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Alnasser SM. The role of glutathione S-transferases in human disease pathogenesis and their current inhibitors. Genes Dis 2025; 12:101482. [PMID: 40290119 PMCID: PMC12022661 DOI: 10.1016/j.gendis.2024.101482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 10/01/2024] [Accepted: 11/02/2024] [Indexed: 04/30/2025] Open
Abstract
Glutathione S-transferases (GSTs) are a family of enzymes detoxifying various harmful compounds by conjugating them with glutathione. While primarily beneficial, dysregulation of GST activity or specific isoforms can contribute to disease pathogenesis. The intricate balance of detoxification processes regulated by GSTs is pivotal in cellular homeostasis, whereby dysregulation in these mechanisms can have profound implications for human health. Certain GSTs neutralize carcinogens, shielding cells and potentially preventing tumorigenesis. Polymorphisms in specific GSTs may result in the accumulation of toxic metabolites, exacerbating oxidative stress, inflammation, and DNA damage, notably observed in neurodegenerative diseases like Parkinson's disease. They can also modulate signaling pathways involved in cell proliferation, survival, and apoptosis, with aberrant activity potentially contributing to uncontrolled cell growth and resistance to cell death, thus promoting cancer development. They may also contribute to autoimmune diseases and chronic inflammatory conditions. This knowledge is useful for designing therapeutic interventions and understanding chemoresistance due to GST polymorphisms. A variety of GST inhibitors have been developed and investigated, with researchers actively working on new inhibitors aimed at preventing off-target effects. By leveraging knowledge of the involvement of specific GST isoforms in disease pathogenesis across different populations, more effective and targeted therapeutics can be designed to enhance patient care and improve treatment outcomes.
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Affiliation(s)
- Sulaiman Mohammad Alnasser
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia
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Ye RQ, Chen YF, Ma C, Cheng X, Guo W, Li S. Advances in identifying risk factors of metabolic dysfunction-associated alcohol-related liver disease. Biomed Pharmacother 2025; 188:118191. [PMID: 40408808 DOI: 10.1016/j.biopha.2025.118191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 05/13/2025] [Accepted: 05/21/2025] [Indexed: 05/25/2025] Open
Abstract
Metabolic dysfunction-associated alcohol-related liver disease (MetALD) is an emerging clinical entity that reflects the coexistence of metabolic dysfunction and alcohol-related liver injury. Unlike classical alcoholic liver disease (ALD), MetALD patients often present with lower to moderate alcohol consumption alongside metabolic risk factors such as obesity, insulin resistance, and dyslipidemia. These factors can synergistically worsen liver injury even at lower alcohol intake levels. Alcohol abuse remains a major global health concern, with the liver being the primary target of alcohol's toxic effects. Long-term alcohol exposure, especially when compounded by metabolic dysfunction, can accelerate the progression from steatosis to inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Besides alcohol itself, various factors, including genetic predispositions, gender, type of alcoholic beverage, drinking patterns, and co-morbidities such as viral infections (HBV, HCV) modulate disease susceptibility and severity. This review summarizes current knowledge of risk factors contributing to MetALD, highlights the synergistic interactions between metabolic dysfunction and alcohol consumption, and discusses potential strategies for disease prevention and management.
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Affiliation(s)
- Rui-Qi Ye
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China; Xinhua Clinical Medical College, Shanghai Jiao Tong University, Shanghai 200135, China
| | - Yi-Fan Chen
- College of Basic Medical Sciences, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Chang Ma
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xi Cheng
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wei Guo
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.
| | - Sha Li
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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Li X, Li M, Chen R, Wang Y, Luo G, Gao X. Affinity-purified targets screening facilitates active components discovery of Chinese formula -HuGan tablets as a case. JOURNAL OF ETHNOPHARMACOLOGY 2025; 347:119703. [PMID: 40188898 DOI: 10.1016/j.jep.2025.119703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 03/23/2025] [Accepted: 03/24/2025] [Indexed: 04/18/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Alcoholic Liver Disease (ALD), a chronic condition caused by long-term heavy alcohol consumption, can progress to cirrhosis or liver failure. HuGan Tablets (HGT) is a compound preparation made of six Chinese herbs, which is used in clinic for the treatment of chronic hepatitis, with studies demonstrating its efficacy in alleviating alcohol-induced liver injury in rats. However, the active components and therapeutic targets of HGT remain unclear and require further investigation. AIM OF THIS STUDY The aim of this study was to develop a systematic pipeline based on the SPR fishing strategy to identify effective components and therapeutic targets in Chinese formulas, using HGT as a representative case. MATERIALS AND METHODS HRMS was employed to analyze HGT ingredients absorbed in rat blood, while network pharmacology, molecular docking and literature mining were utilized to identify potential targets of HGT for ALD alleviation. A systematic SPR-based fishing system was developed by evaluating protein target coupling efficiency, sample recovery rate, specificity of target-small molecule binding, and LOD, and candidate components screened and identified using this system were further screened by SPR affinity tests. Additionally, therapeutic efficacy of the selected compounds was validated in vitro using an ethanol-induced AML12 model and further confirmed in vivo using a mouse model of ALD by assessing markers such as ALT, AST, and oxidative stress indicators. RESULTS A total of 128 compounds were identified in HGT, with 29 metabolites detected in rat blood. MFN2, SOD2, mTOR, RXRA, and GSTP1 were identified as anti-ALD targets of HGT through integrated network pharmacology, molecular docking, and literature analysis. An SPR-based active component fishing system was successfully developed, capturing 15 candidate compounds. SPR affinity analysis revealed strong binding (KD: 3.41-221.7 μM) between (R,S)-goitrin, chlorogenic acid, saikosaponin B2, schisandrin, schisandrol B, schisandrin A, schisandrin C, and schisantherin A and the target proteins. Except for (R,S)-goitrin, the other seven compounds significantly reduced ALT, AST, TG, ROS, and MDA levels while enhancing SOD and GSH activities in cellular models, with comparable therapeutic effects observed in ALD mice. CONCLUSION This study scientifically established an integrated SPR-based pipeline to systematically characterize active ingredients and therapeutic targets in herbal formulations, which was successfully applied to reveal key therapeutic targets and pharmacodynamic components of HGT for ALD. This study provides a valuable framework for SPR-based screening of bioactive components in traditional formulas, as well as for understanding the material basis and mechanism of action of HGT in the treatment of ALD.
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Affiliation(s)
- XueJiao Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Miao Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - RuiShu Chen
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Ying Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Gan Luo
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - XiaoYan Gao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
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Xu T, Pan Y, Ding Q, Cao F, Chang K, Qiu J, Zhuge H, Hao L, Wei H, Si C, Dou X, Li S. The micro-743a-3p-GSTM1 pathway is an endogenous protective mechanism against alcohol-related liver disease in mice. Cell Mol Biol Lett 2024; 29:35. [PMID: 38475733 DOI: 10.1186/s11658-024-00557-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 02/29/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND AND AIMS Epidemiological evidence suggests that the phenotype of glutathione S-transferase mu 1 (GSTM1), a hepatic high-expressed phase II detoxification enzyme, is closely associated with the incidence of alcohol-related liver disease (ALD). However, whether and how hepatic GSTM1 determines the development of ALD is largely unclear. This study was designed to elucidate the role and potential mechanism(s) of hepatic GSTM1 in the pathological process of ALD. METHODS GSTM1 was detected in the liver of various ALD mice models and cultured hepatocytes. Liver-specific GSTM1 or/and micro (miR)-743a-3p deficiency mice were generated by adenoassociated virus-8 delivered shRNA, respectively. The potential signal pathways involving in alcohol-regulated GSTM1 and GSTM1-associated ALD were explored via both genetic manipulation and pharmacological approaches. RESULTS GSTM1 was significantly upregulated in both chronic alcohol-induced mice liver and ethanol-exposed murine primary hepatocytes. Alcohol-reduced miR-743a-3p directly contributed to the upregulation of GSTM1, since liver specific silencing miR-743a-3p enhanced GSTM1 and miR-743a-3p loss protected alcohol-induced liver dysfunctions, which was significantly blocked by GSTM1 knockdown. GSTM1 loss robustly aggravated alcohol-induced hepatic steatosis, oxidative stress, inflammation, and early fibrotic-like changes, which was associated with the activation of apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase (JNK), and p38. GSTM1 antagonized ASK1 phosphorylation and its downstream JNK/p38 signaling pathway upon chronic alcohol consumption via binding with ASK1. ASK1 blockage significantly rescued hepatic GSTM1 loss-enhanced disorders in alcohol-fed mice liver. CONCLUSIONS Chronic alcohol consumption-induced upregulation of GSTM1 in the liver provides a feedback protection against hepatic steatosis and liver injury by counteracting ASK1 activation. Down-regulation of miR-743a-3p improves alcohol intake-induced hepatic steatosis and liver injury via direct targeting on GSTM1. The miR-743a-3p-GSTM1 axis functions as an innate protective pathway to defend the early stage of ALD.
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Affiliation(s)
- Tiantian Xu
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Yan Pan
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Qinchao Ding
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Feiwei Cao
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Kaixin Chang
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Jiannan Qiu
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Hui Zhuge
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Liuyi Hao
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Haibin Wei
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Caijuan Si
- Department of Clinical Nutrition, School of Medicine, Affiliated Zhejiang Hospital, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Xiaobing Dou
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Songtao Li
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China.
- Department of Clinical Nutrition, School of Medicine, Affiliated Zhejiang Hospital, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
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Dasgupta D, Ghosh S, Dey I, Majumdar S, Chowdhury S, Das S, Banerjee S, Saha M, Ghosh A, Roy N, Manna A, Ray S, Agarwal S, Bhaumik P, Datta S, Chowdhury A, Banerjee S. Influence of polymorphisms in TNF-α and IL1β on susceptibility to alcohol induced liver diseases and therapeutic potential of miR-124-3p impeding TNF-α/IL1β mediated multi-cellular signaling in liver microenvironment. Front Immunol 2023; 14:1241755. [PMID: 38146363 PMCID: PMC10749309 DOI: 10.3389/fimmu.2023.1241755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 10/23/2023] [Indexed: 12/27/2023] Open
Abstract
Background and aims Alcoholic liver disease (ALD) is the leading cause of the liver cirrhosis related death worldwide. Excessive alcohol consumption resulting enhanced gut permeability which trigger sensitization of inflammatory cells to bacterial endotoxins and induces secretion of cytokines, chemokines leading to activation of stellate cells, neutrophil infiltration and hepatocyte injury followed by steatohepatitis, fibrosis and cirrhosis. But all chronic alcoholics are not susceptible to ALD. This study investigated the causes of differential immune responses among ALD patients and alcoholic controls (ALC) to identify genetic risk factors and assessed the therapeutic potential of a microRNA, miR-124-3p. Materials and methods Bio-Plex Pro™ Human Chemokine analysis/qRT-PCR array was used for identification of deregulated immune genes. Sequencing/luciferase assay/ELISA detected and confirmed the polymorphisms. THP1 co-cultured with HepG2/LX2/HUVEC and apoptosis assay/qRT-PCR/neutrophil migration assay were employed as required. Results The combined data analysis of the GSE143318/Bio-Plex Pro™ Human Chemokine array and qRT-PCR array revealed that six genes (TNFα/IL1β/IL8/MCP1/IL6/TGFβ) were commonly overexpressed in both serum/liver tissue of ALD-patients compared to ALC. The promoter sequence analysis of these 6 genes among ALD (n=322)/ALC (n=168) samples revealed that only two SNPs, rs361525(G/A) at -238 in TNF-α/rs1143627(C/T) at -31 in IL1β were independently associated with ALD respectively. To evaluate the functional implication of these SNPs on ALD development, the serum level of TNF-α/IL1β was verified and observed significantly higher in ALD patients with risk genotypes TNF-α-238GA/IL1β-31CT+TT than TNF-α-238GG/IL1β-31CC. The TNF-α/IL1β promoter Luciferase-reporter assays showed significantly elevated level of luciferase activities with risk genotypes -238AA/-31TT than -238GG/-31CC respectively. Furthermore, treatment of conditioned medium of TNF-α/IL1β over-expressed THP1 cells to HepG2/LX2/HUVEC cells independently showed enhanced level of ER stress and apoptosis in HepG2/increased TGFβ and collagen-I production by LX2/huge neutrophil infiltration through endothelial layer. However, restoration of miR-124-3p in THP1 attenuated such inter-cellular communications and hepatocyte damage/collagen production/neutrophil infiltration were prohibited. Target analysis/luciferase-reporter assays revealed that both TNF-α/IL1β were inhibited by miR-124-3p along with multiple genes from TLR4 signaling/apoptosis/fibrogenesis pathways including MYD88, TRAF3/TRADD, Caspase8/PDGFRA, TGFβR2/MCP1, and ICAM1 respectively. Conclusion Thus, rs361525(G/A) in TNF-α and rs1143627(C/T) in IL1β gene may be used as early predictors of ALD susceptibility among East Indian population. Impeding overexpressed TNF-α/IL1β and various genes from associated immune response pathways, miR-124-3p exhibits robust therapeutic potential for ALD patients.
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Affiliation(s)
- Debanjali Dasgupta
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Suchandrima Ghosh
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Indrashish Dey
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Swagata Majumdar
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Saheli Chowdhury
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Subhas Das
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Sanjana Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Mehelana Saha
- Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Amit Ghosh
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Neelanjana Roy
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Alak Manna
- Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Sukanta Ray
- Department Gastro-Surgery, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Shaleen Agarwal
- Liver Transplant and Biliary Sciences, Max Saket West Super Speciality Hospital, New Delhi, India
| | - Pradeep Bhaumik
- Department of Medicine, Agartala Government Medical College, West Tripura, India
| | - Simanti Datta
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Abhijit Chowdhury
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Soma Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
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Morgan MY, Sharma M, Atkinson SR. Genetic and Environmental Susceptibility to Alcoholic Hepatitis. Clin Liver Dis 2021; 25:517-535. [PMID: 34229837 DOI: 10.1016/j.cld.2021.04.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Constitutional, environmental, and genetic risk factors influence the development of alcohol-related cirrhosis. The amount of alcohol consumed and whether excessive drinking continues after the identification of pre-cirrhotic liver damage are key risk factors. Female sex, ethnicity, obesity, coffee consumption, cigarette smoking, and exposure to other causes of liver injury also influence the risk of disease development. More recently several genetic loci have been robustly associated with the risk for developing significant alcohol-related liver disease. It remains unclear whether additional risk factors are involved in the development of the clinical syndrome of alcoholic hepatitis, but the genetic evidence is suggestive.
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Affiliation(s)
- Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College, Rowland Hill Street, Hampstead, London NW3 2PF, UK.
| | - Moksh Sharma
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College, Rowland Hill Street, Hampstead, London NW3 2PF, UK
| | - Stephen R Atkinson
- Department of Metabolism, Digestion and Reproduction, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
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Usategui-Martín R, Carbonell C, Novo-Veleiro I, Hernández-Pinchete S, Mirón-Canelo JA, Chamorro AJ, Marcos M. Association between genetic variants in CYP2E1 and CTRC genes and susceptibility to alcoholic pancreatitis: A systematic review and meta-analysis. Drug Alcohol Depend 2020; 209:107873. [PMID: 32045777 DOI: 10.1016/j.drugalcdep.2020.107873] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/13/2020] [Accepted: 01/14/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Genetic predisposition plays an important role in the development of alcoholic pancreatitis (AP), with previous studies suggesting that genetics variants in certain genes, such asCYP2E1 and CTRC, partially explain individual susceptibility to this disease. Therefore, the aim of this work was to conduct a systematic review and meta-analysis of existing studies that analyzed how polymorphisms within CYP2E1 and CTRC genes influence the risk of AP. MATERIAL AND METHODS We performed a systematic review of studies that analyzed the genotype distribution of CYP2E1 and CTRC allelic variants among patients with AP and a group of controls. A meta-analysis was conducted using a random effects model. Odds ratios (ORs) and their confidence intervals (CIs) were calculated. RESULTS The T allele of theCTRC 180 C > T variant was significantly more prevalent among patients with AP compared to all controls (OR = 1.79, 95% CI = 1.43-2.24; P < 0.00001) and healthy subjects (OR = 1.84, 95% CI = 1.46-2.31; P < 0.00001). The Trp variant of CTRC Arg254Trp polymorphism was also more prevalent in patients with AP; however, these results were not significant after excluding one study. We found no clear evidence that CYP2E1-DraI or of CYP2E1-RsaI/PstI polymorphisms modulate the risk of developing AP. CONCLUSIONS Our meta-analysis supports that the T allele ofCTRC 180C > T polymorphisms modulates the risk of alcoholic pancreatitis. No clear evidence was found for the remaining SNPs being associated with this disease.
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Affiliation(s)
- Ricardo Usategui-Martín
- Instituto Universitario de Oftalmobiología Aplicada (IOBA). University of Valladolid, Valladolid, Spain.
| | - Cristina Carbonell
- Alcoholism Unit. Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Working Group on Alcohol and Alcoholism. Spanish Society of Internal Medicine (SEMI), Spain.
| | - Ignacio Novo-Veleiro
- Working Group on Alcohol and Alcoholism. Spanish Society of Internal Medicine (SEMI), Spain; Department of Internal Medicine, University Hospital of Santiago de Compostela, A Coruña, Spain.
| | | | | | - Antonio-Javier Chamorro
- Alcoholism Unit. Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Working Group on Alcohol and Alcoholism. Spanish Society of Internal Medicine (SEMI), Spain; Department of Medicine, University of Salamanca, Salamanca, Spain.
| | - Miguel Marcos
- Alcoholism Unit. Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Working Group on Alcohol and Alcoholism. Spanish Society of Internal Medicine (SEMI), Spain; Department of Medicine, University of Salamanca, Salamanca, Spain.
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8
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Kim JH, Ahn JB, Kim DH, Kim S, Ma HW, Che X, Seo DH, Kim TI, Kim WH, Cheon JH, Kim SW. Glutathione S-transferase theta 1 protects against colitis through goblet cell differentiation via interleukin-22. FASEB J 2020; 34:3289-3304. [PMID: 31916636 DOI: 10.1096/fj.201902421r] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 12/21/2019] [Accepted: 12/23/2019] [Indexed: 01/06/2023]
Abstract
The enzyme glutathione S-transferase theta 1 (GSTT1) is involved in detoxifying chemicals, including reactive oxygen species (ROS). Here, we provide a significant insight into the role of GSTT1 in inflammatory bowel disease (IBD). We identified decreased expression of GSTT1 in inflamed colons from IBD patients compared to controls. We intrarectally or intraperitoneally delivered Gstt1 gene to mice with dextran sodium sulfate (DSS)-induced colitis and noted attenuation of colitis through gene transfer of Gstt1 via an IL-22 dependent pathway. Downregulation of GSTT1 by pathogen-associated molecular patterns (PAMPs) of microbes reduced innate defense responses and goblet cell differentiation. The GSTT1 mutation in intestinal epithelial cells (IECs) and IBD patients decreased its dimerization, which was connected to insufficient phosphorylation of signal transducer and activator of transcription-3 and p38/mitogen-activated protein kinase by their common activator, IL-22. GSTT1 ameliorated colitis and contributed as a modulator of goblet cells through sensing pathogens and host immune responses. Its mutations are linked to chronic intestinal inflammation due to its insufficient dimerization. Our results provide new insights into GSTT1 mutations that are linked to chronic intestinal inflammation due to its insufficient dimerization and their functional consequences in IBDs.
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Affiliation(s)
- Jae Hyeon Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Bum Ahn
- Department of Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Da Hye Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Soochan Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Hyun Woo Ma
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Xiumei Che
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Dong Hyuk Seo
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Tae Il Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Won Ho Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Won Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
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9
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Gao B, Zakhari S. Epidemiology and Pathogenesis of Alcoholic Liver Disease. ZAKIM AND BOYER'S HEPATOLOGY 2018:334-344.e3. [DOI: 10.1016/b978-0-323-37591-7.00022-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
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10
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Stickel F, Moreno C, Hampe J, Morgan MY. The genetics of alcohol dependence and alcohol-related liver disease. J Hepatol 2017; 66:195-211. [PMID: 27575312 DOI: 10.1016/j.jhep.2016.08.011] [Citation(s) in RCA: 114] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 08/15/2016] [Accepted: 08/16/2016] [Indexed: 12/19/2022]
Abstract
The susceptibility to developing alcohol dependence and significant alcohol-related liver injury is determined by a number of constitutional, environmental and genetic factors, although the nature and level of interplay between them remains unclear. The familiality and heritability of alcohol dependence is well-documented but, to date, no strong candidate genes conferring increased risk have emerged, although variants in alcohol dehydrogenase and acetaldehyde dehydrogenase have been shown to confer protection, predominantly in individuals of East Asian ancestry. Population contamination with confounders such as drug co-dependence and psychiatric and physical co-morbidity may explain the essentially negative genome-wide association studies in this disorder. The familiality and hereditability of alcohol-related cirrhosis is not as well-documented but three strong candidate genes PNPLA3, TM6SF2 and MBOAT7, have been identified. The mechanisms by which variants in these genes confer risk and the nature of the functional interplay between them remains to be determined but, when elucidated, will undoubtedly increase our understanding of the pathophysiology of this disease. The way in which this genetic information could potentially inform patient management has yet to be determined and tested.
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Affiliation(s)
- Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Switzerland.
| | - Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, TU Dresden, Germany
| | - Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, UK
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Novo-Veleiro I, Cieza-Borrella C, Pastor I, Chamorro AJ, Laso FJ, González-Sarmiento R, Marcos M. A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men. PLoS One 2016; 11:e0168685. [PMID: 27992614 PMCID: PMC5167392 DOI: 10.1371/journal.pone.0168685] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 12/05/2016] [Indexed: 11/18/2022] Open
Abstract
Background Genetic polymorphisms in the RAS gene family are associated with different diseases, which may include alcohol-related disorders. Previous studies showed an association of the allelic variant rs26907 in RASGRF2 gene with higher alcohol intake. Additionally, the rs61764370 polymorphism in the KRAS gene is located in a binding site for the let-7 micro-RNA family, which is potentially involved in alcohol-induced inflammation. Therefore, this study was designed to explore the association between these two polymorphisms and susceptibility to alcoholism or alcoholic liver disease (ALD). Methods We enrolled 301 male alcoholic patients and 156 healthy male volunteers in this study. Polymorphisms were genotyped by using TaqMan® PCR assays for allelic discrimination. Allelic and genotypic frequencies were compared between the two groups. Logistic regression analysis was performed to analyze the inheritance model. Results The A allele of the RASGRF2 polymorphism (rs26907) was significantly more prevalent among alcoholic patients with cirrhosis (23.2%) compared to alcoholic patients without ALD (14.2%). This difference remained significant in the group of patients with alcohol dependence (28.8% vs. 14.3%) but not in those with alcohol abuse (15.1% vs. 14.4%). Multivariable logistic regression analysis showed that the A allele of this polymorphism (AA or GA genotype) was associated with alcoholic cirrhosis both in the total group of alcoholics (odds ratio [OR]: 2.33, 95% confidence interval [CI]: 1.32–4.11; P = 0.002) and in the group of patients with alcohol dependence (OR: 3.1, 95% CI: 1.50–6.20; P = 0.001). Allelic distributions of the KRAS polymorphism (rs61764370) did not differ between the groups. Conclusions To our knowledge, this genetic association study represents the first to show an association of the RASGRF2 G>A (rs26907) polymorphism with ALD in men, particularly in the subgroup of patients with AD. The findings suggest the potential relevance of the RAS gene family in alcoholism and ALD.
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Affiliation(s)
- Ignacio Novo-Veleiro
- Department of Internal Medicine, University Hospital of Santiago de Compostela, A Coruña, Spain
| | - Clara Cieza-Borrella
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Biomedical Research of Salamanca-IBSAL, Salamanca, Spain
| | - Isabel Pastor
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Biomedical Research of Salamanca-IBSAL, Salamanca, Spain
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain
| | - Antonio-Javier Chamorro
- Institute of Biomedical Research of Salamanca-IBSAL, Salamanca, Spain
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain
| | - Francisco-Javier Laso
- Institute of Biomedical Research of Salamanca-IBSAL, Salamanca, Spain
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain
| | - Rogelio González-Sarmiento
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Biomedical Research of Salamanca-IBSAL, Salamanca, Spain
| | - Miguel Marcos
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Biomedical Research of Salamanca-IBSAL, Salamanca, Spain
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain
- * E-mail:
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Mehal W, To U. New approaches for fibrosis regression in alcoholic cirrhosis. Hepatol Int 2016; 10:773-8. [PMID: 27460408 DOI: 10.1007/s12072-016-9752-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 06/21/2016] [Indexed: 01/18/2023]
Abstract
Liver fibrosis is a dynamic process of fibrinogenesis and fibrinolysis. It is sequelae of recurrent injury and inflammation to the liver. Only recently has there been significant progress in understanding the pathophysiology behind liver fibrosis. This has allowed for the development of identifiable targets for potential therapies. In this article we will discuss the underlying general cellular mechanisms that play a key role in the pathway of fibrinogenesis and fibrinolysis and then focus on the mechanisms that are key in alcohol-induced liver fibrosis. Challenges in formulating potential fibrosis therapies as well as current potential targets for liver fibrosis will be reviewed as well.
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Affiliation(s)
- Wajahat Mehal
- Section of Digestive Diseases, Department of Veterans Affairs Connecticut Healthcare, West Haven, CT, 06516, USA. .,Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, 06520, USA.
| | - Uyen To
- Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, 06520, USA
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13
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Novo-Veleiro I, Alvela-Suárez L, Chamorro AJ, González-Sarmiento R, Laso FJ, Marcos M. Alcoholic liver disease and hepatitis C virus infection. World J Gastroenterol 2016. [PMID: 26819510 DOI: 10.3748/wjg.v22.i4.141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Alcohol consumption and hepatitis C virus (HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher (up to 50%) in alcoholic patients than in the general population. However, the presence of advanced alcoholic liver disease (ALD) or intravenous drug use (IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefit from additional support during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.
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Affiliation(s)
- Ignacio Novo-Veleiro
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Lucía Alvela-Suárez
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Antonio-Javier Chamorro
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Rogelio González-Sarmiento
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Francisco-Javier Laso
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Miguel Marcos
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
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Novo-Veleiro I, Alvela-Suárez L, Chamorro AJ, González-Sarmiento R, Laso FJ, Marcos M. Alcoholic liver disease and hepatitis C virus infection. World J Gastroenterol 2016; 22:1411-1420. [PMID: 26819510 PMCID: PMC4721976 DOI: 10.3748/wjg.v22.i4.1411] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 10/01/2015] [Accepted: 12/01/2015] [Indexed: 02/06/2023] Open
Abstract
Alcohol consumption and hepatitis C virus (HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher (up to 50%) in alcoholic patients than in the general population. However, the presence of advanced alcoholic liver disease (ALD) or intravenous drug use (IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefit from additional support during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.
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15
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Ge B, Song Y, Zhang Y, Liu X, Wen Y, Guo X. Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) null polymorphisms and the risk of hypertension: a meta-analysis. PLoS One 2015; 10:e0118897. [PMID: 25742618 PMCID: PMC4351109 DOI: 10.1371/journal.pone.0118897] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Accepted: 01/12/2015] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Some studies have recently focused on the association between glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) null polymorphisms and hypertension; however, results have been inconsistent. OBJECTIVE In order to drive a more precise estimation, the present systematic review and meta-analysis is performed to investigate the relationship between the GSTM1 and GSTT1 null polymorphisms and hypertension. METHODS Eligible articles were identified by a search of several bibliographic databases for the period up to August 17, 2013. Odds ratios were pooled using either fixed-effects or random-effects models. RESULTS Regarding the GSTM1 null/present genotype, 14 case-control studies were eligible (2773 hypertension cases and 3189 controls). The meta-analysis revealed that it might present a small increased risk for hypertension, although the effect was not statistically significant (odd ratio (OR) = 1.16, 95% confidence interval (CI): 0.96, 1.40; P = 0.002, I2 = 59.8%). Further subgroup analysis by ethnicity and control source suggested that the association was still not significant. Thirteen case-control studies were eligible for GSTT1 (2497 hypertension cases and 3078 controls). No statistically significant association was observed between the GSTT1 null genotype and hypertension risk (OR = 1.14, 95% CI: 0.85, 1.53; P = 0.000, I2 = 80.3%). Furthermore, stratification by ethnicity and control source indicated no association between the GSTT1 null genotype and hypertension risk. We further confirmed the association by sensitivity analysis. No publication bias was detected. CONCLUSION This meta-analysis suggests that the GSTM1 and GSTT1 null polymorphisms are not associated with the risk of hypertension. Future large well-designed epidemiological studies with individual information, lifestyle factors, and environmental factors are warranted to validate the present findings.
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Affiliation(s)
- Beihai Ge
- Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yadong Song
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yi Zhang
- Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaowen Liu
- Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yuxiang Wen
- Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaomei Guo
- Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- * E-mail:
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Theis WS, Andringa KK, Millender-Swain T, Dickinson DA, Postlethwait EM, Bailey SM. Ozone inhalation modifies the rat liver proteome. Redox Biol 2014; 2:52-60. [PMID: 25544660 PMCID: PMC4297937 DOI: 10.1016/j.redox.2013.11.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 11/18/2013] [Accepted: 11/18/2013] [Indexed: 02/06/2023] Open
Abstract
Ozone (O3) is a serious public health concern. Recent findings indicate that the damaging health effects of O3 extend to multiple systemic organ systems. Herein, we hypothesize that O3 inhalation will cause downstream alterations to the liver. To test this, male Sprague-Dawley rats were exposed to 0.5 ppm O3 for 8 h/day for 5 days. Plasma liver enzyme measurements showed that 5 day O3 exposure did not cause liver cell death. Proteomic and mass spectrometry analysis identified 10 proteins in the liver that were significantly altered in abundance following short-term O3 exposure and these included several stress responsive proteins. Glucose-regulated protein 78 and protein disulfide isomerase increased, whereas glutathione S-transferase M1 was significantly decreased by O3 inhalation. In contrast, no significant changes were detected for the stress response protein heme oxygenase-1 or cytochrome P450 2E1 and 2B in liver of O3 exposed rats compared to controls. In summary, these results show that an environmentally-relevant exposure to inhaled O3 can alter the expression of select proteins in the liver. We propose that O3 inhalation may represent an important unrecognized factor that can modulate hepatic metabolic functions.
Rats were exposed to filtered air (FA) or 0.5 ppm ozone (O3) 8 h/day for 5 days. Using this exposure protocol, O3 caused no detectable lung injury or liver cell death. O3 altered the expression of some drug metabolism and stress proteins in liver.
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Affiliation(s)
- Whitney S Theis
- Department of Environmental Health Sciences, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA.
| | - Kelly K Andringa
- Department of Environmental Health Sciences, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA.
| | - Telisha Millender-Swain
- Department of Environmental Health Sciences, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA; Department of Pathology, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA.
| | - Dale A Dickinson
- Department of Environmental Health Sciences, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA; Center for Free Radical Biology, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA.
| | - Edward M Postlethwait
- Department of Environmental Health Sciences, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA; Center for Free Radical Biology, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA.
| | - Shannon M Bailey
- Department of Environmental Health Sciences, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA; Department of Pathology, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA; Center for Free Radical Biology, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA.
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The mitochondrial genome in aging and senescence. Ageing Res Rev 2014; 18:1-15. [PMID: 25042573 DOI: 10.1016/j.arr.2014.07.001] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 07/07/2014] [Accepted: 07/09/2014] [Indexed: 12/15/2022]
Abstract
Aging is characterized by a progressive decline in organism functions due to the impairment of all organs. The deterioration of both proliferative tissues in liver, skin and the vascular system, as well as of largely post-mitotic organs, such as the heart and brain could be attributed at least in part to cell senescence. In this review we examine the role of mitochondrial dysfunction and mtDNA mutations in cell aging and senescence. Specifically, we address how p53 and telomerase reverse transcriptase (TERT) activity switch their roles from cytoprotective to detrimental and also examine the role of microRNAs in cell aging. The proposed role of Reactive Oxygen Species (ROS), both as mutating agents and as signalling molecules, underlying these processes is also described.
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18
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Evidence of genotoxicity in lymphocytes of non-smoking alcoholics. Mol Biol Rep 2014; 42:53-9. [PMID: 25223858 DOI: 10.1007/s11033-014-3739-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 09/11/2014] [Indexed: 12/20/2022]
Abstract
Alcohol abuse is a significant public health issue. Epidemiological studies conducted on different populations consistently showed that consumption of alcoholic beverages is associated with cytogenetic damages and higher risk for several types of cancer. However, the interpretation of many cytogenetic studies resulted complicated because some confounding factors, such as smoking habit, are not always taken into account. In the present study, the frequency of sister chromatid exchanges (SCEs), chromosome aberrations (CAs) and micronuclei (MNs) in cultured human lymphocytes was assessed on 15 alcoholic and 15 non-alcoholic control male subjects. Moreover, considering the implication of the Glutathione S-transferases gene polymorphisms in the genetic susceptibility to alcoholic liver diseases, we considered an important issue to evaluate the relationship between these gene polymorphisms and the cytogenetic damage. In our sample we exclusively considered individuals that did not smoke nor consume drugs for a period of at least 2 years prior to the analysis. Statistically significant differences were found between alcoholics and controls in the frequency of SCEs/cell (P = 0.001), RI value (P = 0.001), CAs (P = 0.002) and CAB (P = 0.002). Vice versa, no significant differences were found between alcoholics and controls in terms of MNs frequency and CBPI value. In both samples, no statistically significant association was found between the analysed GSTs gene polymorphisms and the frequencies of MNs, SCEs and CAs. Finally, among alcoholics we found a positive correlation between SCEs and CAs frequencies and the duration of alcohol abuse.
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Chamorro AJ, Torres JL, Mirón-Canelo JA, González-Sarmiento R, Laso FJ, Marcos M. Systematic review with meta-analysis: the I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is significantly associated with alcoholic liver cirrhosis. Aliment Pharmacol Ther 2014; 40:571-81. [PMID: 25060292 DOI: 10.1111/apt.12890] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 05/02/2014] [Accepted: 07/07/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND Several studies have reported an association between alcoholic liver cirrhosis (ALC) or other forms of alcoholic liver disease (ALD) and the genetic variant rs738409 (C>G) in adiponutrin/patatin-like phospholipase domain-containing 3 gene (PNPLA3). AIM To evaluate the influence of this variant on ALC and other forms of ALD. METHODS We performed a systematic review of previous studies on the relationship between rs738409 of PNPLA3 and ALD and meta-analysis was conducted in a random-effects model. Calculations of the odds ratios (ORs) and their confidence intervals (CIs), tests for heterogeneity and sensitivity analyses were performed. RESULTS Database search identified 11 previous studies available for inclusion with a total of 3495 patients with ALD (2087 with ALC) and 5038 controls (4007 healthy subjects and 1031 alcoholics without ALD). Patients with ALC compared to controls had a significantly higher prevalence of the G allele when comparing GG vs. CC (OR 4.30, 95% CI 3.25-5.69; P < 0.00001) or GC vs. CC genotypes (GC vs. CC: OR 1.91, 95% CI 1.67-2.17) or under a recessive or dominant model. Similar results were found when comparing separately patients with ALC vs. alcoholics without ALD or healthy subjects. An association of the G allele with ALD emerged when comparing ALD patients vs. alcoholics without ALD and/or healthy subjects although moderate to large heterogeneity was observed. Our data suggested an additive genetic model for this variant in ALD. CONCLUSION Our meta-analysis shows that the rs738409 variant of PNPLA3 is clearly associated with alcoholic liver cirrhosis.
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Affiliation(s)
- A-J Chamorro
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
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Impact of the genes UGT1A1, GSTT1, GSTM1, GSTA1, GSTP1 and NAT2 on acute alcohol-toxic hepatitis. Open Life Sci 2014. [DOI: 10.2478/s11535-013-0249-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AbstractAlcohol metabolism causes cellular damage by changing the redox status of cells. In this study, we investigated the relationship between genetic markers in genes coding for enzymes involved in cellular redox stabilization and their potential role in the clinical outcome of acute alcohol-induced hepatitis. Study subjects comprised 60 patients with acute alcohol-induced hepatitis. The control group consisted of 122 healthy non-related individuals. Eight genetic markers of the genes UGT1A1, GSTA1, GSTP1, NAT2, GSTT1 and GSTM1 were genotyped. GSTT1 null genotype was identified as a risk allele for alcohol-toxic hepatitis progression (OR 2.146, P=0.013). It was also found to correlate negatively with the level of prothrombin (β= −11.05, P=0.037) and positively with hyaluronic acid (β=170.4, P=0.014). NAT2 gene alleles rs1799929 and rs1799930 showed opposing associations with the activity of the biochemical markers γ-glutamyltransferase and alkaline phosphatase; rs1799929 was negatively correlated with γ-glutamyltransferase (β=−261.3, P=0.018) and alkaline phosphatase (β= −270.5, P=0.032), whereas rs1799930 was positively correlated with Γ-glutamyltransferase (β=325.8, P=0.011) and alkaline phosphatase (β=374.8, P=0.011). Enzymes of the glutathione S-transferase family and NAT2 enzyme play an important role in the detoxification process in the liver and demonstrate an impact on the clinical outcome of acute alcohol-induced hepatitis.
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Wang T, Wang B. Association between Glutathione S-transferase M1/Glutathione S-transferase T1 polymorphisms and Parkinson's disease: a meta-analysis. J Neurol Sci 2013; 338:65-70. [PMID: 24382428 DOI: 10.1016/j.jns.2013.12.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Revised: 11/03/2013] [Accepted: 12/10/2013] [Indexed: 01/28/2023]
Abstract
The Glutathione S-transferase M1 (GSTM1) and Glutathione S-transferase T1 (GSTT1) genes have been studied extensively as potential candidate genes for the risk of Parkinson's disease (PD). However, direct evidence from genetic association studies remains inconclusive. In order to address this issue, we performed an updated and refined meta-analysis to determine the effect of GSTM1 and GSTT1 polymorphisms on Parkinson's disease. A fixed-effect model was utilized to calculate the combined odds ratio (OR), OR of different ethnicities, and 95% confidence intervals (CIs). Potential publication bias was estimated. Homogeneity of the included studies was also evaluated. The pooled OR was 1.13 [95% CI (1.03, 1.24)] and 0.96 [95% CI (0.82, 1.12)] for GSTM1 and GSTT1 polymorphisms, respectively. Analysis according to different races found no association between GSTM1/GSTT1 polymorphisms and PD risks except for GSTM1 variant in Caucasians, which showed a weak correlation (OR 1.16 [95% CI (1.04, 1.29), I squared=6.2%, p=0.384]). Neither publication bias nor heterogeneity was found among the included studies. The results of this meta-analysis suggest that GSTM1 polymorphism is weakly associated with the risk of PD in Caucasians whereas GSTT1 polymorphism is not a PD risk factor.
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Affiliation(s)
- Tengfei Wang
- Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, USA.
| | - Bin Wang
- Department of Pharmacology, Shaanxi University of Traditional Chinese Medicine, Xianyang, Shaanxi, PR China.
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Association between CD14-159C>T polymorphisms and the risk for alcoholic liver disease: a meta-analysis. Eur J Gastroenterol Hepatol 2013; 25:1183-9. [PMID: 23587862 DOI: 10.1097/meg.0b013e3283612ff1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
AIMS The association between CD14-159C>T polymorphisms and alcoholic liver disease (ALD) risk has been investigated in many studies, but the results were inconsistent. Therefore, we performed a meta-analysis to investigate the association between the CD14-159C>T polymorphisms and the risk for ALD. METHODS A comprehensive literature search was conducted to identify the relevant studies from PubMed, ISI Web of Science, and Embase. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using either the fixed-effects model or random-effects model on the basis of the heterogeneity test. RESULTS A total of eight eligible studies were included in the meta-analyses. The combined results showed no significant association between CD14-159C>T polymorphisms and ALD risk when ALD patients were compared with alcoholics without ALD (T vs. C, OR=1.22, 95% CI 0.84-1.77; TT/TC vs. CC, OR=1.43, 95% CI 0.86-2.37) and when ALD patients were compared with nonalcoholics (T vs. C, OR=1.13, 95% CI 0.90-1.43; TT/TC vs. CC, OR=1.05, 95% CI 0.76-1.46). However, a significant association was observed in the heterozygous comparison (TC vs. CC, OR=3.47, 95% CI 1.93-6.22), whereas a marginal association was observed in the dominant model (TT/CT vs. CC, OR=2.43, 95% CI 1.00-5.91) when alcoholic cirrhosis patients were compared with alcoholics without ALD. CONCLUSION This meta-analysis suggests that the CD14-159C>T polymorphism may not be significantly associated with the risk for ALD. Although a significant association was observed between the -159C>T polymorphism and the risk for alcoholic cirrhosis, well-designed studies with large sample sizes are warranted to confirm these results.
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Peter N, Chiramel KJ, A R S. Effect of Alcohol Withdrawl on Glutathione S-transferase, Total Antioxidant Capacity and Amylase in Blood and Saliva of Alcohol-Dependent Males. J Clin Diagn Res 2013; 7:797-800. [PMID: 23814713 DOI: 10.7860/jcdr/2013/4658.2942] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Accepted: 03/02/2013] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Alcohol biomarkers help in the early detection of alcoholism and its complications. There is a paucity of studies in India on the salivary markers of systemic diseases in general and on salivary alcohol biomarkers in particular. OBJECTIVES The present study was aimed at assessing the effect of alcohol withdrawal on the antioxidants and amylase in blood and saliva, and at finding the correlation between the blood and the salivary parameters in alcoholics. METHODS Sixty alcohol-dependent males who were in the age group of 30 - 70 years, who were admitted to the Deaddiction Centre for alcohol withdrawal treatment for one month, were the subjects of this study; age-matched healthy individuals were the controls. In the blood and saliva samples, the activities of Glutathione S-Transferase (GST) and amylase and the Total Antioxidant Capacity (TAC) were assayed. RESULTS The alcohol-dependent subjects showed significantly lower GST and amylase activities and the TAC in blood and saliva as compared to those in the controls (P<0.001). The alcohol withdrawal caused a significant increase in the GST and amylase activities and the TAC to near-control values. In the alcohol-dependent subjects, there was a significant correlation between the values in blood and saliva with respect to GST and TAC. CONCLUSIONS Alcoholism causes an impaired antioxidant capacity and a decreased secretion of amylase, which is ameliorated due to the alcohol withdrawal regimen . The strong correlation between blood and saliva with respect to the antioxidants suggests the potential future use of saliva as a laboratory tool in clinical medicine.
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Affiliation(s)
- Neethumol Peter
- Lecturer in Biochemistry, Presentation College , Puthenvellikara, Kerala
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Abstract
Background and Objectives The GSTM1, GSTT1 and GSTP1 polymorphisms might be involved in inactivation of procarcinogens that contribute to the genesis and progression of cancers. However, studies investigating the association between GSTM1, GSTT1 or GSTP1 polymorphisms and prostate cancer (PCa) risk report conflicting results, therefore, we conducted a meta-analysis to re-examine the controversy. Methods Published literature from PubMed, Embase, Google Scholar and China National Knowledge Infrastructure (CNKI) were searched (updated to June 2, 2012). According to our inclusion criteria, studies that observed the association between GSTM1, GSTT1 or GSTP1 polymorphisms and PCa risk were included. The principal outcome measure was the odds ratio (OR) with 95% confidence interval (CI) for the risk of PCa associated with GSTM1, GSTT1 and GSTP1 polymorphisms. Results Fifty-seven studies involving 11313 cases and 12934 controls were recruited. The overall OR, which was 1.2854 (95% CI = 1.1405–1.4487), revealed a significant risk of PCa and GSTM1 null genotype, and the similar results were observed when stratified by ethnicity and control source. Further, the more important is that the present study first reported the high risks of PCa for people who with dual null genotype of GSTM1 and GSTT1 (OR = 1.4353, 95% CI = 1.0345–1.9913), or who with GSTT1 null genotype and GSTP1 A131G polymorphism (OR = 1.7335, 95% CI = 1.1067–2.7152). But no association was determined between GSTT1 null genotype (OR = 1.102, 95% CI = 0.9596–1.2655) or GSTP1 A131G polymorphism (OR = 1.0845, 95% CI = 0.96–1.2251) and the PCa risk. Conclusions Our meta-analysis suggested that the people with GSTM1 null genotype, with dual null genotype of GSTM1 and GSTT1, or with GSTT1 null genotype and GSTP1 A131G polymorphism are associated with high risks of PCa, but no association was found between GSTT1 null genotype or GSTP1 A131G polymorphism and the risk of PCa. Further rigorous analytical studies are highly expected to confirm our conclusions and assess gene-environment interactions with PCa risk.
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