- Department of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - A. Eylul Donmez
- Department of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Merih Deniz Toruner
- Brown University Warren Alpert, School of Medicine School, Providence, Rhode Island, USA
| | - Cem Simsek
- Department of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ahmet Gurakar
- Department of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 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: 0] [Impact Index Per Article: 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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Nataraj K, Schonfeld M, Rodriguez A, Sharma M, Weinman S, Tikhanovich I. Androgen Effects on Alcohol-induced Liver Fibrosis Are Controlled by a Notch-dependent Epigenetic Switch. Cell Mol Gastroenterol Hepatol 2024; 19:101414. [PMID: 39349250 PMCID: PMC11609386 DOI: 10.1016/j.jcmgh.2024.101414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 09/23/2024] [Accepted: 09/24/2024] [Indexed: 10/02/2024]
Abstract
BACKGROUND & AIMS Alcohol-associated liver disease (ALD) is a major cause of alcohol-related mortality. Sex is an important variable; however, the mechanism behind sex differences is not yet established. METHODS Kdm5b flox/flox Kdm5c flox male mice were subjected to gonadectomy or sham surgery. Mice were fed a Western diet and 20% alcohol in the drinking water for 18 weeks. To induce knockout, mice received 2 × 1011 genome copies of AAV8-CMV-Cre or AAV8-control. To test the role of Notch, mice were treated with 10 mg/kg of avagacestat for 4 weeks. RESULTS We found that Kdm5b/Kdm5c knockout promoted alcohol-induced liver disease, whereas gonadectomy abolished this effect, suggesting that male sex hormones promote liver disease in the absence of KDM5 demethylases. In contrast, in the thioacetamide-induced fibrosis model, male sex hormones showed a protective effect regardless of genotype. In human liver disease samples, we found that androgen receptor expression positively correlated with fibrosis levels when KDM5B levels were low and negatively when KDM5B was high, suggesting that a KDM5B-dependent epigenetic state defines the androgen receptor role in liver fibrosis. Using isolated cells, we found that this difference was due to the differential effect of testosterone on hepatic stellate cell activation in the absence or presence of KDM5B/KDM5C. Moreover, this effect was mediated by KDM5-dependent suppression of Notch signaling. In KDM5-deficient mice, Notch3 and Jag1 gene expression was induced, facilitating testosterone-mediated induction of Notch signaling and stellate cell activation. Inhibiting Notch with avagacestat greatly reduced liver fibrosis and abolished the effect of Kdm5b/Kdm5c loss. CONCLUSIONS Male sex hormone signaling can promote or prevent alcohol-associated liver fibrosis depending on the KDM5-dependent epigenetic state.
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Affiliation(s)
- Kruti Nataraj
- Department of Internal Medicine, Kansas City VA Medical Center, Kansas City, Missouri
| | - Michael Schonfeld
- Department of Internal Medicine, Kansas City VA Medical Center, Kansas City, Missouri
| | - Adriana Rodriguez
- Department of Internal Medicine, Kansas City VA Medical Center, Kansas City, Missouri
| | - Madhulika Sharma
- Department of Internal Medicine, Kansas City VA Medical Center, Kansas City, Missouri
| | - Steven Weinman
- Department of Internal Medicine, Kansas City VA Medical Center, Kansas City, Missouri; Kansas City VA Medical Center, Kansas City, Missouri
| | - Irina Tikhanovich
- Department of Internal Medicine, Kansas City VA Medical Center, Kansas City, Missouri.
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Zhang X, Wu S, Cao Y, Ma S, Sun H, Liu Z. Association of life's essential 8 with mortalities in patients with alcohol-related liver disease. BMC Gastroenterol 2024; 24:326. [PMID: 39342138 PMCID: PMC11439271 DOI: 10.1186/s12876-024-03432-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 09/24/2024] [Indexed: 10/01/2024] Open
Abstract
BACKGROUND Alcohol-related liver disease (ALD) and cardiovascular diseases share some common risk factors. This study aims to investigate the associations between Life's Essential 8 (LE8), a comprehensive measure of cardiovascular health (CVH), and outcomes of ALD. METHODS Data were obtained from the 2011-2018 National Health and Nutrition Examination Survey (NHANES). Cox proportional hazards models were employed to assess the relationships between LE8 and all-cause and cardiovascular mortality in patients with ALD. Additionally, restricted cubic splines (RCS), piecewise regression, and subgroup analyses were conducted. RESULTS A total of 5321 ALD patients were included in this study with a mean LE8 score of 67.38. During a median follow-up period of 63 months, 228 all-cause deaths were recorded. After adjusting for potential confounders, the risk of all-cause mortality in the high CVH group decreased by 53.7% compared to the low CVH group (HR = 0.463, 95%CI = 0.223-0.965). The result was robust in subgroup analyses. The RCS analysis indicated a non-linear relationship between LE8 and cardiovascular mortality, showing that the risk of cardiovascular mortality decreased with increasing LE8 scores for values below 71.12 (HR = 0.949, 95% CI = 0.915-0.984). CONCLUSIONS LE8 score is inversely and linearly linked to all-cause mortality in ALD patients. Promoting adherence to optimal cardiovascular health may unveil additional strategies for the effective management of ALD patients and contribute to reducing their long-term mortality.
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Affiliation(s)
- Xiaohui Zhang
- Department of General Surgery, Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, China
| | - Shimou Wu
- Guangning County People's Hospital, Zhaoqing, China
| | - Yang Cao
- Department of Cardiology, The 963 Hospital of the PLA Joint Logistics Support Force, Jiamusi, Heilongjiang, China
| | - Sicong Ma
- Southern medical university, Guangzhou, China
| | - Hongfei Sun
- Department of Gastroenterology, Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, China
| | - Zhen Liu
- Department of General Surgery, Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, China.
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Liu R, Mo C, Wei X, Ma A. Hepatoprotective Effect of Annulohypoxylon stygium Melanin on Acute Alcoholic Liver Injury in Mice. Appl Biochem Biotechnol 2024; 196:6395-6408. [PMID: 38381310 DOI: 10.1007/s12010-024-04863-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2024] [Indexed: 02/22/2024]
Abstract
Annulohypoxylon stygium melanin (AsM) has various functional properties such as antioxidant and anti-radiation, but its biological activity in vivo has not been fully investigated. In this study, we researched the effects of AsM on the protection against acute liver injury in mice and its mechanism. The results showed that AsM had no significant effect on body weight in mice but reduced the liver index. It was able to significantly decrease the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), the contents of triglyceride (TG) and total cholesterol (TC) in mice. Simultaneously, it raised the levels of superoxide dismutase (SOD), peroxidase (CAT), and glutathione peroxidase (GSH-Px), which obviously exceeded those of the EtOH group. AsM could significantly lower the levels of inflammatory factors, with inhibition rates of 68.30%, 29.0%, and 19.50% for IL-1β, IL-6, and TNF-α, respectively. H&E and Oil red O staining also showed that AsM ameliorated liver damage and lipid accumulation in mice. The protective mechanism of AsM may be associated to the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant signaling pathway, which could activate the downstream antioxidant enzymes heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GCLM), and glutamate-cysteine ligase catalytic subunit (GCLC). These findings confirmed that AsM had an alleviating effect on alcoholic liver injury and provided new thoughts for the development of natural product.
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Affiliation(s)
- Ruofan Liu
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Cuiyuan Mo
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Xuetuan Wei
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
- Key Laboratory of Environment Correlative Dietology, Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China
| | - Aimin Ma
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China.
- Key Laboratory of Agro-Microbial Resources and Utilization, Ministry of Agriculture, Wuhan, 430070, China.
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Wei H, Zhao T, Liu X, Ding Q, Yang J, Bi X, Cheng Z, Ding C, Liu W. Mechanism of Action of Dihydroquercetin in the Prevention and Therapy of Experimental Liver Injury. Molecules 2024; 29:3537. [PMID: 39124941 PMCID: PMC11314611 DOI: 10.3390/molecules29153537] [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: 06/27/2024] [Revised: 07/23/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
Liver disease is a global health problem that affects the well-being of tens of thousands of people. Dihydroquercetin (DHQ) is a flavonoid compound derived from various plants. Furthermore, DHQ has shown excellent activity in the prevention and treatment of liver injury, such as the inhibition of hepatocellular carcinoma cell proliferation after administration, the normalization of oxidative indices (like SOD, GSH) in this tissue, and the down-regulation of pro-inflammatory molecules (such as IL-6 and TNF-α). DHQ also exerts its therapeutic effects by affecting molecular pathways such as NF-κB and Nrf2. This paper discusses the latest research progress of DHQ in the treatment of various liver diseases (including viral liver injury, drug liver injury, alcoholic liver injury, non-alcoholic liver injury, fatty liver injury, and immune liver injury). It explores how to optimize the application of DHQ to improve its effectiveness in treating liver diseases, which is valuable for preparing potential therapeutic drugs for human liver diseases in conjunction with DHQ.
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Affiliation(s)
- Hewei Wei
- College of Traditional Chinese Medicine, Jilin Agricultural University, Changchun 130118, China; (H.W.); (Q.D.); (J.Y.); (X.B.); (Z.C.)
| | - Ting Zhao
- School of Food and Pharmaceutical Engineering, Wuzhou University, Wuzhou 543002, China; (T.Z.); (X.L.)
| | - Xinglong Liu
- School of Food and Pharmaceutical Engineering, Wuzhou University, Wuzhou 543002, China; (T.Z.); (X.L.)
| | - Qiteng Ding
- College of Traditional Chinese Medicine, Jilin Agricultural University, Changchun 130118, China; (H.W.); (Q.D.); (J.Y.); (X.B.); (Z.C.)
- School of Food and Pharmaceutical Engineering, Wuzhou University, Wuzhou 543002, China; (T.Z.); (X.L.)
| | - Junran Yang
- College of Traditional Chinese Medicine, Jilin Agricultural University, Changchun 130118, China; (H.W.); (Q.D.); (J.Y.); (X.B.); (Z.C.)
| | - Xiaoyu Bi
- College of Traditional Chinese Medicine, Jilin Agricultural University, Changchun 130118, China; (H.W.); (Q.D.); (J.Y.); (X.B.); (Z.C.)
| | - Zhiqiang Cheng
- College of Traditional Chinese Medicine, Jilin Agricultural University, Changchun 130118, China; (H.W.); (Q.D.); (J.Y.); (X.B.); (Z.C.)
| | - Chuanbo Ding
- College of Traditional Chinese Medicine, Jilin Agricultural University, Changchun 130118, China; (H.W.); (Q.D.); (J.Y.); (X.B.); (Z.C.)
- College of Traditional Chinese Medicine, Jilin Agriculture Science and Technology College, Jilin 132101, China
| | - Wencong Liu
- School of Food and Pharmaceutical Engineering, Wuzhou University, Wuzhou 543002, China; (T.Z.); (X.L.)
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Ghare SS, Charpentier BT, Ghooray DT, Zhang J, Vadhanam MV, Reddy S, Joshi-Barve S, McClain CJ, Barve SS. Tributyrin Mitigates Ethanol-Induced Lysine Acetylation of Histone-H3 and p65-NFκB Downregulating CCL2 Expression and Consequent Liver Inflammation and Injury. Nutrients 2023; 15:4397. [PMID: 37892472 PMCID: PMC10610222 DOI: 10.3390/nu15204397] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 09/27/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
PURPOSE Chemokine-driven leukocyte infiltration and sustained inflammation contribute to alcohol-associated liver disease (ALD). Elevated hepatic CCL2 expression, seen in ALD, is associated with disease severity. However, mechanisms of CCL2 regulation are not completely elucidated. Post-translational modifications (PTMs) of proteins, particularly acetylation, modulate gene expression. This study examined the acetylation changes of promoter-associated histone-H3 and key transcription factor-NFκB in regulating hepatic CCL2 expression and subsequent inflammation and injury. Further, the effect of therapeutic modulation of the acetylation state by tributyrin (TB), a butyrate prodrug, was assessed. METHODS Hepatic CCL2 expression was assessed in mice fed control (PF) or an ethanol-containing Lieber-DeCarli (5% v/v, EF) diet for 7 weeks with or without oral administration of tributyrin (TB, 2 g/kg, 5 days/week). A chromatin immunoprecipitation (ChIP) assay evaluated promoter-associated modifications. Nuclear association between SIRT1, p300, and NFκB-p65 and acetylation changes of p65 were determined using immunoprecipitation and Western blot analyses. A Student's t-test and one-way ANOVA determined the significance. RESULTS Ethanol significantly increased promoter-associated histone-H3-lysine-9 acetylation (H3K9Ac), reflecting a transcriptionally permissive state with a resultant increase in hepatic CCL2 mRNA and protein expression. Moreover, increased lysine-310-acetylation of nuclear RelA/p65 decreased its association with SIRT1, a class III HDAC, but concomitantly increased with p300, a histone acetyltransferase. This further led to enhanced recruitment of NF-κB/p65 and RNA polymerase-II to the CCL2 promoter. Oral TB administration prevented ethanol-associated acetylation changes, thus downregulating CCL2 expression, hepatic neutrophil infiltration, and inflammation/ injury. CONCLUSION The modulation of a protein acetylation state via ethanol or TB mechanistically regulates hepatic CCL2 upregulation in ALD.
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Affiliation(s)
- Smita S. Ghare
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
| | - Benjamin T. Charpentier
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- Department of Anatomical Science and Neurobiology, University of Louisville, Louisville, KY 40202, USA
| | - Dushan T. Ghooray
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
| | - Jingwen Zhang
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
| | - Manicka V. Vadhanam
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
| | - Sreelatha Reddy
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
| | - Swati Joshi-Barve
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
| | - Craig J. McClain
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
- Robley Rex VA Medical Center, University of Louisville, Louisville, KY 40202, USA
| | - Shirish S. Barve
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA
- UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA
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Wu M, Qin S, Tan C, Li S, Xie O, Wan X. Estimated projection of incidence and mortality of alcohol-related liver disease in China from 2022 to 2040: a modeling study. BMC Med 2023; 21:277. [PMID: 37501074 PMCID: PMC10375628 DOI: 10.1186/s12916-023-02984-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 07/18/2023] [Indexed: 07/29/2023] Open
Abstract
BACKGROUND China has one of the highest numbers of liver disease cases in the world, including 6.4 million cirrhosis associated with alcohol-related liver disease (ALD) cases. However, there is still a lack of urgent awareness about the growth of alcohol consumption and the increased burden of ALD in China. Therefore, we aimed to project the potential impact of changes in alcohol consumption on the burden of ALD in China up to 2040 under different scenarios. METHODS We developed a Markov model to simulate the natural history of ALD until 2040 in China. We estimated the incidence and mortality of alcohol-related cirrhosis and hepatocellular carcinoma between 2022 and 2040 under four projected scenarios: status quo scenario and scenarios with a 2%, 4%, and 8% annual decrease in excessive alcohol consumption, respectively. RESULTS Under the status quo scenario, the cumulative new cases of cirrhosis from 2022 to 2040 was projected to be 3.61 million (95% UI 3.03-4.44 million), resulting in a cumulative 1.96 million (1.66-2.32 million) deaths from alcohol-related cirrhosis and hepatocellular carcinoma. However, a 2% annual reduction in excessive alcohol consumption was expected to avert 0.3 million deaths associated with ALD, and a 4% annual reduction was projected to prevent about 1.36 million new cases of cirrhosis and prevent 0.5 million ALD-related deaths. Moreover, an 8% annual reduction would prevent about 2 million new cases of cirrhosis and 0.82 million deaths. CONCLUSIONS Without any substantial change in alcohol attitudes and policies to regulate excessive drinking, the disease burden of ALD in China will increase enormously. Strengthening the implementation of alcohol restriction interventions is critical and urgent to reduce the impact of ALD on the Chinese population.
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Affiliation(s)
- Meiyu Wu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Institute of Clinical Pharmacy, Central South University, Changsha, 410011, Hunan, China
| | - Shuxia Qin
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Institute of Clinical Pharmacy, Central South University, Changsha, 410011, Hunan, China
| | - Chongqing Tan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Institute of Clinical Pharmacy, Central South University, Changsha, 410011, Hunan, China
| | - Sini Li
- The Nethersole School of Nursing, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Ouyang Xie
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Institute of Clinical Pharmacy, Central South University, Changsha, 410011, Hunan, China
| | - Xiaomin Wan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
- Institute of Clinical Pharmacy, Central South University, Changsha, 410011, Hunan, China.
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Geng Y, Xie Y, Li W, Mou Y, Chen F, Xiao J, Liao X, Hu X, Ji J, Ma L. Toward the bioactive potential of myricitrin in food production: state-of-the-art green extraction and trends in biosynthesis. Crit Rev Food Sci Nutr 2023; 64:10668-10694. [PMID: 37395263 DOI: 10.1080/10408398.2023.2227262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Myricitrin is a member of flavonols, natural phenolic compounds extracted from plant resources. It has gained great attention for various biological activities, such as anti-inflammatory, anti-cancer, anti-diabetic, as well as cardio-/neuro-/hepatoprotective activities. These effects have been demonstrated in both in vitro and in vivo models, making myricitrin a favorable candidate for the exploitation of novel functional foods with potential protective or preventive effects against diseases. This review summarized the health benefits of myricitrin and attempted to uncover its action mechanism, expecting to provide a theoretical basis for their application. Despite enormous bioactive potential of myricitrin, low production, high cost, and environmental damage caused by extracting it from plant resources greatly constrain its practical application. Fortunately, innovative, green, and sustainable extraction techniques are emerging to extract myricitrin, which function as alternatives to conventional techniques. Additionally, biosynthesis based on synthetic biology plays an essential role in industrial-scale manufacturing, which has not been reported for myricitrin exclusively. The construction of microbial cell factories is absolutely an appealing and competitive option to produce myricitrin in large-scale manufacturing. Consequently, state-of-the-art green extraction techniques and trends in biosynthesis were reviewed and discussed to endow an innovative perspective for the large-scale production of myricitrin.
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Affiliation(s)
- Yaqian Geng
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruits and Vegetables Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing, China
| | - Yingfeng Xie
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruits and Vegetables Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing, China
| | - Wei Li
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruits and Vegetables Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing, China
| | - Yao Mou
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruits and Vegetables Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing, China
| | - Fang Chen
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruits and Vegetables Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing, China
| | - Jianbo Xiao
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, Ourense, Spain
| | - Xiaojun Liao
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruits and Vegetables Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing, China
| | - Xiaosong Hu
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruits and Vegetables Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing, China
| | - Junfu Ji
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruits and Vegetables Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing, China
| | - Lingjun Ma
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruits and Vegetables Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing, China
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10
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Mishra G, Singh P, Molla M, Yimer YS, Dinda SC, Chandra P, Singh BK, Dagnew SB, Assefa AN, Ewunetie A. Harnessing the potential of probiotics in the treatment of alcoholic liver disorders. Front Pharmacol 2023; 14:1212742. [PMID: 37361234 PMCID: PMC10287977 DOI: 10.3389/fphar.2023.1212742] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 05/22/2023] [Indexed: 06/28/2023] Open
Abstract
In the current scenario, prolonged consumption of alcohol across the globe is upsurging an appreciable number of patients with the risk of alcohol-associated liver diseases. According to the recent report, the gut-liver axis is crucial in the progression of alcohol-induced liver diseases, including steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Despite several factors associated with alcoholic liver diseases, the complexity of the gut microflora and its great interaction with the liver have become a fascinating area for researchers due to the high exposure of the liver to free radicals, bacterial endotoxins, lipopolysaccharides, inflammatory markers, etc. Undoubtedly, alcohol-induced gut microbiota imbalance stimulates dysbiosis, disrupts the intestinal barrier function, and trigger immune as well as inflammatory responses which further aggravate hepatic injury. Since currently available drugs to mitigate liver disorders have significant side effects, hence, probiotics have been widely researched to alleviate alcohol-associated liver diseases and to improve liver health. A broad range of probiotic bacteria like Lactobacillus, Bifidobacteria, Escherichia coli, Sacchromyces, and Lactococcus are used to reduce or halt the progression of alcohol-associated liver diseases. Several underlying mechanisms, including alteration of the gut microbiome, modulation of intestinal barrier function and immune response, reduction in the level of endotoxins, and bacterial translocation, have been implicated through which probiotics can effectively suppress the occurrence of alcohol-induced liver disorders. This review addresses the therapeutic applications of probiotics in the treatment of alcohol-associated liver diseases. Novel insights into the mechanisms by which probiotics prevent alcohol-associated liver diseases have also been elaborated.
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Affiliation(s)
- Garima Mishra
- Pharmaceutical Chemistry Unit, Department of Pharmacy, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Pradeep Singh
- Pharmaceutical Chemistry Unit, Department of Pharmacy, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Mulugeta Molla
- Pharmacology and Toxicology Unit, Department of Pharmacy, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Yohannes Shumet Yimer
- Social Pharmacy Unit, Department of Pharmacy, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | | | - Phool Chandra
- Department of Pharmacology, Teerthanker Mahaveer College of Pharmacy, Teerthanker Mahaveer University, Moradabad, India
| | | | - Samuel Berihun Dagnew
- Clinical Pharmacy Unit, Department of Pharmacy, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Abraham Nigussie Assefa
- Social Pharmacy Unit, Department of Pharmacy, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Amien Ewunetie
- Pharmacology and Toxicology Unit, Department of Pharmacy, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
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11
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Chang W, Cai L, Chen T, Ni W, Xie Z, Yang C, Liao J. Current Helicobacter pylori Infection Is Associated with Early Liver Injury: A Cross-Sectional Study in the General Population. Am J Trop Med Hyg 2023; 108:684-692. [PMID: 36878209 PMCID: PMC10076991 DOI: 10.4269/ajtmh.22-0340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 12/05/2022] [Indexed: 03/08/2023] Open
Abstract
Early prevention of liver injury by controlling risk factors deserves concern because of the heavy liver disease burden. Helicobacter pylori (HP) infection affects half of the world's population and the relationship between it and early liver damage is unclear. This study focuses on assessing the correlation between them in the general population to provide clues to prevent liver disease. A total of 12,931 individuals underwent liver function and imaging tests as well as 13C/14C-urea breath tests. Results showed that the detection rate of HP was 35.9%, and the HP-positive group had a higher rate of liver injury (47.0% versus 44.5%, P = 0.007). Specifically, Fibrosis-4 (FIB-4) and alpha-fetoprotein levels in the HP-positive group were higher whereas the serum albumin level was lower. HP infection would raise the percentage of elevated aspartate aminotransferase (AST; 2.5% versus 1.7%, P = 0.006), elevated FIB-4 (20.2% versus 17.9%, P = 0.002), and abnormal liver imaging (31.0% versus 29.3%, P = 0.048). Most of these results remained stable after covariate adjustment but, for liver injury and liver imaging, the conclusions only held in young people (ORliver injury, odds ratio of liver injury, 1.127, P = 0.040; ORAST, 1.33, P = 0.034; ORFIB-4, 1.145, P = 0.032; ORimaging, 1.149, P = 0.043). Overall, HP infection might be associated with early liver injury, particularly in youth, suggesting that people with early liver injury should pay more attention to HP infection to prevent the occurrence of severe liver diseases.
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Affiliation(s)
- Wenling Chang
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Lin Cai
- Department of Gastroenterology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- Non-Communicable Diseases Research Center, West China-Peking Union Medical College C. C. Chen Institute of Health, Sichuan University, Chengdu, China
| | - Tingting Chen
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Weigui Ni
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Zhihao Xie
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Chunxia Yang
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- Non-Communicable Diseases Research Center, West China-Peking Union Medical College C. C. Chen Institute of Health, Sichuan University, Chengdu, China
| | - Juan Liao
- Department of Gastroenterology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- Non-Communicable Diseases Research Center, West China-Peking Union Medical College C. C. Chen Institute of Health, Sichuan University, Chengdu, China
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12
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Kharbanda KK, Chokshi S, Tikhanovich I, Weinman SA, New-Aaron M, Ganesan M, Osna NA. A Pathogenic Role of Non-Parenchymal Liver Cells in Alcohol-Associated Liver Disease of Infectious and Non-Infectious Origin. BIOLOGY 2023; 12:255. [PMID: 36829532 PMCID: PMC9953685 DOI: 10.3390/biology12020255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/30/2023] [Accepted: 02/02/2023] [Indexed: 02/08/2023]
Abstract
Now, much is known regarding the impact of chronic and heavy alcohol consumption on the disruption of physiological liver functions and the induction of structural distortions in the hepatic tissues in alcohol-associated liver disease (ALD). This review deliberates the effects of alcohol on the activity and properties of liver non-parenchymal cells (NPCs), which are either residential or infiltrated into the liver from the general circulation. NPCs play a pivotal role in the regulation of organ inflammation and fibrosis, both in the context of hepatotropic infections and in non-infectious settings. Here, we overview how NPC functions in ALD are regulated by second hits, such as gender and the exposure to bacterial or viral infections. As an example of the virus-mediated trigger of liver injury, we focused on HIV infections potentiated by alcohol exposure, since this combination was only limitedly studied in relation to the role of hepatic stellate cells (HSCs) in the development of liver fibrosis. The review specifically focusses on liver macrophages, HSC, and T-lymphocytes and their regulation of ALD pathogenesis and outcomes. It also illustrates the activation of NPCs by the engulfment of apoptotic bodies, a frequent event observed when hepatocytes are exposed to ethanol metabolites and infections. As an example of such a double-hit-induced apoptotic hepatocyte death, we deliberate on the hepatotoxic accumulation of HIV proteins, which in combination with ethanol metabolites, causes intensive hepatic cell death and pro-fibrotic activation of HSCs engulfing these HIV- and malondialdehyde-expressing apoptotic hepatocytes.
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Affiliation(s)
- Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Shilpa Chokshi
- Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK
- Faculty of Life Sciences and Medicine, King’s College London, London SE5 8AF, UK
| | - Irina Tikhanovich
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, MO 66160, USA
| | - Steven A. Weinman
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, MO 66160, USA
- Research Service, Kansas City Veterans Administration Medical Center, Kansas City, MO 64128, USA
| | - Moses New-Aaron
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
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13
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Di Tommaso N, Santopaolo F, Gasbarrini A, Ponziani FR. The Gut-Vascular Barrier as a New Protagonist in Intestinal and Extraintestinal Diseases. Int J Mol Sci 2023; 24:ijms24021470. [PMID: 36674986 PMCID: PMC9864173 DOI: 10.3390/ijms24021470] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/07/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023] Open
Abstract
The intestinal barrier, with its multiple layers, is the first line of defense between the outside world and the intestine. Its disruption, resulting in increased intestinal permeability, is a recognized pathogenic factor of intestinal and extra-intestinal diseases. The identification of a gut-vascular barrier (GVB), consisting of a structured endothelium below the epithelial layer, has led to new evidence on the etiology and management of diseases of the gut-liver axis and the gut-brain axis, with recent implications in oncology as well. The gut-brain axis is involved in several neuroinflammatory processes. In particular, the recent description of a choroid plexus vascular barrier regulating brain permeability under conditions of gut inflammation identifies the endothelium as a key regulator in maintaining tissue homeostasis and health.
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Affiliation(s)
- Natalia Di Tommaso
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Correspondence:
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14
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The Protective Effects of Corn Oligopeptides on Acute Alcoholic Liver Disease by Inhibiting the Activation of Kupffer Cells NF-κB/AMPK Signal Pathway. Nutrients 2022; 14:nu14194194. [PMID: 36235846 PMCID: PMC9572984 DOI: 10.3390/nu14194194] [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] [Received: 08/29/2022] [Revised: 09/25/2022] [Accepted: 09/27/2022] [Indexed: 11/05/2022] Open
Abstract
Alcohol can cause injury and lead to an inflammatory response in the liver. The NF-κB/AMPK signaling pathway plays a vital role in regulating intracellular inflammatory cytokine levels. In this study, corn oligopeptides (CPs), as the research objects, were obtained from corn gluten meal, and their regulation of the activation of the Kupffer cell NF-κB/AMPK signal pathway induced by LPS was investigated. Results showed that ALT, AST, and inflammatory cytokines in mice serum after the administration of CPs at 0.2, 0.4, and 0.8 g/kg of body weight displayed a distinct (p < 0.05) reduction. On the other hand, the CPs also inhibited the expression of recognized receptor CD14 and TLR4, down-regulated P-JNK, P-ERK, and P-p-38, and thus inhibited inflammatory cytokine levels in Kupffer cells (KCs). Furthermore, four kinds of dipeptides with a leucine residue at the C-terminus that might exhibit down-regulated inflammatory cytokines in the NF-κB/AMPK signaling pathway functions were detected using HPLC-MS/MS. These results indicated that CPs have a potential application value in acute alcoholic liver disease.
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15
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Zajkowska M, Mroczko B. Chemokines in Primary Liver Cancer. Int J Mol Sci 2022; 23:ijms23168846. [PMID: 36012108 PMCID: PMC9408270 DOI: 10.3390/ijms23168846] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/04/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
The liver is responsible for extremely important functions in the human body. In the liver’s structure, we distinguish between connective tissue (stroma) and parenchyma, the latter of which is formed from the basic structural and functional units of the liver—hepatocytes. There are many factors, that negatively affect the liver cells, contributing to their damage. This may lead to fibrosis, liver failure and, in consequence, primary liver cancer, which is the sixth most commonly diagnosed malignancy and the fourth leading cause of cancer death worldwide. Chemokines are a large family of secreted proteins. Their main role is to direct the recruitment and migration of cells to sites of inflammation or injury. Some authors suggest that these proteins might play a potential role in the development of many malignancies, including primary liver cancer. The aim of this study was to evaluate and summarize the knowledge regarding liver diseases, especially primary liver cancer (HCC) and the participation of chemokines in the development of this malignancy. Chemokines involved in the initiation of this type of tumor belong mainly to the CC and CXC chemokines. Their significant role in the course of hepatocellular carcinoma proves their usefulness in detecting and monitoring the course and treatment in patients with this disease.
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Affiliation(s)
- Monika Zajkowska
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Correspondence: ; Tel.: +48-686-5168; Fax: +48-686-5169
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
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16
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Charkoftaki G, Tan WY, Berrios-Carcamo P, Orlicky DJ, Golla JP, Garcia-Milian R, Aalizadeh R, Thomaidis NS, Thompson DC, Vasiliou V. Liver metabolomics identifies bile acid profile changes at early stages of alcoholic liver disease in mice. Chem Biol Interact 2022; 360:109931. [PMID: 35429548 PMCID: PMC9364420 DOI: 10.1016/j.cbi.2022.109931] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/30/2022] [Accepted: 04/03/2022] [Indexed: 12/18/2022]
Abstract
Alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. The liver sustains the earliest and the greatest degree of tissue injury due to chronic alcohol consumption and it has been estimated that alcoholic liver disease (ALD) accounts for almost 50% of all deaths from cirrhosis in the world. In this study, we used a modified Lieber-DeCarli (LD) diet to treat mice with alcohol and simulate chronic alcohol drinking. Using an untargeted metabolomics approach, our aim was to identify the various metabolites and pathways that are altered in the early stages of ALD. Histopathology showed minimal changes in the liver after 6 weeks of alcohol consumption. However, untargeted metabolomics analyses identified 304 metabolic features that were either up- or down-regulated in the livers of ethanol-consuming mice. Pathway analysis revealed significant alcohol-induced alterations, the most significant of which was in the FXR/RXR activation pathway. Targeted metabolomics focusing on bile acid biosynthesis showed elevated taurine-conjugated cholic acid compounds in ethanol-consuming mice. In summary, we showed that the changes in the liver metabolome manifest very early in the development of ALD, and when minimal changes in liver histopathology have occurred. Although alterations in biochemical pathways indicate a complex pathology in the very early stages of alcohol consumption, bile acid changes may serve as biomarkers of the early onset of ALD.
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Affiliation(s)
- Georgia Charkoftaki
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
| | - Wan Ying Tan
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
| | - Pablo Berrios-Carcamo
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA; Center for Regenerative Medicine, Faculty of Medicine Clínica Alemana-Universidad del Desarrollo, Santiago 7610658, Chile
| | - David J Orlicky
- Department of Pathology, University of Colorado Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA
| | - Jaya Prakash Golla
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA
| | - Rolando Garcia-Milian
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA; Bioinformatics Support Program, Cushing/Whitney Medical Library, Yale School of Medicine, New Haven, CT, 06210, USA
| | - Reza Aalizadeh
- Laboratory of Analytical Chemistry, Department of Chemistry, National Kapodistrian University of Athens University Campus, Zografou, 15771, Athens, Greece
| | - Nikolaos S Thomaidis
- Laboratory of Analytical Chemistry, Department of Chemistry, National Kapodistrian University of Athens University Campus, Zografou, 15771, Athens, Greece
| | - David C Thompson
- Department of Clinical Pharmacy, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA.
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17
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Mai B, Han L, Zhong J, Shu J, Cao Z, Fang J, Zhang X, Gao Z, Xiao F. Rhoifolin Alleviates Alcoholic Liver Disease In Vivo and In Vitro via Inhibition of the TLR4/NF-κB Signaling Pathway. Front Pharmacol 2022; 13:878898. [PMID: 35685625 PMCID: PMC9171502 DOI: 10.3389/fphar.2022.878898] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/13/2022] [Indexed: 01/16/2023] Open
Abstract
Background: Alcoholic liver disease (ALD) is a common chronic liver disorder worldwide, which is detrimental to human health. A preliminary study showed that the total flavonoids within Citrus grandis “Tomentosa” exerted a remarkable effect on the treatment of experimental ALD. However, the active substances of Citrus grandis “Tomentosa” were not elucidated. Rhoifolin (ROF) is a flavonoid component present in high levels. Therefore, this research aimed to evaluate the hepatoprotective effects of ROF and its possible mechanisms. Methods: Molecular docking was performed to analyze the binding energy of ROF to the main target proteins related to ALD. Subsequently, mice were fed ethanol (ETH) for 49 days to establish the chronic alcoholic liver injury models. The liver pathological injury, serum aminotransferase levels, and oxidative stress levels in the liver tissue were measured. Human normal hepatocytes (LO2 cells) were incubated with ETH to construct the alcoholic liver cell model. The inflammatory markers and apoptosis factors were evaluated using real-time PCR and flow cytometry. Finally, the effects of ROF on the CYP2E1 and NF-κB signaling pathways were tested in vitro and in vivo. Results: Molecular docking results demonstrated that ROF was able to successfully dock with the target proteins associated with ALD. In animal studies, ROF attenuated ETH-induced liver damage in mice by decreasing the serum concentrations of AST and ALT, reducing the expression of inflammatory cytokines, and maintaining antioxidant balance in the liver tissue. The in vitro experiments demonstrated that ROF suppressed ETH-induced apoptosis in LO2 cells by promoting Bcl-2 mRNA and inhibiting Bax mRNA and caspase 3 protein expression. ROF decreased the level of LDH, ALT, AST, ROS, and MDA in the supernatant; induced the activity of GSH and SOD; and inhibited TNF-α, IL-6, and IL-1β expression levels. Mechanistically, ROF could significantly downregulate the expression levels of CYP2E1, TLR4, and NF-κB phosphorylation. Conclusion: This study indicates that ROF is the active component within the total flavonoids, which may alleviate ETH-induced liver injury by inhibiting NF-κB phosphorylation. Therefore, ROF may serve as a promising compound for treating ALD.
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Affiliation(s)
- Baoyu Mai
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ling Han
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
- Guangdong Provincial Clinical Medicine Research Center for Chinese Medicine Dermatology, Guangzhou, China
| | - Jiarui Zhong
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingqi Shu
- College of Acumox and Tuina, Jiangxi University of Chinese Medicine, Jiangxi, China
| | - Zelin Cao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, China
| | - Jiaqi Fang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaoying Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zelin Gao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fengxia Xiao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Maoming, China
- *Correspondence: Fengxia Xiao,
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18
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Torres S, Segalés P, García-Ruiz C, Fernández-Checa JC. Mitochondria and the NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis. Cells 2022; 11:1475. [PMID: 35563780 PMCID: PMC9105698 DOI: 10.3390/cells11091475] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/18/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022] Open
Abstract
Alcoholic (ASH) and nonalcoholic steatohepatitis (NASH) are advanced stages of fatty liver disease and two of the most prevalent forms of chronic liver disease. ASH and NASH are associated with significant risk of further progression to cirrhosis and hepatocellular carcinoma (HCC), the most common type of liver cancer, and a major cause of cancer-related mortality. Despite extensive research and progress in the last decades to elucidate the mechanisms of the development of ASH and NASH, the pathogenesis of both diseases is still poorly understood. Mitochondrial damage and activation of inflammasome complexes have a role in inducing and sustaining liver damage. Mitochondrial dysfunction produces inflammatory factors that activate the inflammasome complexes. NLRP3 inflammasome (nucleotide-binding oligomerization domain-like receptor protein 3) is a multiprotein complex that activates caspase 1 and the release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-18 (IL-18), and contributes to inflammatory pyroptotic cell death. The present review, which is part of the issue "Mitochondria in Liver Pathobiology", provides an overview of the role of mitochondrial dysfunction and NLRP3 activation in ASH and NASH.
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Affiliation(s)
- Sandra Torres
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Paula Segalés
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Carmen García-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - José C. Fernández-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Guo M, Gu L, Hui H, Li X, Jin L. Extracts of Dracocephalum tanguticum Maxim Ameliorate Acute Alcoholic Liver Disease via Regulating Transcription Factors in Mice. Front Pharmacol 2022; 13:830532. [PMID: 35370722 PMCID: PMC8966672 DOI: 10.3389/fphar.2022.830532] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 02/02/2022] [Indexed: 12/12/2022] Open
Abstract
Alcoholic liver disease (ALD) caused by excessive drinking is a health and economic concern worldwide. Given the high morbidity, mortality, and the progressive nature of ALD, finding effective interventions is essential. Previous studies have confirmed that edible food plants and their bioactive compounds exert a protective effect against ALD. Dracocephalum tanguticum Maxim (DTM) is one of the important traditional Tibetan medicines in China with the effect of clearing away liver heat, used for the treatment of hepatitis. In this study, the DTM chloroform extract (DtM-C), ethyl acetate extract (DtM-E), and n-butanol extract (DtM-B) were obtained by ethanol extraction combined with fractional extraction. Acute ALD was induced in mice given intragastric ethanol. Serum and liver biochemical markers were detected by ELISA. Liver histological observation, Oil Red O, and Masson's trichrome staining were performed. Liver injury cells were induced by ethanol. The cell vitality was detected by using MTT colorimetry. The expressions of Nrf2, NF-κB, STAT3, AP-1, CREB, HIF-1α, HO-1, NQO-1, GSTA1, IKB2, and Keap1 were detected by real-time polymerase chain reaction (PCR) to elucidate the mechanism of hepatoprotective effect, and the results were verified by using Western blot. The results of serum liver function indicators (ALT, AST, and ADH), serum hepatic lipid indicators (TC, TG, HDL-C, and LDL-C), and lipid peroxidation indicators (ADH, MDA, SOD, CAT, and GSH-Px) in liver tissue and liver histological observation showed that DtM-E could improve liver function, alleviate fatty degeneration, edema, cell necrosis, and liver fibrosis caused by alcohol. DtM-E also increased the vitality of EtOH-induced liver injury cells, upregulated the mRNA expression of Nrf2, HO-1, NQO-1, and GSTA1, while downregulated the expression of Keap-1, p65, and NF-κB. Western blot results were consistent with PCR. The results suggest that DtM-E has a protective effect against ALD in vitro and in vivo, and its mechanism of action may be related to the activation of Nrf2/Keap-1 and inhibition of the P65/NF-κB signaling pathways.
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Affiliation(s)
- Min Guo
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, China.,Institute of Chinese Materia Medica, Gansu Academy of Traditional Chinese Medicine, Lanzhou, China.,Laboratory of Chinese Medicine, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, China
| | - Liwei Gu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Heping Hui
- Gansu Agriculture Technology College, Lanzhou, China
| | - Xiaodong Li
- Institute of Chinese Materia Medica, Gansu Academy of Traditional Chinese Medicine, Lanzhou, China.,Laboratory of Chinese Medicine, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, China
| | - Ling Jin
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, China
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20
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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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21
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Ahmad SB, Rashid SM, Wali AF, Ali S, Rehman MU, Maqbool MT, Nadeem A, Ahmad SF, Siddiqui N. Myricetin (3,3 ',4 ',5,5 ',7-hexahydroxyflavone) prevents ethanol-induced biochemical and inflammatory damage in the liver of Wistar rats. Hum Exp Toxicol 2022; 41:9603271211066843. [PMID: 35156864 DOI: 10.1177/09603271211066843] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Purpose: The current investigation was carried out to evaluate the efficacy of myricetin in ethanol-induced liver toxicity in Wistar rats. Research Design: Twenty-four rats were randomly divided into four groups with six animals per group. Group-I animals were administered with vehicle (distilled water), Group II, III, and IV were treated orally with sequential (per week) increase in the dose of ethanol (5, 8, 10, and 12 g/kg b wt per week in each group) for 28 days. Myricetin was treated orally to Group-III and IV animals at the respective doses of 25 mg/kg b wt. and 50 mg/kg b wt. Results: Our results showed that myricetin prevented hepatotoxicity by modulating the production of free radicals, ethanol metabolizing enzymes, and inflammatory markers in vivo. Myricetin also helped maintain lipid membrane integrity, oxidant-antioxidant status, and histoarchitecture. Ethanol administration caused elevation in XO, ADH, and CYP2E1 in hepatic tissue, which significantly normalized with myricetin administration. After ethanol administration, there was a steep increase in the hepatotoxicity biomarkers, including ALT, MDA, and AST. The level of cytotoxicity marker LDH also increased after ethanol administration; myricetin administration decreased the level of all these markers. Moreover, myricetin treatment also reduced ethanol-induced inflammatory markers such as NF-κB and IL-6. Conclusion: Findings from the current study demonstrate that myricetin administration prevents alcohol-induced hepatic injury by influencing the metabolism of ethanol, inhibiting oxidative stress, maintaining lipid profile, and suppressing inflammatory markers.
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Affiliation(s)
- Sheikh Bilal Ahmad
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, 77177SKUAST-Kashmir, Srinagar, J&K, India
| | - Shahzada Mudaisr Rashid
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, 77177SKUAST-Kashmir, Srinagar, J&K, India
| | - Adil Farooq Wali
- Department of Pharmaceutical Chemistry, RAK College of Pharmaceutical Sciences, 286661RAK Medical and Health Sciences University, Ras Al Khaimah, UAE
| | - Shafat Ali
- Department of Biochemistry, Government Medical College, (GMC-Srinagar), KaranNagar Srinagar, J&K, India
| | - Muneeb U Rehman
- Department of Clinical Pharmacy, College of Pharmacy, 37850King Saud University, Riyadh, Saudi Arabia
| | - Mir Tahir Maqbool
- National Center for Natural Products Research, School of Pharmacy, 8083University of Mississippi, University, MS, USA
| | - Ahmed Nadeem
- Department of Pharmacology & Toxicology, College of Pharmacy, 37850King Saud University, Riyadh, Saudi Arabia
| | - Sheikh Fayaz Ahmad
- Department of Pharmacology & Toxicology, College of Pharmacy, 37850King Saud University, Riyadh, Saudi Arabia
| | - Nahid Siddiqui
- Amity Institute of Biotechnology, 77282Amity University, Noida, Uttar Pradesh, India
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22
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Yoshiji H, Namisaki T, Kaji K, Francque S. Therapies for Alcohol-Related Liver Disease and for Non-Alcoholic Fatty Liver Disease. PORTAL HYPERTENSION VII 2022:221-238. [DOI: 10.1007/978-3-031-08552-9_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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23
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Parrish A, Srivastava A, Juskeviciute E, Hoek JB, Vadigepalli R. Dysregulation of miR-21-associated miRNA regulatory networks by chronic ethanol consumption impairs liver regeneration. Physiol Genomics 2021; 53:546-555. [PMID: 34796728 PMCID: PMC8820682 DOI: 10.1152/physiolgenomics.00113.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/25/2021] [Accepted: 11/15/2021] [Indexed: 11/22/2022] Open
Abstract
Impaired liver regeneration has been considered as a hallmark of progression of alcohol-associated liver disease. Our previous studies demonstrated that in vivo inhibition of the microRNA (miRNA) miR21 can restore regenerative capacity of the liver in chronic ethanol-fed animals. The present study focuses on the role of microRNA regulatory networks that are likely to mediate the miR-21 action. Rats were chronically fed an ethanol-enriched diet along with pair-fed control animals and treated with AM21 (anti-miR-21), a locked nucleic acid antisense to miR-21. Partial hepatectomy (PHx) was performed and miRNA expression profiling over the course of liver regeneration was assessed. Our results showed dynamic expression changes in several miRNAs after PHx, notably with altered miRNA expression profiles between ethanol and control groups. We found that in vivo inhibition of miR-21 led to correlated differential expression of miR-340-5p and anticorrelated expression of miR-365, let-7a, miR-1224, and miR-146a across all sample groups after PHx. Gene set enrichment analysis identified a miRNA signature significantly associated with hepatic stellate cell activation within whole liver tissue data. We hypothesized that at least part of the PHx-induced miRNA network changes responsive to miR-21 inhibition is localized to hepatic stellate cells. We validated this hypothesis using AM21 and TGF-β treatments in LX-2 human hepatic stellate cells in culture and measured expression levels of select miRNAs by quantitative RT-PCR. Based on the in vivo and in vitro results, we propose a hepatic stellate cell miRNA regulatory network as contributing to the restoration of liver regenerative capacity by miR-21 inhibition.
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Affiliation(s)
- Austin Parrish
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Ankita Srivastava
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Egle Juskeviciute
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Jan B Hoek
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Rajanikanth Vadigepalli
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
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24
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Schonfeld M, O’Neil M, Villar MT, Artigues A, Averilla J, Gunewardena S, Weinman SA, Tikhanovich I. A Western diet with alcohol in drinking water recapitulates features of alcohol-associated liver disease in mice. Alcohol Clin Exp Res 2021; 45:1980-1993. [PMID: 34523155 PMCID: PMC9006178 DOI: 10.1111/acer.14700] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/17/2021] [Accepted: 08/18/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Mouse models of alcohol-associated liver disease vary greatly in their ease of implementation and the pathology they produce. Effects range from steatosis and mild inflammation with the Lieber-DeCarli liquid diet to severe inflammation, fibrosis, and pyroptosis seen with the Tsukamoto-French intragastric feeding model. Implementation of all of these models is limited by the labor-intensive nature of the protocols and the specialized skills necessary for successful intragastric feeding. We thus sought to develop a new model to reproduce features of alcohol-induced inflammation and fibrosis with minimal operational requirements. METHODS Over a 16-week period, mice were fed ad libitum with a pelleted high-fat Western diet (WD; 40% calories from fat) and alcohol added to the drinking water. We found the optimal alcohol consumption to be that at which the alcohol concentration was 20% for 4 days and 10% for 3 days per week. Control mice received WD pellets with water alone. RESULTS Alcohol consumption was 18 to 20 g/kg/day in males and 20 to 22 g/kg/day in females. Mice in the alcohol groups developed elevated serum transaminase levels after 12 weeks in males and 10 weeks in females. At 16 weeks, both males and females developed liver inflammation, steatosis, and pericellular fibrosis. Control mice on WD without alcohol had mild steatosis only. Alcohol-fed mice showed reduced HNF4α mRNA and protein expression. HNF4α is a master regulator of hepatocyte differentiation, down-regulation of which is a known driver of hepatocellular failure in alcoholic hepatitis. CONCLUSION A simple-to-administer, 16-week WD alcohol model recapitulates the inflammatory, fibrotic, and gene expression aspects of human alcohol-associated steatohepatitis.
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Affiliation(s)
- Michael Schonfeld
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Maura O’Neil
- Department of Pathology, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
- Liver Center, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Maria T Villar
- Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Antonio Artigues
- Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Janice Averilla
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Steven A. Weinman
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
- Liver Center, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Irina Tikhanovich
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
- Liver Center, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
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25
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Brovold M, Keller D, Devarasetty M, Dominijanni A, Shirwaiker R, Soker S. Biofabricated 3D in vitro model of fibrosis-induced abnormal hepatoblast/biliary progenitors' expansion of the developing liver. Bioeng Transl Med 2021; 6:e10207. [PMID: 34589593 PMCID: PMC8459590 DOI: 10.1002/btm2.10207] [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] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/25/2020] [Accepted: 11/29/2020] [Indexed: 11/19/2022] Open
Abstract
Congenital disorders of the biliary tract are the primary reason for pediatric liver failure and ultimately for pediatric liver transplant needs. Not all causes of these disorders are well understood, but it is known that liver fibrosis occurs in many of those afflicted. The goal of this study is to develop a simple yet robust model that recapitulates physico-mechanical and cellular aspects of fibrosis mediated via hepatic stellate cells (HSCs) and their effects on biliary progenitor cells. Liver organoids were fabricated by embedding various HSCs, with distinctive abilities to generate mild to severe fibrotic environments, together with undifferentiated liver progenitor cell line, HepaRG, within a collagen I hydrogel. The fibrotic state of each organoid was characterized by examination of extracellular matrix (ECM) remodeling through quantitative image analysis, rheometry, and qPCR. In tandem, the phenotype of the liver progenitor cell and cluster formation was assessed through histology. Activated HSCs (aHSCs) created a more severe fibrotic state, exemplified by a more highly contracted and rigid ECM, as well higher relative expression of TGF-β, TIMP-1, LOXL2, and COL1A2 as compared to immortalized HSCs (LX-2). Within the more severe fibrotic environment, generated by the aHSCs, higher Notch signaling was associated with an expansion of CK19+ cells as well as the formation of larger, more densely populated cell biliary like-clusters as compared to mild and non-fibrotic controls. The expansion of CK19+ cells, coupled with a severely fibrotic environment, are phenomena found within patients suffering from a variety of congenital liver disorders of the biliary tract. Thus, the model presented here can be utilized as a novel in vitro testing platform to test drugs and identify new targets that could benefit pediatric patients that suffer from the biliary dysgenesis associated with a multitude of congenital liver diseases.
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Affiliation(s)
- Matthew Brovold
- Wake Forest Institute for Regenerative MedicineWake Forest Baptist Medical Center, Medical Center BoulevardWinston‐SalemNorth CarolinaUSA
| | - Dale Keller
- Wake Forest Institute for Regenerative MedicineWake Forest Baptist Medical Center, Medical Center BoulevardWinston‐SalemNorth CarolinaUSA
| | - Mahesh Devarasetty
- Wake Forest Institute for Regenerative MedicineWake Forest Baptist Medical Center, Medical Center BoulevardWinston‐SalemNorth CarolinaUSA
| | - Anthony Dominijanni
- Wake Forest Institute for Regenerative MedicineWake Forest Baptist Medical Center, Medical Center BoulevardWinston‐SalemNorth CarolinaUSA
| | - Rohan Shirwaiker
- Department of Industrial and Systems EngineeringNorth Carolina State UniversityRaleighNorth CarolinaUSA
| | - Shay Soker
- Wake Forest Institute for Regenerative MedicineWake Forest Baptist Medical Center, Medical Center BoulevardWinston‐SalemNorth CarolinaUSA
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26
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Pasqualotto A, Ayres R, Longo L, Del Duca Lima D, Losch de Oliveira D, Alvares-da-Silva MR, Reverbel da Silveira T, Uribe-Cruz C. Chronic exposure to ethanol alters the expression of miR-155, miR-122 and miR-217 in alcoholic liver disease in an adult zebrafish model. Biomarkers 2021; 26:146-151. [PMID: 33435755 DOI: 10.1080/1354750x.2021.1874051] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIM The aim of this study was to evaluate the hepatic and circulating expression of miR-155, miR-122 and miR-217 in a model of chronic exposure to ethanol in adult zebrafish. METHODS Wild-type adult zebrafish were divided into two groups (n = 281): an EG (exposed to 0.5% v/v Ethanol in aquarium water) and a CG (without ethanol). After 28 days the animals were euthanized, followed by histopathological analysis, quantification of lipids, triglycerides and inflammatory cytokines in liver tissue. miR-155, miR-122 and miR-217 gene expression was quantified in liver tissue and serum. RESULTS We observed hepatic lesions and increased accumulation of hepatic lipids in the EG. The expression of il-1β was higher in the EG, but there were no differences in il-10 and tnf-α between groups. In the liver, expression of miR-122 and miR-155 was higher in the EG. The circulating expression of miR-155 and miR-217 was significantly higher in the EG. CONCLUSION Chronic exposure to ethanol in zebrafish leads to altered hepatic and circulating expression of miR-155, miR-122 and miR-217. This confirms its potential as a biomarker and therapeutic target.
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Affiliation(s)
- Amanda Pasqualotto
- Experimental Hepatology and Gastroenterology Laboratory, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Raquel Ayres
- Experimental Hepatology and Gastroenterology Laboratory, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Larisse Longo
- Experimental Hepatology and Gastroenterology Laboratory, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Diego Del Duca Lima
- Graduate Program in Biological Sciences-Biochemistry, Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Diogo Losch de Oliveira
- Graduate Program in Biological Sciences-Biochemistry, Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Mário Reis Alvares-da-Silva
- Experimental Hepatology and Gastroenterology Laboratory, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Themis Reverbel da Silveira
- Experimental Hepatology and Gastroenterology Laboratory, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Carolina Uribe-Cruz
- Experimental Hepatology and Gastroenterology Laboratory, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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27
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Blázovics A. Alcoholic liver disease. INFLUENCE OF NUTRIENTS, BIOACTIVE COMPOUNDS, AND PLANT EXTRACTS IN LIVER DISEASES 2021:57-82. [DOI: 10.1016/b978-0-12-816488-4.00010-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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28
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Bhandari R, Khaliq K, Ravat V, Kaur P, Patel RS. Chronic Alcoholic Liver Disease and Mortality Risk in Spontaneous Bacterial Peritonitis: Analysis of 6,530 Hospitalizations. Cureus 2020; 12:e8189. [PMID: 32566430 PMCID: PMC7301415 DOI: 10.7759/cureus.8189] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Objective Our study aimed to assess the risk of in-hospital mortality due to chronic alcoholic liver disease (CALD) and other comorbidities in spontaneous bacterial peritonitis (SBP) inpatients. Methods We conducted a cross-sectional study using the Nationwide Inpatient Sample (NIS, 2012 to 2014) from the United States and included 6,530 patients (age 18-50 years) with a primary diagnosis of SBP. Logistic regression was used to evaluate the odds ratio (OR) for in-hospital mortality in SBP by comorbidities. Results The prevalence of CALD in SBP patients is 43.6%, and a higher proportion were males (68.8%) and whites (67%). Middle-aged adults (OR 2.8, 95% CI 1.74-4.45) had higher odds of in-hospital mortality in SBP patients. Race and sex were non-significant predictors for mortality risk. Patients with comorbid coagulopathy (OR 1.9, 95% CI 1.45-2.48) and heart failure (OR 3.9, 95% CI 2.46-6.36) have increased mortality in SBP inpatients. After controlling confounders, CALD was significantly associated with increased in-hospital mortality (OR 1.5, 95% CI 1.12-1.94) in SBP inpatients. Conclusion CALD is an independent factor in increasing the risk of in-hospital mortality in SBP patients by 48%. Alcohol use screening, and alcohol abstinence and supportive therapy need to be implemented at an earlier stage to improve health-related quality of life and reduce in-hospital mortality in SBP patients.
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Affiliation(s)
- Renu Bhandari
- Medicine, Manipal College of Medical Sciences, Kaski, NPL
| | - Khalida Khaliq
- Psychiatry/Medicine, North Tampa Behavioral Health, Tampa, USA
| | | | - Pawandeep Kaur
- Medicine, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, IND
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Kirpich IA, Warner DR, Feng W, Joshi-Barve S, McClain CJ, Seth D, Zhong W, Zhou Z, Osna NA, Kharbanda KK. Mechanisms, biomarkers and targets for therapy in alcohol-associated liver injury: From Genetics to nutrition: Summary of the ISBRA 2018 symposium. Alcohol 2020; 83:105-114. [PMID: 31129175 PMCID: PMC7043088 DOI: 10.1016/j.alcohol.2019.05.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 05/13/2019] [Accepted: 05/14/2019] [Indexed: 02/06/2023]
Abstract
The symposium "Mechanisms, Biomarkers and Targets for Therapy in Alcohol-associated Liver Injury: From Genetics to Nutrition" was held at the 19th Congress of International Society for Biomedical Research on Alcoholism on September 13th, 2018 in Kyoto, Japan. The goal of the symposium was to discuss the importance of genetics and nutrition in alcoholic liver disease (ALD) development from mechanistic and therapeutic perspectives. The following is a summary of this session addressing the gene polymorphisms in ALD, the role of zinc in gut-liver axis perturbations associated with ALD, highlighting the importance of dietary fat in ALD pathogenesis, the hepatic n6 and n3 PUFA oxylipin pattern associated with ethanol-induced liver injury, and finally deliberating on new biomarkers for alcoholic hepatitis and their implications for diagnosis and therapy. This summary of the symposium will benefit junior and senior faculty currently investigating alcohol-induced organ pathology as well as undergraduate, graduate, and post-graduate students and fellows.
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Affiliation(s)
- Irina A Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA; Robley Rex Veterans Medical Center, Louisville, KY, USA; Hepatobiology & Toxicology Program, University of Louisville, Louisville, KY, USA
| | - Dennis R Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Wenke Feng
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA; Hepatobiology & Toxicology Program, University of Louisville, Louisville, KY, USA
| | - Swati Joshi-Barve
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA; Hepatobiology & Toxicology Program, University of Louisville, Louisville, KY, USA
| | - Craig J McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA; Robley Rex Veterans Medical Center, Louisville, KY, USA; Hepatobiology & Toxicology Program, University of Louisville, Louisville, KY, USA
| | - Devanshi Seth
- Drug Health Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia, And Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, Australia
| | - Wei Zhong
- Center for Translational Biomedical Research, Department of Nutrition, University of North Carolina at Greensboro, Kannapolis, NC, 28081, USA
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research, Department of Nutrition, University of North Carolina at Greensboro, Kannapolis, NC, 28081, USA
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
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30
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Testino G, Vignoli T, Patussi V, Scafato E, Caputo F. Management of end-stage alcohol-related liver disease and severe acute alcohol-related hepatitis: position paper of the Italian Society on Alcohol (SIA). Dig Liver Dis 2020; 52:21-32. [PMID: 31757596 DOI: 10.1016/j.dld.2019.09.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 08/28/2019] [Accepted: 09/23/2019] [Indexed: 02/07/2023]
Abstract
Worldwide, the prevalence of alcohol use disorder (AUD) is 20-30% in men and 10-15% in women, and cirrhosis due to alcohol-related liver disease (ALD) is responsible for 0.9% of global deaths and 47.9% of cirrhosis-related deaths. End-stage ALD (ESALD) is the final condition of alcohol-related cirrhosis, and severe acute alcohol-related hepatitis (SAAH) is a distinct clinical syndrome associated with the consumption of large amounts of alcohol. In some cases, ESALD, and SAAH may need liver transplantation (LT). Thus, the management of ESALD and SAAH in patients affected by AUD may be an essential part of the clinical skills for hepatologists. For these reasons, the national board of the Italian Society on Alcohol have reviewed the most recent data on the management of ESALD, SAAH and LT for ALD in patients with AUD, formulating a position paper with related recommendations regarding four issues of specific clinical interest in this field: (a) the management of hepatic encephalopathy in patients with AUD, and LT in patients with ESALD; (b) the management of SAAH; (c) the management of AUD in patients with ESALD and SAAH; (d) special populations: polydrug addicts.
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Affiliation(s)
- Gianni Testino
- Unit of Addiction and Hepatology ASL3 Liguria, San Martino Hospital, Genova, Italy
| | - Teo Vignoli
- Unit of Addiction Treatment, Lugo, Ravenna, Italy
| | | | - Emanuele Scafato
- National Observatory on Alcohol, National Institute of Health, Roma, Italy
| | - Fabio Caputo
- Department of Internal Medicine, SS Annunziata Hospital, Cento, Ferrara, Italy; "G. Fontana" Centre for the Study and Multidisciplinary Treatment of Alcohol Addiction, Department of Medical and Surgical Sciences, University of Bologna, Italy.
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31
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Donohue TM, Osna NA, Kharbanda KK, Thomes PG. Lysosome and proteasome dysfunction in alcohol-induced liver injury. LIVER RESEARCH 2019; 3:191-205. [DOI: 10.1016/j.livres.2019.11.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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32
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Deda O, Virgiliou C, Orfanidis A, Gika HG. Study of Fecal and Urinary Metabolite Perturbations Induced by Chronic Ethanol Treatment in Mice by UHPLC-MS/MS Targeted Profiling. Metabolites 2019; 9:E232. [PMID: 31623107 PMCID: PMC6836053 DOI: 10.3390/metabo9100232] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/12/2019] [Accepted: 10/13/2019] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) as a consequence of ethanol chronic consumption could lead to hepatic cirrhosis that is linked to high morbidity and mortality. Disease diagnosis is still very challenging and usually clear findings are obtained in the later stage of ALD. The profound effect of ethanol on metabolism can be depicted using metabolomics; thus, the discovery of novel biomarkers could shed light on the initiation and the progression of the ALD, serving diagnostic purposes. In the present study, Hydrophilic Interaction Liquid Chromatography tandem Mass Spectrometry HILIC-MS/MS based metabolomics analyisis of urine and fecal samples of C57BL/6 mice of both sexes at two sampling time points was performed, monitoring the effect of eight-week ethanol consumption. The altered hepatic metabolism caused by ethanol consumption induces extensive biochemical perturbations and changes in gut microbiota population on a great scale. Fecal samples were proven to be a suitable specimen for studying ALD since it was more vulnerable to the metabolic changes in comparison to urine samples. The metabolome of male mice was affected on a greater scale than the female metabolome due to ethanol exposure. Precursor small molecules of essential pathways of energy production responded to ethanol exposure. A meaningful correlation between the two studied specimens demonstrated the impact of ethanol in endogenous and symbiome metabolism.
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Affiliation(s)
- Olga Deda
- Department of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
- Center for Interdisciplinary Research of the Aristotle University of Thessaloniki (KEDEK), 57001 Thessaloniki, Greece.
| | - Christina Virgiliou
- Center for Interdisciplinary Research of the Aristotle University of Thessaloniki (KEDEK), 57001 Thessaloniki, Greece.
- Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
| | - Amvrosios Orfanidis
- Department of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
- Center for Interdisciplinary Research of the Aristotle University of Thessaloniki (KEDEK), 57001 Thessaloniki, Greece.
| | - Helen G Gika
- Department of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
- Center for Interdisciplinary Research of the Aristotle University of Thessaloniki (KEDEK), 57001 Thessaloniki, Greece.
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33
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Zhou Z, Ye TJ, DeCaro E, Buehler B, Stahl Z, Bonavita G, Daniels M, You M. Intestinal SIRT1 Deficiency Protects Mice from Ethanol-Induced Liver Injury by Mitigating Ferroptosis. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 190:82-92. [PMID: 31610175 DOI: 10.1016/j.ajpath.2019.09.012] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 09/13/2019] [Accepted: 09/24/2019] [Indexed: 02/06/2023]
Abstract
Aberrant liver sirtuin 1 (SIRT1), a mammalian NAD+-dependent protein deacetylase, is implicated in the pathogenesis of alcoholic liver disease (ALD). However, the role of intestinal SIRT1 in ALD is presently unknown. This study investigated the involvement of intestine-specific SIRT1 in ethanol-induced liver dysfunction in mice. Ethanol feeding studies were performed on knockout mice with intestinal-specific SIRT1 deletion [SIRT1i knockout (KO)] and flox control [wild-type (WT)] mice with a chronic-plus-binge ethanol feeding protocol. After ethanol administration, hepatic inflammation and liver injury were substantially attenuated in the SIRT1iKO mice compared with the WT mice, suggesting that intestinal SIRT1 played a detrimental role in the ethanol-induced liver injury. Mechanistically, the hepatic protective effect of intestinal SIRT1 deficiency was attributable to ameliorated dysfunctional iron metabolism, increased hepatic glutathione contents, and attenuated lipid peroxidation, along with inhibition of a panel of genes implicated in the ferroptosis process in the livers of ethanol-fed mice. This study demonstrates that ablation of intestinal SIRT1 protected mice from the ethanol-induced inflammation and liver damage. The protective effects of intestinal SIRT1 deficiency are mediated, at least partially, by mitigating hepatic ferroptosis. Targeting intestinal SIRT1 or dampening hepatic ferroptosis signaling may have therapeutic potential for ALD in humans.
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Affiliation(s)
- Zhou Zhou
- College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio
| | - Ting Jie Ye
- College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio; Department of Biology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Elizabeth DeCaro
- College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio
| | - Brian Buehler
- College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio
| | - Zachary Stahl
- College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio
| | - Gregory Bonavita
- College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio
| | - Michael Daniels
- College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio
| | - Min You
- College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio.
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Marinello PC, Cella P, Testa M, Guirro P, Brito W, Borges F, Cecchini R, Cecchini A, Duarte J, Deminice R. Creatine supplementation exacerbates ethanol-induced hepatic damage in mice. Nutrition 2019; 66:122-130. [DOI: 10.1016/j.nut.2019.05.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 05/02/2019] [Accepted: 05/26/2019] [Indexed: 02/08/2023]
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35
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Philips CA, Augustine P, Yerol PK, Rajesh S, Mahadevan P. Severe alcoholic hepatitis: current perspectives. Hepat Med 2019; 11:97-108. [PMID: 31496843 PMCID: PMC6691395 DOI: 10.2147/hmer.s197933] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 07/18/2019] [Indexed: 12/12/2022] Open
Abstract
Severe acute alcoholic hepatitis (AH) is a catastrophic disease in the natural history of alcoholic liver disease with a very high 180-day mortality. It can present as acute on chronic liver failure with worse prognosis in the presence of infections and higher grades of liver disease severity. The clinical scenario involves a patient with a recent history of heavy alcohol consumption within three months of presentation with jaundice and characteristic liver enzyme elevation pattern with coagulopathy, hepatic encephalopathy, variceal bleeding and sepsis that results in extrahepatic organ failures. Several liver disease severities and therapy response indicators are in clinical use. Even though not approved, the only recommended treatment option for patients with severe AH is corticosteroids, which is without long term survival benefit. Novel efficacious treatment options awaiting high-quality multi-center studies include liver transplantation (involves strict selection criteria), growth factor therapy and fecal microbiota transplantation. In this exhaustive review, we discuss the definitions, disease severity, histopathology, and treatment options – past, present, and future, in patients with severe alcoholic hepatitis.
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Affiliation(s)
- Cyriac Abby Philips
- The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Centre, Cochin, Kerala, India
| | - Philip Augustine
- Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Centre, Cochin, Kerala, India
| | - Praveen Kumar Yerol
- Department of Gastroenterology, Government Medical College and Hospital, Thrissur, Kerala, India
| | - Sasidharan Rajesh
- Interventional Radiology, Hepatobiliary Division, Cochin Gastroenterology Group, Ernakulam Medical Centre, Cochin, Kerala, India
| | - Pushpa Mahadevan
- Clinical Pathology, VPS Lakeshore Hospital, Nettoor, Kerala, India
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Zhao J, Adams A, Weinman SA, Tikhanovich I. Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses. Sci Rep 2019; 9:9111. [PMID: 31235809 PMCID: PMC6591482 DOI: 10.1038/s41598-019-45585-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 02/11/2019] [Indexed: 01/23/2023] Open
Abstract
Protein Arginine methyltransferase 1 (PRMT1) is the main enzyme of cellular arginine methylation. Previously we found that PRMT1 activity in the liver is altered after alcohol exposure resulting in epigenetic changes. To determine the impact of these PRMT1 changes on the liver's response to alcohol, we induced a hepatocyte specific PRMT1 knockout using AAV mediated Cre delivery in mice fed either alcohol or control Lieber-DeCarli liquid diet. We found that in alcohol fed mice, PRMT1 prevents oxidative stress and promotes hepatocyte survival. PRMT1 knockout in alcohol fed mice resulted in a dramatic increase in hepatocyte death, inflammation and fibrosis. Additionally, we found that alcohol promotes PRMT1 dephosphorylation at S297. Phosphorylation at this site is necessary for PRMT1-dependent protein arginine methylation. PRMT1 S297A, a dephosphorylation mimic of PRMT1 had reduced ability to promote gene expression of pro-inflammatory cytokines, pro-apoptotic genes BIM and TRAIL and expression of a suppressor of hepatocyte proliferation, Hnf4α. On the other hand, several functions of PRMT1 were phosphorylation-independent, including expression of oxidative stress response genes, Sod1, Sod2 and others. In vitro, both wild type and S297A PRMT1 protected hepatocytes from oxidative stress induced apoptosis, however S297D phosphorylation mimic PRMT1 promoted cell death. Taken together these data suggest that PRMT1 is an essential factor of liver adaptation to alcohol; alcohol-induced dephosphorylation shifts PRMT1 toward a less pro-inflammatory, more pro-proliferative and pro-survival form.
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Affiliation(s)
- Jie Zhao
- Department of Internal Medicine, University of Kansas Medical Center, Kansas, United States
| | - Abby Adams
- Department of Internal Medicine, University of Kansas Medical Center, Kansas, United States.,Liver Center, University of Kansas Medical Center, Kansas, United States
| | - Steven A Weinman
- Department of Internal Medicine, University of Kansas Medical Center, Kansas, United States.,Liver Center, University of Kansas Medical Center, Kansas, United States
| | - Irina Tikhanovich
- Department of Internal Medicine, University of Kansas Medical Center, Kansas, United States.
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Wang WJ, Xiao P, Xu HQ, Niu JQ, Gao YH. Growing burden of alcoholic liver disease in China: A review. World J Gastroenterol 2019; 25:1445-1456. [PMID: 30948908 PMCID: PMC6441911 DOI: 10.3748/wjg.v25.i12.1445] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 02/22/2019] [Accepted: 03/01/2019] [Indexed: 02/06/2023] Open
Abstract
Explosive economic growth and increasing social openness in China over the last 30 years have significantly boosted alcohol consumption, and consequently, the incidence of alcoholic liver disease (ALD) in China has increased. Because the epidemiologic and clinical features of ALD in the Chinese population may differ from those of the Caucasian population, this review describes the epidemiology, pathogenesis, genetic polymorphisms, diagnosis, and treatment of ALD in the Chinese population. This updated knowledge of ALD in China provides information needed for a global understanding of ALD and may help in the development of useful strategies for reducing the global ALD burden.
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Affiliation(s)
- Wen-Jun Wang
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Peng Xiao
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Hong-Qin Xu
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Jun-Qi Niu
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Yan-Hang Gao
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
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38
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Treatment retention in a specialized alcohol programme after an episode of alcoholic hepatitis: Impact on alcohol relapse. J Psychosom Res 2019; 116:75-82. [PMID: 30654998 DOI: 10.1016/j.jpsychores.2018.11.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 11/27/2018] [Indexed: 12/20/2022]
Abstract
AIMS Alcoholic hepatitis (AH) is a life-threatening complication of alcohol use disorder (AUD). Alcohol abstinence is the main predictor of the long-term prognosis of AH. It is unknown whether AUD treatment retention (TR) after an AH episode impacts alcohol relapse and mortality or what baseline factors influence TR. METHODS Design: case-control study; Study population: hospitalized patients (1999-2012) with an episode of biopsy-proven AH were included (n = 120); Assessment: demographic and clinical data, the High-Risk Alcoholism Relapse (HRAR) scale, mortality and alcohol relapse were assessed through clinical records and telephone or personal interviews; Follow-up period: short-term and long-term TRs were assessed at 12 and 24 months, respectively. RESULTS The overall short-term and long-term TRs were 37% and 27.8%, respectively. The severity of liver disease at baseline predicted both short-term and long-term TR (OR 3.7 and 3.3, respectively), whereas HRAR >3 and a history of psychiatric disorders predicted long-term TR (OR 2.9 and 2.6, respectively). Moreover, HRAR >3 (OR 3.0) and previous treatment for AUD (OR 2.9) increased the risk of relapse in the short term. Importantly, receiving alcohol therapy in a centre different from the hospital where the patient was admitted was associated with increased risk of alcohol relapse over the long term (OR 5.4). CONCLUSION Experiencing an alcohol-related life-threatening complication is insufficient motivation to seek treatment for AUD. AUD treatment after an episode of AH is suboptimal, with a low TR rate, high risk of alcohol relapse and poor impact of treatment on alcohol relapse.
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Effect of Lycosome-Formulated Phosphatidylcholine on Parameters of Biological Oxidation after Single Intake of Moderate Amount of Alcohol. Adv Prev Med 2018; 2018:5840451. [PMID: 30155314 PMCID: PMC6091444 DOI: 10.1155/2018/5840451] [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: 03/06/2018] [Accepted: 06/27/2018] [Indexed: 12/02/2022] Open
Abstract
Ingestion of a single dose of alcohol, ranging from the intake of a moderate amount alcohol to binge drinking, is the most frequent form of alcohol consumption with poorly understood medical consequences and obscure prophylactics. The study was aimed to determine whether lycosome formulated phosphatidylcholine (PC-Lyc) containing two highly bioavailable antioxidants (PC and lycopene) ingested shortly before the alcohol-containing beverage may alleviate the biochemical markers of liver damage and parameters of biological oxidation associated with the intake of a moderate amount of alcohol. Healthy middle-aged volunteers were requested to consume a moderate amount of alcohol – 0.5 ml/kg or 1.0 ml/kg shortly after ingestion of a capsule containing 450 mg of regular phosphatidylcholine (PC, n=10), PC-Lyc (n=10), or placebo pill (PP, n=10). Serum levels of ethanol (EtOH), acetaldehyde (AA), liver-specific enzymes, total antioxidant capacity of serum (TAC), oxidized LDL (LDL-Px), and malonic dialdehyde (MDA) were measured at 1, 2.5, and 5 hours after dosing with alcohol. Ingestion of PC regardless of the formulation used had no effect on serum EtOH concentration dynamics. However, volunteers supplemented with PC-Lyc showed a better clearance of AA in serum as compared to other groups. There was a reduction in serum TAC values by 18.5% and 16.1% in both placebo groups ingesting 0.5 and 1.0 ml/kg of alcohol, respectively, at the end of observational period. This decline was preventable by supplementation of volunteers with PC and especially with PC-Lyc. Moreover, PC-Lyc promoted a reduction of serum MDA and reversed an increase in serum LDL-Px. In addition, ingestion of alcohol at 1.0 ml/kg dose caused a transient increase in serum alanine-aminotransferase activity which was abolished by both formulations of PC. Therefore, combinatory lycosomal formulation of PC and lycopene may prevent some metabolic abnormalities associated with single intake of moderate amount of alcohol. This trial is registered with ACTRN12617001335381.
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40
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Wang J, Kainrad N, Shen H, Zhou Z, Rote P, Zhang Y, Nagy LE, Wu J, You M. Hepatic Knockdown of Splicing Regulator Slu7 Ameliorates Inflammation and Attenuates Liver Injury in Ethanol-Fed Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:1807-1819. [PMID: 29870742 DOI: 10.1016/j.ajpath.2018.05.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 04/16/2018] [Accepted: 05/03/2018] [Indexed: 12/11/2022]
Abstract
Aberrant precursor mRNA splicing plays a pivotal role in liver diseases. However, roles of splicing regulators in alcoholic liver disease are unknown. Herein, we investigated a splicing regulator, Slu7, in the development of alcoholic steatohepatitis. Adenovirus-mediated alteration of hepatic Slu7 expression in mice pair fed either with or without (as control) ethanol in their diet was used. Knockdown of hepatic Slu7 by adenovirus-Slu7shRNA treatment ameliorated inflammation and attenuated liver injury in mice after ethanol administration. Mechanistically, reducing liver Slu7 expression increased the expression of sirtuin 1 (SIRT1) full-length and repressed the splicing of SIRT1 into SIRT1-ΔExon8 isoform in ethanol-fed mice. Knockdown of hepatic Slu7 in the ethanol-fed mice also ameliorated splicing of lipin-1 and serine/arginine-rich splicing factor 3 (Srsf3). In concordance with ameliorated splicing of SIRT1, lipin-1, and Srsf3, knockdown of hepatic Slu7 inhibited the activity of NF-κB, normalized iron and zinc homeostasis, reduced oxidative stress, and attenuated liver damage in ethanol-fed mice. In addition, hepatic Slu7 was significantly elevated in patients with alcoholic steatohepatitis. Our present study illustrates a novel role of Slu7 in alcoholic liver injury and suggests that dysregulated Slu7 may contribute to the pathogenesis of human alcoholic steatohepatitis.
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Affiliation(s)
- Jiayou Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio; Department of Anatomy, School of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Noah Kainrad
- Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio
| | - Hong Shen
- Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio; Department of Liver Diseases, Guangdong Hospital of Traditional Chinese Medicine in Zhuhai, Zhuhai, People's Republic of China
| | - Zhou Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio
| | - Paula Rote
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio
| | - Yanqiao Zhang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio
| | - Laura E Nagy
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Jiashin Wu
- Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio
| | - Min You
- Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio.
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Abstract
Alcoholic hepatitis is the most severe and acute form of alcoholic liver disease. The mortality rate associated with alcoholic hepatitis is high, largely due to the lack of suitable pharmacological interventions. While there has been substantial research in the area, generating pharmacological interventions has been plagued by the lack of a robust mouse model both for testing and for understanding the underlying pathology. A number of major notable advances have been made in this area recently, with the goal of generating a mouse model of alcoholic hepatitis. The purpose of this article is to review recent advances in modeling alcoholic liver disease both in vitro and in vivo in the mouse, and place them in the context of the greater spectrum of alcoholic liver disease, with a focus on how we can translate current advances into a high-fidelity model of alcoholic hepatitis. In addition, we will review the basic mechanisms of alcoholic hepatitis as it is currently understood, focusing on recent advancements in diagnosis, prognosis and current pathophysiology, especially as it relates to the profound immune dysfunction present during alcoholic hepatitis.
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Affiliation(s)
- Benjamin L. Woolbright
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
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42
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Tong J, Sun CY, Yang LB, Kang YN. Clinical efficacy of tauroursodeoxycholic acid combined with S-adenosyl methionine in treatment of cholestasis in patients with compensated alcoholic cirrhosis. Shijie Huaren Xiaohua Zazhi 2018; 26:31-35. [DOI: 10.11569/wcjd.v26.i1.31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To observe the clinical effects of taursodeoxycholic acid combined with S-adenosyl methionine in the treatment of cholestasis in patients with compensated alcoholic cirrhosis.
METHODS One hundred patients with compensated alcoholic cirrhosis treated at our hospital from January 2012 to January 2017 were randomly divided into an experimental group and a control group, with 50 cases in each group. Both groups of patients were given S-adenosyl methionine and hepatoprotective drugs, and the experimental group was additionally given tauroursodeoxycholic acid. After 12 wk of treatment, the changes of liver biochemical indicators [alkaline phosphatase (ALP), gamma glutamyl transaminase (GGT), and total bilirubin (TBIL)] and prothrombin activity (PTA) were detected to evaluate the therapeutic effect.
RESULTS The total effective rate in the experimental group was significantly higher than that of the control group (92% vs 56%, P < 0.05). After treatment, ALP, GGT, and TBIL in both groups decreased significantly compared with pretreatment values (P < 0.05), and the thereapeutic effect in the experimental group was better than that in the control group (P < 0.05).
CONCLUSION Tauroursodeoxycholic acid combined with S-adenosyl methionine is effective in treating cholestasis in patients with compensated alcoholic cirrhosis, and can effectively improve the clinical symptoms and biochemical indexes.
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Affiliation(s)
- Jing Tong
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, He'nan Province, China
| | - Chang-Yu Sun
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, He'nan Province, China
| | - Li-Bing Yang
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, He'nan Province, China
| | - Yan-Nan Kang
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, He'nan Province, China
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Su CW, Yang YY, Lin HC. Impact of etiological treatment on prognosis. Hepatol Int 2017; 12:56-67. [PMID: 28702738 DOI: 10.1007/s12072-017-9807-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 06/08/2017] [Indexed: 02/07/2023]
Abstract
Portal hypertension (PHT) is a frequent and severe complication of cirrhosis. PHT may lead to the development of various complications with high mortality. Liver transplantation is the gold standard as a surgical curative treatment for end-stage liver disease. Theoretically, etiological treatment focusing on the pathophysiology of the underlying disease should be the objective of the nonsurgical management of cirrhotic PHT. Chronic viral hepatitis is the major etiology of cirrhosis and PHT. In cirrhotic patients with chronic hepatitis B virus infection, antiviral therapies can suppress viral replication, ameliorate hepatic inflammation, regress fibrosis, and restore liver functional reserve. Moreover, they can delay the progression of liver cirrhosis and ameliorate the severity of PHT. In patients with hepatitis C virus-induced liver cirrhosis, interferon and ribavirin combination therapy provide a favorable long-term prognosis, including lower rates of liver-related and non-liver-related deaths, hepatic decompensation, and hepatocellular carcinoma, particularly in those who have successful eradication of the virus after therapy. In patients with PHT, direct antivirals (DAAs) for hepatitis C virus infection have good safety profiles and excellent viral suppression. Moreover, DAAs can reduce hepatic venous pressure gradient. However, these effects are stronger during the earlier stage of liver cirrhosis. Abstinence is the cornerstone of etiological treatment for alcoholic liver disease. The effects of pharmacological treatments are not satisfactory, and additional studies are mandatory.
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Affiliation(s)
- Chien-Wei Su
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, 201, Sec. 2, Shih-Pai Road, Taipei, 11217, Taiwan.,Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Ying-Ying Yang
- Division of Clinical Training, Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, 201, Sec. 2, Shih-Pai Road, Taipei, 11217, Taiwan. .,Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
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Abstract
酒精性肝病(alcoholic liver disease, ALD)是一种慢性肝脏疾病, 包括肝脂肪变性、酒精性脂肪性肝炎、肝硬化、肝细胞癌和肝衰竭. 许多因素被认为能促进ALD的发展, 特别是氧化应激, 在酒精代谢期间活性氧物质的产生, 来自内脏脂肪组织的脂肪因子和来自肠道的内毒素等. 目前, ALD的发病机制已被广泛研究, 精确的机制尚待阐明. 在我国随着人类生活水平提高和生活方式的改变, 人群中的嗜酒者的比率逐年上升, 乙醇也已成为导致肝脏损害的第二大原因. 因此, ALD相关治疗也受到人们的广泛关注. 在本文中, 我们就ALD的发病机制、治疗等方面的最新研究进展作一综述.
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Osna NA, Feng D, Ganesan M, Maillacheruvu PF, Orlicky DJ, French SW, Tuma DJ, Kharbanda KK. Prolonged feeding with guanidinoacetate, a methyl group consumer, exacerbates ethanol-induced liver injury. World J Gastroenterol 2016; 22:8497-8508. [PMID: 27784962 PMCID: PMC5064031 DOI: 10.3748/wjg.v22.i38.8497] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 08/27/2016] [Accepted: 09/08/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the hypothesis that exposure to guanidinoacetate (GAA, a potent methyl-group consumer) either alone or combined with ethanol intake for a prolonged period of time would cause more advanced liver pathology thus identifying methylation defects as the initiator and stimulator for progressive liver damage. METHODS Adult male Wistar rats were fed the control or ethanol Lieber DeCarli diet in the absence or presence of GAA supplementation. At the end of 6 wk of the feeding regimen, various biochemical and histological analyses were conducted. RESULTS Contrary to our expectations, we observed that GAA treatment alone resulted in a histologically normal liver without evidence of hepatosteatosis despite persistence of some abnormal biochemical parameters. This protection could result from the generation of creatine from the ingested GAA. Ethanol treatment for 6 wk exhibited changes in liver methionine metabolism and persistence of histological and biochemical defects as reported before. Further, when the rats were fed the GAA-supplemented ethanol diet, similar histological and biochemical changes as observed after 2 wk of combined treatment, including inflammation, macro- and micro-vesicular steatosis and a marked decrease in the methylation index were noted. In addition, rats on the combined treatment exhibited increased liver toxicity and even early fibrotic changes in a subset of animals in this group. The worsening liver pathology could be related to the profound reduction in the hepatic methylation index, an increased accumulation of GAA and the inability of creatine generated to exert its hepato-protective effects in the setting of ethanol. CONCLUSION To conclude, prolonged exposure to a methyl consumer superimposed on chronic ethanol consumption causes persistent and pronounced liver damage.
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