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Seo HY, Park JY, Lee SH, Cho SH, Han E, Hwang JS, Kim MK, Jang BK. Clusterin inhibits lipopolysaccharide induced liver injury. Sci Rep 2025; 15:5975. [PMID: 39966409 PMCID: PMC11836311 DOI: 10.1038/s41598-024-80903-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 11/22/2024] [Indexed: 02/20/2025] Open
Abstract
Lipopolysaccharide (LPS) exacerbates liver injury by activating various inflammatory pathways. Clusterin, a glycoprotein involved in lipid transport, and cytoprotection, is known to have inhibitory effects on liver steatosis and fibrosis. In this study, we investigated the role of clusterin in regulating LPS-induced liver injury and its effects on liver injury in C57BL/6 mice and clusterin knockout mice injected with LPS for 3 h. Primary Kupffer cells (KCs) and hepatocytes (HCs) were isolated from these mice and examined using immunohistochemistry, real-time RT-PCR, ELISA, and western blot analysis to assess the effects of clusterin. Clusterin deficiency significantly exacerbated LPS-induced liver injury, as evidenced by increased inflammatory cell infiltration, elevated serum alanine aminotransferase and aspartate aminotransferase levels, and upregulated expression of pro-inflammatory cytokines and components of the NLRP3 inflammasome. By contrast, overexpression of clusterin in primary Kupffer cells and hepatocytes significantly reduced these inflammatory markers. Furthermore, the protective mechanism of clusterin involved inhibition of the STAT3 signaling pathway. These findings suggest that clusterin is a useful therapeutic target to modulate cytokine production and key inflammatory signaling pathways in inflammatory liver diseases.
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Yasmeen F, Pirzada RH, Ahmad B, Choi B, Choi S. Understanding Autoimmunity: Mechanisms, Predisposing Factors, and Cytokine Therapies. Int J Mol Sci 2024; 25:7666. [PMID: 39062908 PMCID: PMC11277571 DOI: 10.3390/ijms25147666] [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: 06/27/2024] [Revised: 07/05/2024] [Accepted: 07/06/2024] [Indexed: 07/28/2024] Open
Abstract
Autoimmunity refers to an organism's immune response against its own healthy cells, tissues, or components, potentially leading to irreversible damage to vital organs. Central and peripheral tolerance mechanisms play crucial roles in preventing autoimmunity by eliminating self-reactive T and B cells. The disruption of immunological tolerance, characterized by the failure of these mechanisms, results in the aberrant activation of autoreactive lymphocytes that target self-tissues, culminating in the pathogenesis of autoimmune disorders. Genetic predispositions, environmental exposures, and immunoregulatory disturbances synergistically contribute to the susceptibility and initiation of autoimmune pathologies. Within the realm of immune therapies for autoimmune diseases, cytokine therapies have emerged as a specialized strategy, targeting cytokine-mediated regulatory pathways to rectify immunological imbalances. Proinflammatory cytokines are key players in inducing and propagating autoimmune inflammation, highlighting the potential of cytokine therapies in managing autoimmune conditions. This review discusses the etiology of autoimmune diseases, current therapeutic approaches, and prospects for future drug design.
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Affiliation(s)
- Farzana Yasmeen
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea; (F.Y.); (B.C.)
- S&K Therapeutics, Ajou University Campus Plaza 418, Worldcup-ro 199, Yeongtong-gu, Suwon 16502, Republic of Korea
| | - Rameez Hassan Pirzada
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea; (F.Y.); (B.C.)
- S&K Therapeutics, Ajou University Campus Plaza 418, Worldcup-ro 199, Yeongtong-gu, Suwon 16502, Republic of Korea
| | - Bilal Ahmad
- S&K Therapeutics, Ajou University Campus Plaza 418, Worldcup-ro 199, Yeongtong-gu, Suwon 16502, Republic of Korea
| | - Bogeum Choi
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea; (F.Y.); (B.C.)
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea; (F.Y.); (B.C.)
- S&K Therapeutics, Ajou University Campus Plaza 418, Worldcup-ro 199, Yeongtong-gu, Suwon 16502, Republic of Korea
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Ganesan R, Gupta H, Jeong JJ, Sharma SP, Won SM, Oh KK, Yoon SJ, Han SH, Yang YJ, Baik GH, Bang CS, Kim DJ, Suk KT. Characteristics of microbiome-derived metabolomics according to the progression of alcoholic liver disease. Hepatol Int 2024; 18:486-499. [PMID: 37000389 DOI: 10.1007/s12072-023-10518-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 03/07/2023] [Indexed: 04/01/2023]
Abstract
BACKGROUND AND AIM The prevalence and severity of alcoholic liver disease (ALD) are increasing. The incidence of alcohol-related cirrhosis has risen up to 2.5%. This study aimed to identify novel metabolite mechanisms involved in the development of ALD in patients. The use of gut microbiome-derived metabolites is increasing in targeted therapies. Identifying metabolic compounds is challenging due to the complex patterns that have long-term effects on ALD. We investigated the specific metabolite signatures in ALD patients. METHODS This study included 247 patients (heathy control, HC: n = 62, alcoholic fatty liver, AFL; n = 25, alcoholic hepatitis, AH; n = 80, and alcoholic cirrhosis, AC, n = 80) identified, and stool samples were collected. 16S rRNA sequencing and metabolomics were performed with MiSeq sequencer and liquid chromatography coupled to time-of-flight-mass spectrometry (LC-TOF-MS), respectively. The untargeted metabolites in AFL, AH, and AC samples were evaluated by multivariate statistical analysis and metabolic pathotypic expression. Metabolic network classifiers were used to predict the pathway expression of the AFL, AH, and AC stages. RESULTS The relative abundance of Proteobacteria was increased and the abundance of Bacteroides was decreased in ALD samples (p = 0.001) compared with that in HC samples. Fusobacteria levels were higher in AH samples (p = 0.0001) than in HC samples. Untargeted metabolomics was applied to quantitatively screen 103 metabolites from each stool sample. Indole-3-propionic acid levels are significantly lower in AH and AC (vs. HC, p = 0.001). Indole-3-lactic acid (ILA: p = 0.04) levels were increased in AC samples. AC group showed an increase in indole-3-lactic acid (vs. HC, p = 0.040) level. Compared with that in HC samples, the levels of short-chain fatty acids (SCFAs: acetic acid, butyric acid, propionic acid, iso-butyric acid, and iso-valeric acid) and bile acids (lithocholic acids) were significantly decreased in AC. The pathways of linoleic acid metabolism, indole compounds, histidine metabolism, fatty acid degradation, and glutamate metabolism were closely associated with ALD metabolism. CONCLUSIONS This study identified that microbial metabolic dysbiosis is associated with ALD-related metabolic dysfunction. The SCFAs, bile acids, and indole compounds were depleted during ALD progression. CLINICAL TRIAL Clinicaltrials.gov, number NCT04339725.
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Affiliation(s)
- Raja Ganesan
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, 24253, Republic of Korea
| | - Haripriya Gupta
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, 24253, Republic of Korea
| | - Jin-Ju Jeong
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, 24253, Republic of Korea
| | - Satya Priya Sharma
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, 24253, Republic of Korea
| | - Sung-Min Won
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, 24253, Republic of Korea
| | - Ki-Kwang Oh
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, 24253, Republic of Korea
| | - Sang Jun Yoon
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, 24253, Republic of Korea
| | - Sang Hak Han
- Department of Pathology, Hallym University College of Medicine, Chuncheon, Republic of Korea
| | - Young Joo Yang
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, 24253, Republic of Korea
| | - Gwang Ho Baik
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, 24253, Republic of Korea
| | - Chang Seok Bang
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, 24253, Republic of Korea
| | - Dong Joon Kim
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, 24253, Republic of Korea
| | - Ki Tae Suk
- Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon, 24253, Republic of Korea.
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Osna NA, Tikhanovich I, Ortega-Ribera M, Mueller S, Zheng C, Mueller J, Li S, Sakane S, Weber RCG, Kim HY, Lee W, Ganguly S, Kimura Y, Liu X, Dhar D, Diggle K, Brenner DA, Kisseleva T, Attal N, McKillop IH, Chokshi S, Mahato R, Rasineni K, Szabo G, Kharbanda KK. Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression. Biomolecules 2024; 14:404. [PMID: 38672422 PMCID: PMC11048648 DOI: 10.3390/biom14040404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 03/20/2024] [Accepted: 03/24/2024] [Indexed: 04/28/2024] Open
Abstract
Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide and represents a spectrum of liver injury beginning with hepatic steatosis (fatty liver) progressing to inflammation and culminating in cirrhosis. Multiple factors contribute to ALD progression and disease severity. Here, we overview several crucial mechanisms related to ALD end-stage outcome development, such as epigenetic changes, cell death, hemolysis, hepatic stellate cells activation, and hepatic fatty acid binding protein 4. Additionally, in this review, we also present two clinically relevant models using human precision-cut liver slices and hepatic organoids to examine ALD pathogenesis and progression.
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Affiliation(s)
- Natalia A. Osna
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68106, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68106, USA
| | - Irina Tikhanovich
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA;
| | - Martí Ortega-Ribera
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (M.O.-R.); (G.S.)
| | - Sebastian Mueller
- Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany; (S.M.); (C.Z.); (J.M.); (S.L.)
- Viscera AG Bauchmedizin, 83011 Bern, Switzerland
| | - Chaowen Zheng
- Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany; (S.M.); (C.Z.); (J.M.); (S.L.)
| | - Johannes Mueller
- Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany; (S.M.); (C.Z.); (J.M.); (S.L.)
| | - Siyuan Li
- Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany; (S.M.); (C.Z.); (J.M.); (S.L.)
| | - Sadatsugu Sakane
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Raquel Carvalho Gontijo Weber
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Hyun Young Kim
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Wonseok Lee
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Souradipta Ganguly
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Yusuke Kimura
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Xiao Liu
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Debanjan Dhar
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
| | - Karin Diggle
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - David A. Brenner
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Neha Attal
- Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC 28203, USA; (N.A.); (I.H.M.)
| | - Iain H. McKillop
- Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC 28203, USA; (N.A.); (I.H.M.)
| | - Shilpa Chokshi
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE59NT, UK;
- School of Microbial Sciences, King’s College, London SE59NT, UK
| | - Ram Mahato
- Department of Pharmaceutical Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68106, USA;
| | - Karuna Rasineni
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68106, USA;
| | - Gyongyi Szabo
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (M.O.-R.); (G.S.)
| | - Kusum K. Kharbanda
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68106, USA
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68106, USA;
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
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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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Siggins RW, McTernan PM, Simon L, Souza-Smith FM, Molina PE. Mitochondrial Dysfunction: At the Nexus between Alcohol-Associated Immunometabolic Dysregulation and Tissue Injury. Int J Mol Sci 2023; 24:8650. [PMID: 37239997 PMCID: PMC10218577 DOI: 10.3390/ijms24108650] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 05/05/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Alcohol misuse, directly or indirectly as a result of its metabolism, negatively impacts most tissues, including four with critical roles in energy metabolism regulation: the liver, pancreas, adipose, and skeletal muscle. Mitochondria have long been studied for their biosynthetic roles, such as ATP synthesis and initiation of apoptosis. However, current research has provided evidence that mitochondria participate in myriad cellular processes, including immune activation, nutrient sensing in pancreatic β-cells, and skeletal muscle stem and progenitor cell differentiation. The literature indicates that alcohol impairs mitochondrial respiratory capacity, promoting reactive oxygen species (ROS) generation and disrupting mitochondrial dynamics, leading to dysfunctional mitochondria accumulation. As discussed in this review, mitochondrial dyshomeostasis emerges at a nexus between alcohol-disrupted cellular energy metabolism and tissue injury. Here, we highlight this link and focus on alcohol-mediated disruption of immunometabolism, which refers to two distinct, yet interrelated processes. Extrinsic immunometabolism involves processes whereby immune cells and their products influence cellular and/or tissue metabolism. Intrinsic immunometabolism describes immune cell fuel utilization and bioenergetics that affect intracellular processes. Alcohol-induced mitochondrial dysregulation negatively impacts immunometabolism in immune cells, contributing to tissue injury. This review will present the current state of literature, describing alcohol-mediated metabolic and immunometabolic dysregulation from a mitochondrial perspective.
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Affiliation(s)
- Robert W. Siggins
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; (R.W.S.); (P.M.M.); (L.S.); (F.M.S.-S.)
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Patrick M. McTernan
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; (R.W.S.); (P.M.M.); (L.S.); (F.M.S.-S.)
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Liz Simon
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; (R.W.S.); (P.M.M.); (L.S.); (F.M.S.-S.)
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Flavia M. Souza-Smith
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; (R.W.S.); (P.M.M.); (L.S.); (F.M.S.-S.)
| | - Patricia E. Molina
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; (R.W.S.); (P.M.M.); (L.S.); (F.M.S.-S.)
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
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Potential Therapeutic Implication of Herbal Medicine in Mitochondria-Mediated Oxidative Stress-Related Liver Diseases. Antioxidants (Basel) 2022; 11:antiox11102041. [PMID: 36290765 PMCID: PMC9598588 DOI: 10.3390/antiox11102041] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/10/2022] [Accepted: 10/10/2022] [Indexed: 11/22/2022] Open
Abstract
Mitochondria are double-membrane organelles that play a role in ATP synthesis, calcium homeostasis, oxidation-reduction status, apoptosis, and inflammation. Several human disorders have been linked to mitochondrial dysfunction. It has been found that traditional therapeutic herbs are effective on alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) which are leading causes of liver cirrhosis and hepatocellular carcinoma. The generation of reactive oxygen species (ROS) in response to oxidative stress is caused by mitochondrial dysfunction and is considered critical for treatment. The role of oxidative stress, lipid toxicity, and inflammation in NAFLD are well known. NAFLD is a chronic liver disease that commonly progresses to cirrhosis and chronic liver disease, and people with obesity, insulin resistance, diabetes, hyperlipidemia, and hypertension are at a higher risk of developing NAFLD. NAFLD is associated with a number of pathological factors, including insulin resistance, lipid metabolic dysfunction, oxidative stress, inflammation, apoptosis, and fibrosis. As a result, the improvement in steatosis and inflammation is enough to entice researchers to look into liver disease treatment. However, antioxidant treatment has not been very effective for liver disease. Additionally, it has been suggested that the beneficial effects of herbal medicines on immunity and inflammation are governed by various mechanisms for lipid metabolism and inflammation control. This review provided a summary of research on herbal medicines for the therapeutic implementation of mitochondria-mediated ROS production in liver disease as well as clinical applications through herbal medicine. In addition, the pathophysiology of common liver disorders such as ALD and NAFLD would be investigated in the role that mitochondria play in the process to open new therapeutic avenues in the management of patients with liver disease.
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Kronsten VT, Argemi J, Kurt AS, Mannakat Vijay G, Ryan JM, Bataller R, Shawcross DL. Plasma angiopoietin 2 as a novel prognostic biomarker in alcohol-related cirrhosis and hepatitis. LIVER RESEARCH 2022; 6:21-29. [PMID: 39959809 PMCID: PMC11791857 DOI: 10.1016/j.livres.2022.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/27/2021] [Accepted: 01/29/2022] [Indexed: 11/22/2022]
Abstract
Background and aim Severe alcoholic hepatitis (SAH), the most florid form of alcohol-related liver disease (ALD), has a mortality rate of 16% at 28 days. The angiopoietin-Tie 2 system regulates angiogenesis and inflammation, both of which are implicated in the pathogenesis of ALD. This study examined plasma and hepatic gene expression of angiopoietin 1 (ANG1) and angiopoietin 2 (ANG2) in patients with SAH and ALD and investigated their roles as prognostic biomarkers. Methods A case-control study was performed measuring plasma levels of ANG1 and ANG2 by enzyme-linked immunosorbent assay (ELISA) from 30 patients with SAH (Maddrey's discriminant function ≥32), 32 patients with ALD cirrhosis and 15 healthy controls (HC). RNA sequencing for ANG1, ANG2, TIE1 (codes for Tie1 receptor) and TEK (codes for Tie2 receptor) gene expression from a separate cohort study of 79 patients was also performed. Results Plasma levels of ANG1 were lower (P = 0.010) and ANG2 were higher (P < 0.0001) in patients with ALD/SAH compared to HC. The ANG2: ANG1 ratio was higher in those with ALD/SAH compared to HC (P < 0.0001). ANG2 levels were the highest in patients who developed sepsis (P = 0.030) and those dying within 90 days (P = 0.020). ANG2 levels correlated positively with model for end-stage liver disease (MELD) score (r = 0.30, P = 0.020), Child-Pugh score (r = 0.38, P = 0.003), international normalized ratio (r = 0.41, P = 0.001) and white blood cell count (r = 0.28, P = 0.040) and inversely correlated with albumin (r = -0.26, P = 0.040).ANG1 gene expression from liver biopsies was higher in SAH than that in HC (P < 0.0001), and greater in severe disease (P < 0.0001). ANG2 gene expression trended towards being lower in SAH than that in HC (P = 0.070) though was upregulated in severe disease (P = 0.0003). Conclusions Plasma ANG2 is raised in SAH and ALD and could be useful as a prognostic biomarker in this patient population.
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Affiliation(s)
- Victoria Tatiana Kronsten
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, UK
| | - Josepmaria Argemi
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Liver Unit. University of Navarra Clinic, Hepatology Program. Center for Applied Medical Research (CIMA), Navarra Research Institute, Pamplona, Spain
| | - Ada Sera Kurt
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, UK
| | - Godhev Mannakat Vijay
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, UK
| | - Jennifer Marie Ryan
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, UK
- Department of Hepatology, Royal Free Hospital, London, UK
| | - Ramón Bataller
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Debbie Lindsay Shawcross
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, UK
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9
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Jiang J, Tan Y, Liu A, Yan R, Ma Y, Guo L, Sun J, Guo Z, Fan H. Tissue engineered artificial liver model based on viscoelastic hyaluronan-collagen hydrogel and the effect of EGCG intervention on ALD. Colloids Surf B Biointerfaces 2021; 206:111980. [PMID: 34293578 DOI: 10.1016/j.colsurfb.2021.111980] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/29/2021] [Accepted: 07/14/2021] [Indexed: 02/07/2023]
Abstract
In alcoholic liver disease (ALD) research, animal models, as one of the most popular methods to explore pathology and therapeutic drug screening, show the limitations of expensive cost and ethic, as well as long modeling time. To minimize the use of animal models in ALD research, an artificial liver model has been developed by incorporating HepG2 cells into hydrogel matrix based on difunctional hyaluronan and collagen. And on this basis an alcohol-induced ALD model in vitro by adding alcohol in the engineering process has been established. Results showed that the construct exhibited a simulated synthetic and metabolic liver function thanks to the bionic fibrillar and viscoelastic characteristics of hydrogels. And the in vitro alcohol-induced ALD model was also proved to be successfully established, even presenting equal results with ALD mice. Furthermore, epigallocatechin gallate (EGCG) as an intervention on ALD was confirmed in both in vitro and in vivo model. The findings indicate our simple artificial liver model is not only highly predictive but also easy to apply to drug screening and implantation studies, suggesting a promising alternative to animal models. Moreover, as the main active ingredient of tea, EGCG's effective intervention and reversal effect on fatty liver provides support for the theory that green tea could prevent alcoholic fatty liver.
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Affiliation(s)
- Ji Jiang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Yanfei Tan
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Amin Liu
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Rentai Yan
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Yanzhe Ma
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Likun Guo
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Jing Sun
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, Sichuan, China.
| | - Zhenzhen Guo
- Department of Gastroenterology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China; Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China.
| | - Hongsong Fan
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, Sichuan, China
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10
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Ambade A, Lowe P, Kodys K, Catalano D, Gyongyosi B, Cho Y, Vellve AI, Adejumo A, Saha B, Calenda C, Mehta J, Lefebvre E, Vig P, Szabo G. Pharmacological Inhibition of CCR2/5 Signaling Prevents and Reverses Alcohol-Induced Liver Damage, Steatosis, and Inflammation in Mice. Hepatology 2019; 69:1105-1121. [PMID: 30179264 PMCID: PMC6393202 DOI: 10.1002/hep.30249] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 08/17/2018] [Indexed: 12/17/2022]
Abstract
Kupffer cell and macrophage (MØ) activation contributes to steatosis, inflammation, and fibrosis in alcoholic liver disease (ALD). We found increased frequency of MØ, T cells, and expression of C-C chemokine receptor type 2 (Ccr2) and C-C chemokine receptor type 5 (Ccr5) in the livers of patients with ALD, and increased circulating chemokines, C-C chemokine ligand types 2 (CCL2), and C-C chemokine ligand types 5 (CCL5) in patients with alcoholic hepatitis. We hypothesized that inhibition of CCL2 signaling with the dual CCR2/5 inhibitor, cenicriviroc (CVC), would attenuate ALD. In a mouse model of ALD, liver injury (alanine aminotransferase [ALT]) and steatosis were prevented by CVC whether administered as "prevention" throughout the alcohol feeding or as "treatment" started after the development of ALD. Alcohol-induced increases in early liver fibrosis markers (sirius red, hydroxyproline, and collagen-1) were normalized by both modes of CVC administration. We found that prevention and treatment with CVC reversed alcohol-related increases in liver mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and CCL2. CVC administration regimens prevented the increase in infiltrating MØ (F4/80lo CD11bhi ) and reduced proinflammatory Ly6Chi MØ in livers of alcohol-fed mice. CVC increased liver T-cell numbers and attenuated Il-2 expression without an effect on CD69+ or CD25+ T-cell expression. In vitro, CVC inhibited CCL2-induced increases in hepatocyte fatty acid synthase (Fasn) and adipose differentiation-related protein (Adrp), whereas it augmented acyl-coenzyme A oxidase 1 (Acox-1), proliferator-activated receptor gamma co-activator alpha (Pgc1α) and uncoupling protein 2 expression, suggesting mechanisms for attenuated hepatocyte steatosis. We found that CCL2 and CCL5 sensitized hepatocytes to lipopolysaccharide-induced liver injury (TNF-α, ALT, and lactate dehydrogenase release). Alcohol feeding induced apoptosis (poly ADP-ribose polymerase [PARP] and caspase-3 [CASP-3] cleavage) and pyroptosis (gasdermin D [GSDMD] cleavage) in livers, and CVC prevented both of these forms of cell death. Conclusion: Together, our data demonstrate preclinical evidence for CCR2/CCR5 inhibition with CVC as a potent intervention to ameliorate alcohol-induced steatohepatitis and liver damage.
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Affiliation(s)
- Aditya Ambade
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Patrick Lowe
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Karen Kodys
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Donna Catalano
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Benedek Gyongyosi
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Yeonhee Cho
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Arvin-Iracheta Vellve
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Adeyinka Adejumo
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Banishree Saha
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Charles Calenda
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Jeeval Mehta
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | | | - Pamela Vig
- Allergan plc, South San Francisco, CA, 94080, USA
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.,Contact Information: Gyongyi Szabo, MD, PhD, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA, 01605, USA., Tel: 1-508-856-5276, Fax: 1-528-856-5033,
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11
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García-Ruiz C, Fernández-Checa JC. Mitochondrial Oxidative Stress and Antioxidants Balance in Fatty Liver Disease. Hepatol Commun 2018; 2:1425-1439. [PMID: 30556032 PMCID: PMC6287487 DOI: 10.1002/hep4.1271] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 10/09/2018] [Indexed: 12/19/2022] Open
Abstract
Fatty liver disease is one of the most prevalent forms of chronic liver disease that encompasses both alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are intermediate stages of ALD and NAFLD, which can progress to more advanced forms, including cirrhosis and hepatocellular carcinoma. Oxidative stress and particularly alterations in mitochondrial function are thought to play a significant role in both ASH and NASH and recognized to contribute to the generation of reactive oxygen species (ROS), as documented in experimental models. Despite the evidence of ROS generation, the therapeutic efficacy of treatment with antioxidants in patients with fatty liver disease has yielded poor results. Although oxidative stress is considered to be the disequilibrium between ROS and antioxidants, there is evidence that a subtle balance among antioxidants, particularly in mitochondria, is necessary to avoid the generation of ROS and hence oxidative stress. Conclusion: As mitochondria are a major source of ROS, the present review summarizes the role of mitochondrial oxidative stress in ASH and NASH and presents emerging data indicating the need to preserve mitochondrial antioxidant balance as a potential approach for the treatment of human fatty liver disease, which may pave the way for the design of future trials to test the therapeutic role of antioxidants in fatty liver disease.
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Affiliation(s)
- Carmen García-Ruiz
- Cell Death and Proliferation Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior Investigaciones Científicas Barcelona Spain.,Liver Unit, Hospital Cínic, IDIBAPS and CIBEREHD Barcelona Spain
| | - José C Fernández-Checa
- Cell Death and Proliferation Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior Investigaciones Científicas Barcelona Spain.,Liver Unit, Hospital Cínic, IDIBAPS and CIBEREHD Barcelona Spain.,University of Southern California Research Center for ALPD Keck School of Medicine Los Angeles CA
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12
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Shen C, Ma W, Ding L, Li S, Dou X, Song Z. The TLR4-IRE1α pathway activation contributes to palmitate-elicited lipotoxicity in hepatocytes. J Cell Mol Med 2018; 22:3572-3581. [PMID: 29673059 PMCID: PMC6010797 DOI: 10.1111/jcmm.13636] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 03/10/2018] [Indexed: 02/06/2023] Open
Abstract
Lipotoxicity induced by saturated fatty acids (SFAs) plays a pathological role in the development of non‐alcoholic fatty liver disease (NAFLD); however, the exact mechanism(s) remain to be clearly elucidated. Toll‐like receptor (TLR) 4 plays a fundamental role in activating the innate immune system. Intriguingly, hepatocytes express TLR4 and machinery for TLR4 signalling pathway. That liver‐specific TLR4 knockout mice are protective against diet‐induced NAFLD suggests that hepatocyte TLR4 signalling pathway plays an important role in NAFLD pathogenesis. Herein, using cultured hepatocytes, we sought to directly examine the role of TLR4 signalling pathway in palmitate‐elicited hepatotoxicity and to elucidate underlying mechanism(s). Our data reveal that palmitate exposure up‐regulates TLR4 expression at both mRNA and protein levels in hepatocytes, which are associated with NF‐κB activation. The inhibition of TLR4 signalling pathway through both pharmacological and genetic approaches abolished palmitate‐induced cell death, suggesting that TLR4 signalling pathway activation contributes to palmitate‐induced hepatotoxicity. Mechanistic investigations demonstrate that inositol‐requiring enzyme 1α (IRE1α), one of three major signal transduction pathways activated during endoplasmic reticulum (ER) stress, is the downstream target of palmitate‐elicited TLR4 activation and mechanistically implicated in TLR4 activation‐triggered cell death in response to palmitate exposure. Collectively, our data identify that the TLR4‐IRE1α pathway activation contributes to palmitate‐elicited lipotoxicity in hepatocytes. Our findings suggest that targeting TLR4‐IRE1α pathway can be a potential therapeutic choice for the treatment of NAFLD as well as other metabolic disorders, with lipotoxicity being the principal pathomechanism.
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Affiliation(s)
- Chen Shen
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA
| | - Wang Ma
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Lei Ding
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Songtao Li
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, China
| | - Xiaobing Dou
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhenyuan Song
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA.,College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Pathology, University of Illinois, Medical Center, Chicago, IL, USA
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13
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Does Hypoxia Cause Carcinogenic Iron Accumulation in Alcoholic Liver Disease (ALD)? Cancers (Basel) 2017; 9:cancers9110145. [PMID: 29068390 PMCID: PMC5704163 DOI: 10.3390/cancers9110145] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Revised: 10/19/2017] [Accepted: 10/20/2017] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) is a leading health risk worldwide. Hepatic iron overload is frequently observed in ALD patients and it is an important and independent factor for disease progression, survival, and the development of primary liver cancer (HCC). At a systemic level, iron homeostasis is controlled by the liver-secreted hormone hepcidin. Hepcidin regulation is complex and still not completely understood. It is modulated by many pathophysiological conditions associated with ALD, such as inflammation, anemia, oxidative stress/H2O2, or hypoxia. Namely, the data on hypoxia-signaling of hepcidin are conflicting, which seems to be mainly due to interpretational limitations of in vivo data and methodological challenges. Hence, it is often overlooked that hepcidin-secreting hepatocytes are physiologically exposed to 2–7% oxygen, and that key oxygen species such as H2O2 act as signaling messengers in such a hypoxic environment. Indeed, with the recently introduced glucose oxidase/catalase (GOX/CAT) system it has been possible to independently study hypoxia and H2O2 signaling. First preliminary data indicate that hypoxia enhances H2O2-mediated induction of hepcidin, pointing towards oxidases such as NADPH oxidase 4 (NOX4). We here review and discuss novel concepts of hypoxia signaling that could help to better understand hepcidin-associated iron overload in ALD.
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14
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Kawaratani H, Moriya K, Namisaki T, Uejima M, Kitade M, Takeda K, Okura Y, Kaji K, Takaya H, Nishimura N, Sato S, Sawada Y, Seki K, Kubo T, Mitoro A, Yamao J, Yoshiji H. Therapeutic strategies for alcoholic liver disease: Focusing on inflammation and fibrosis (Review). Int J Mol Med 2017; 40:263-270. [PMID: 28627645 DOI: 10.3892/ijmm.2017.3015] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 03/30/2017] [Indexed: 11/06/2022] Open
Abstract
Excessive alcohol consumption is the most common cause of liver disease in the world. Chronic alcohol abuse leads to liver damage, liver inflammation, fibrosis and hepatocellular carcinoma. Inflammatory cytokines, such as tumor necrosis factor-α and interferon-γ, induce liver injury, which leads to the develo-pment of alcoholic liver disease (ALD). Hepatoprotective cytokines, such as interleukin (IL)-6 and IL-10, are also associated with ALD. IL-6 improves ALD via the activation of STAT3 and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. Alcohol consumption promotes liver inflammation by incre-asing the translocation of gut-derived endotoxins to the portal circulation and by activating Kupffer cells through the lipopolysaccharide/Toll-like receptor 4 pathways. Oxidative stress and microflora products are also associated with ALD. Hepatic stellate cells play an important role in angiogenesis and liver fibrosis. Anti-angiogenic therapy has been found to be effective in the prevention of fibrosis. This suggests that blocking angiogenesis could be a promising therapeutic option for patients with advanced fibrosis. This review discusses the main pathways associated with liver inflammation and liver fibrosis as well as new therapeutic strategies.
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Affiliation(s)
- Hideto Kawaratani
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kei Moriya
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Tadashi Namisaki
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Masakazu Uejima
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Mitsuteru Kitade
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kousuke Takeda
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Yasushi Okura
- Department of Endoscopy and Ultrasound, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kousuke Kaji
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hiroaki Takaya
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Norihisa Nishimura
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Shinya Sato
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Yasuhiko Sawada
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kenichiro Seki
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Takuya Kubo
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Akira Mitoro
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Junichi Yamao
- Department of Endoscopy and Ultrasound, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hitoshi Yoshiji
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
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15
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Abstract
The three common themes that underlie the induction and perpetuation of autoimmunity are genetic predisposition, environmental factors, and immune regulation. Environmental factors have gained much attention for their role in triggering autoimmunity, with increasing evidence of their influence as demonstrated by epidemiological studies, laboratory research, and animal studies. Environmental factors known to trigger and perpetuate autoimmunity include infections, gut microbiota, as well as physical and environmental agents. To address these issues, we will review major potential mechanisms that underlie autoimmunity including molecular mimicry, epitope spreading, bystander activation, polyclonal activation of B and T cells, infections, and autoinflammatory activation of innate immunity. The association of the gut microbiota on autoimmunity will be particularly highlighted by their interaction with pharmaceutical agents that may lead to organ-specific autoimmunity. Nonetheless, and we will emphasize this point, the precise mechanism of environmental influence on disease pathogenesis remains elusive.
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Affiliation(s)
- Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy.
| | - Patrick S C Leung
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis, CA, USA
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16
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Zhang Y, Wang C, Tian Y, Zhang F, Xu W, Li X, Shu Z, Wang Y, Huang K, Huang D. Inhibition of Poly(ADP-Ribose) Polymerase-1 Protects Chronic Alcoholic Liver Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 186:3117-3130. [PMID: 27746183 DOI: 10.1016/j.ajpath.2016.08.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 08/02/2016] [Accepted: 08/22/2016] [Indexed: 02/08/2023]
Abstract
Activation of Kupffer cells (KCs) by gut-derived endotoxin plays a pivotal role in the pathogenesis of alcoholic liver diseases (ALD). Limiting the activation of resident KCs attenuates chronic ethanol-induced liver steatosis and injury. Poly (ADP-ribose) polymerase (PARP)-1 is suggested to play a role in a number of chronic inflammatory diseases. In this study, we found a significant increase of hepatic PARP activity in mice with short-term and long-term ethanol-induced ALD. Male mice on a long-term ethanol diet exhibited severe hepatic steatosis and apoptosis and enhanced KC activation and neutrophil infiltration. However, pharmacologic inhibition of PARP activity or genetic depletion of PARP1 significantly attenuated these detrimental effects in vivo. We found that inhibition of PARP1 effectively reduced hepatic expression of genes involved in lipogenesis and elevated hepatic expression of genes involved in lipolysis. Moreover, limited KC activation and neutrophil infiltration were observed in PARP1 knockout mice or PARP inhibitor-treated mice. Furthermore, in vitro experiments found that LPS-induced macrophage activation was limited by PARP inhibitor, and exposure of ethanol-treated hepatocytes to this conditioned medium further decreased the number of apoptotic and steatotic cells. Taken together, these findings suggest that PARP1 inhibition protects against long-term ethanol-induced liver injury, as indicated by limited hepatocytes steatosis, apoptosis, inflammation levels, and neutrophil infiltration, mainly by limiting KC activation during the initiation of ALD.
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Affiliation(s)
- Yanqing Zhang
- Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cheng Wang
- Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yunli Tian
- Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fengxiao Zhang
- Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjing Xu
- Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangrao Li
- Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiping Shu
- Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Wang
- Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Huang
- Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dan Huang
- Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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17
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Renon M, Legrand B, Blanc E, Daubigney F, Bokobza C, Mortreux M, Paul JL, Delabar JM, Rouach H, Andreau K, Janel N. Impact of Dyrk1A level on alcohol metabolism. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1862:1495-503. [PMID: 27216978 DOI: 10.1016/j.bbadis.2016.05.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 05/09/2016] [Accepted: 05/18/2016] [Indexed: 12/15/2022]
Abstract
Alcoholic liver diseases arise from complex phenotypes involving many genetic factors. It is quite common to find hyperhomocysteinemia in chronic alcoholic liver diseases, mainly due to deregulation of hepatic homocysteine metabolism. Dyrk1A, involved in homocysteine metabolism at different crossroads, is decreased in liver of hyperhomocysteinemic mice. Here, we hypothesized that Dyrk1A contributes to alcohol-induced hepatic impairment in mice. Control, hyperhomocysteinemic and mice overexpressing Dyrk1A were fed using a Lieber-DeCarli liquid diet with or without ethanol (5% v/v ethanol) for one month, and liver histological examination and liver biochemical function tests were performed. Plasma alanine aminotransferase and homocysteine levels were significantly decreased in mice overexpressing Dyrk1A compared to control mice with or without alcohol administration. On the contrary, the mean plasma alanine aminotransferase and homocysteine levels were significantly higher in hyperhomocysteinemic mice than that of control mice after alcohol administration. Paraoxonase 1 and CYP2E1, two phase I xenobiotic metabolizing enzymes, were found increased in the three groups of mice after alcohol administration. However, NQO1, a phase II enzyme, was only found increased in hyperhomocysteinemic mice after alcohol exposure, suggesting a greater effect of alcohol in liver of hyperhomocysteinemic mice. We observed positive correlations between hepatic alcohol dehydrogenase activity, Dyrk1A and ADH4 protein levels. Importantly, a deleterious effect of alcohol consumption on hepatic Dyrk1A protein level was found. Our study reveals on the one hand a role of Dyrk1A in ethanol metabolism and on the other hand a deleterious effect of alcohol administration on hepatic Dyrk1A level.
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Affiliation(s)
- Marjorie Renon
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR 8251 CNRS, F-75205 Paris, France
| | - Béatrice Legrand
- Univ René Descartes, Sorbonne Paris Cité, Unité de Pharmacologie, Toxicologie et Signalisation Cellulaire, INSERM UMR-S 1124, Paris, France
| | - Etienne Blanc
- Univ René Descartes, Sorbonne Paris Cité, Unité de Pharmacologie, Toxicologie et Signalisation Cellulaire, INSERM UMR-S 1124, Paris, France
| | - Fabrice Daubigney
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR 8251 CNRS, F-75205 Paris, France
| | - Cindy Bokobza
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR 8251 CNRS, F-75205 Paris, France
| | - Marie Mortreux
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR 8251 CNRS, F-75205 Paris, France
| | - Jean-Louis Paul
- AP-HP, Hôpital Européen Georges Pompidou, Service de Biochimie, 75015 Paris, France
| | - Jean-Maurice Delabar
- Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France
| | - Hélène Rouach
- Univ René Descartes, Sorbonne Paris Cité, Unité de Pharmacologie, Toxicologie et Signalisation Cellulaire, INSERM UMR-S 1124, Paris, France
| | - Karine Andreau
- Univ René Descartes, Sorbonne Paris Cité, Unité de Pharmacologie, Toxicologie et Signalisation Cellulaire, INSERM UMR-S 1124, Paris, France
| | - Nathalie Janel
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR 8251 CNRS, F-75205 Paris, France.
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Rosa-Toledo O, Almeida-Chuffa LG, Martinez M, Felipe-Pinheiro PF, Padovani CR, Martinez FE. Maternal separation on the ethanol-preferring adult rat liver structure. Ann Hepatol 2016; 14:910-8. [PMID: 26436364 DOI: 10.5604/16652681.1171783] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
UNLABELLED Background and rationale for the study. We designed to test whether there is interaction of maternal separation (MS) on the ethanol-preferring rats liver structure. The UCh rat pups were separated daily from their mothers during the stress hyporesponsive period (SHRP), between four and 14 days-old, always at the same time for four hours in a cage containing eight subdivisions, one for each pup. Subsequently, rats that presented the highest (UChB) and the lowest (UChA) ethanol (EtOH) consumption were selected to the study. Both UChB and UChA rats received 10% (v/v) EtOH and distilled water ad libitum until the end of the experiment (120 days-old). The liver was collected to histological routine for morphometric and stereological analyses, and immunohistochemistry. RESULTS There was an interaction of MS and EtOH on the liver: increased liver mass, peritubular vessels, stellate cell numbers, steatosis and cell death, decreased necrosis, sinusoidal capillary diameters and cell proliferation. While there was a decrease in FSH, testosterone and 5α-di-hidrotestosterone, and increasing corticosterone and cholesterol. CONCLUSIONS There is interaction of MS and EtOH on the liver structure, dependent on the amount of EtOH intake. Furthermore, the interaction of stress and drugs can increase or decrease their effects on the liver or indirectly via hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes.
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Affiliation(s)
| | | | - Marcelo Martinez
- Department of Morphology and Pathology, UFSCar-Federal University of São Carlos, São Carlos, SP, Brazil
| | | | - Carlos R Padovani
- Department of Biostatistic, Biosciences Institute, UNESP-Univ. Estadual Paulista, Botucatu, SP, Brazil
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Murugan S, Boyadjieva N, Sarkar DK. Protective effects of hypothalamic beta-endorphin neurons against alcohol-induced liver injuries and liver cancers in rat animal models. Alcohol Clin Exp Res 2015; 38:2988-97. [PMID: 25581653 DOI: 10.1111/acer.12580] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 09/16/2014] [Indexed: 01/14/2023]
Abstract
BACKGROUND Recently, retrograde tracing has provided evidence for an influence of hypothalamic β-endorphin (BEP) neurons on the liver, but functions of these neurons are not known. We evaluated the effect of BEP neuronal activation on alcohol-induced liver injury and hepatocellular cancer. METHODS Male rats received either BEP neuron transplants or control transplants in the hypothalamus and were randomly assigned to feeding alcohol-containing liquid diet or control liquid diet for 8 weeks or to treatment of a carcinogen diethylnitrosamine (DEN). Liver tissues of these animals were analyzed histochemically and biochemically for tissue injuries or cancer. RESULTS Alcohol feeding increased liver weight and induced several histopathological changes such as prominent microvesicular steatosis and hepatic fibrosis. Alcohol feeding also increased the levels of triglyceride, hepatic stellate cell (HSC) activation factors, and catecholamines in the liver and endotoxin levels in the plasma. However, these effects of alcohol on the liver were reduced in animals with BEP neuron transplants. BEP neuron transplants also suppressed carcinogen-induced liver histopathologies such as extensive fibrosis, large focus of inflammatory infiltration, hepatocellular carcinoma (HCC), collagen deposition, numbers of preneoplastic foci, levels of HSC activation factors and catecholamines, as well as inflammatory milieu and increased the levels of natural killer cell cytotoxic factors in the liver. CONCLUSIONS These findings are the first evidence for a role of hypothalamic BEP neurons in influencing liver functions. Additionally, the data identify that BEP neuron transplantation prevents hepatocellular injury and HCC formation possibly via influencing the immune function.
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Affiliation(s)
- Sengottuvelan Murugan
- Endocrine Program, Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
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20
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Støy S, Dige A, Sandahl TD, Laursen TL, Buus C, Hokland M, Vilstrup H. Cytotoxic T lymphocytes and natural killer cells display impaired cytotoxic functions and reduced activation in patients with alcoholic hepatitis. Am J Physiol Gastrointest Liver Physiol 2015; 308:G269-76. [PMID: 25501547 DOI: 10.1152/ajpgi.00200.2014] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The dynamics and role of cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and NKT cells in the life-threatening inflammatory disease alcoholic hepatitis is largely unknown. These cells directly kill infected and damaged cells through, e.g., degranulation and interferon-γ (IFNγ) production, but cause tissue damage if overactivated. They also assist tissue repair via IL-22 production. We, therefore, aimed to investigate the frequency, functionality, and activation state of such cells in alcoholic hepatitis. We analyzed blood samples from 24 severe alcoholic hepatitis patients followed for 30 days after diagnosis. Ten healthy abstinent volunteers and 10 stable abstinent alcoholic cirrhosis patients were controls. Using flow cytometry we assessed cell frequencies, NK cell degranulation capacity following K562 cell stimulation, activation by natural killer group 2 D (NKG2D) expression, and IL-22 and IFNγ production. In alcoholic hepatitis we found a decreased frequency of CTLs compared with healthy controls (P < 0.001) and a similar trend for NK cells (P = 0.089). The NK cell degranulation capacity was reduced by 25% compared with healthy controls (P = 0.02) and by 50% compared with cirrhosis patients (P = 0.04). Accordingly, the NKG2D receptor expression was markedly decreased on NK cells, CTLs, and NKT cells (P < 0.05, all). The frequencies of IL-22-producing CTLs and NK cells were doubled compared with healthy controls (P < 0.05, all) but not different from cirrhosis patients. This exploratory study for the first time showed impaired cellular cytotoxicity and activation in alcoholic hepatitis. This is unlikely to cause hepatocyte death but may contribute toward the severe immune incompetence. The results warrant detailed and mechanistic studies.
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Affiliation(s)
- Sidsel Støy
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; and
| | - Anders Dige
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; and
| | - Thomas Damgaard Sandahl
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; and
| | - Tea Lund Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; and
| | - Christian Buus
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | | | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; and
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Wang Z, Su B, Fan S, Fei H, Zhao W. Protective effect of oligomeric proanthocyanidins against alcohol-induced liver steatosis and injury in mice. Biochem Biophys Res Commun 2015; 458:757-62. [PMID: 25680468 DOI: 10.1016/j.bbrc.2015.01.153] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 01/28/2015] [Indexed: 12/29/2022]
Abstract
The long-term consumption of alcohol has been associated with multiple pathologies at all levels, such as alcoholism, chronic pancreatitis, malnutrition, alcoholic liver disease (ALD) and cancer. In the current study, we investigated the protective effect of oligomeric proanthocyanidins (OPC) against alcohol-induced liver steatosis and injury and the possible mechanisms using ethanol-induced chronic liver damage mouse models. The results showed that OPC significantly improved alcohol-induced dyslipidemia and alleviated liver steatosis by reducing levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total triglyceride (TG), total cholesterol (TC), low-density cholesterol (LDL-c) and liver malondialdehyde (MDA), and increasing levels of serum high-density lipoprotein (HDL-c), liver superoxide dismutase (SOD). Further investigation indicated that OPC markedly decreased the expressions of lipid synthesis genes and inflammation genes such as sterol regulatory element-binding protein-1c (Srebp-1c), protein-2 (Srebp2), interleukin IL-1β, IL-6 and TNF-α. Furthermore, AML-12 cells line was used to investigate the possible mechanisms which indicated that OPC might alleviate liver steatosis and damage through AMP-activated protein kinase (AMPK) activation involving oxidative stress. In conclusion, our study demonstrated excellent protective effect of OPC against alcohol-induced liver steatosis and injury, which could a potential drug for the treatment of alcohol-induced liver injury in the future.
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Affiliation(s)
- Zhiguo Wang
- Hospital of Integrated Chinese and Western Medicine in Jiangsu Province, Jiangsu, China
| | - Bo Su
- Huai'an Maternity and Child Health-Care Hospital, Huai'an, China
| | - Sumei Fan
- Huai'an Second People's Hospital, Huai'an, China
| | - Haixia Fei
- Jiangsu Province Official Hospital, Jiangsu, China.
| | - Wei Zhao
- Nanjing Maternity and Child Health-Care Hospital, Nanjing, China.
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Kasztelan-Szczerbinska B, Surdacka A, Slomka M, Rolinski J, Celinski K, Cichoz-Lach H, Madro A, Szczerbinski M. Angiogenesis-related biomarkers in patients with alcoholic liver disease: their association with liver disease complications and outcome. Mediators Inflamm 2014; 2014:673032. [PMID: 24959006 PMCID: PMC4052180 DOI: 10.1155/2014/673032] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 05/06/2014] [Indexed: 12/17/2022] Open
Abstract
Angiogenesis is believed to be implicated in the pathogenesis of alcoholic liver disease (ALD). We aimed to explore the usefulness and accuracy of plasma angiogenic biomarkers for noninvasive evaluation of the severity of liver failure and ALD outcome. One hundred and forty-seven patients with ALD were prospectively enrolled and assessed based on their (1) gender, (2) age, (3) severity of liver dysfunction according to the Child-Turcotte-Pugh and MELD scores, and (4) the presence of ALD complications. Plasma levels of vascular endothelial growth factor (VEGF-A) and angiopoietins 1 and 2 (Ang1 and Ang2) were investigated using ELISAs. Multivariable logistic regression was applied in order to select independent predictors of advanced liver dysfunction and the disease complications. Significantly higher concentrations of Ang2 and VEGF-A in ALD patients as compared to controls were found. There was no difference in Ang1 levels in both groups. A positive correlation of Ang2 levels with INR (Rho 0.66; P < 0.0001) and its inverse correlation with plasma albumin levels (Rho -0.62; P < 0.0001) were found. High Ang2 concentrations turned out to be an independent predictor of severe liver dysfunction, as well as hepatic encephalopathy and renal impairment. Ang2 possessed the highest diagnostic and prognostic potential among three studied angiogenesis-related molecules.
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Affiliation(s)
- Beata Kasztelan-Szczerbinska
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
| | - Agata Surdacka
- Department of Clinical Immunology, Medical University of Lublin, 4A Chodzki Street, 20-093 Lublin, Poland
| | - Maria Slomka
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
| | - Jacek Rolinski
- Department of Clinical Immunology, Medical University of Lublin, 4A Chodzki Street, 20-093 Lublin, Poland
| | - Krzysztof Celinski
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
| | - Halina Cichoz-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
| | - Agnieszka Madro
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
| | - Mariusz Szczerbinski
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
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Kir6.2 knockout aggravates lipopolysaccharide-induced mouse liver injury via enhancing NLRP3 inflammasome activation. J Gastroenterol 2014; 49:727-36. [PMID: 23771404 DOI: 10.1007/s00535-013-0823-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2013] [Accepted: 04/18/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND ATP-sensitive potassium (K-ATP) channels couple cellular metabolism to electric activity. Although Kir6.2-composed K-ATP channel (Kir6.2/K-ATP channel) has been demonstrated to regulate inflammation, a common cause of most liver diseases, its role in liver injury remains elusive. METHODS Kir6.2 knockout mice were used to prepared LPS-induced liver injury model so as to investigate the role of Kir6.2/K-ATP channels in the injury. Histochemistry was applied to evaluate the extent of liver injury. Proinflammatory cytokines were analyzed by ELISA. Endoplasmic reticulum (ER) stress and autophagy were assessed by western blotting. RESULTS We showed that Kir6.2 knockout markedly promoted the infiltration of lymphocytes and neutrophils in liver and significantly elevated serum levels of alanine transaminase (ALT) in respond to LPS treatment. We further found that Kir6.2 deficiency enhanced the activation of NF-κB and NLRP3 inflammasome following LPS challenge, and thereby increased the levels of pro-inflammatory cytokines IL-1β, IL-18 and TNF-α. Treatment of wild-type mice with the K-ATP channel opener iptakalim (IPT) could protect against LPS-induced liver injury through attenuating NLRP3 inflammasome-mediated inflammatory responses. Furthermore, Kir6.2 knockout-induced activation of NLRP3 inflammasome aggravated endoplasmic reticulum (ER) stress, autophagy and subsequent hepatocyte death. CONCLUSION Kir6.2 deficiency exacerbated LPS-induced liver injury by enhancing NLRP3 inflammasome-mediated inflammatory response. Thus, Kir6.2/K-ATP channel may be a potential candidate target for the treatment and prevention of liver injury.
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The Protective Effect of a Metallic Selenopeptide with Superoxide Dismutase and Glutathione Peroxidase Activities Against Alcohol Induced Injury in Hepatic L02 Cells. Int J Pept Res Ther 2014. [DOI: 10.1007/s10989-014-9396-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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McDaniel K, Herrera L, Zhou T, Francis H, Han Y, Levine P, Lin E, Glaser S, Alpini G, Meng F. The functional role of microRNAs in alcoholic liver injury. J Cell Mol Med 2014; 18:197-207. [PMID: 24400890 PMCID: PMC3930407 DOI: 10.1111/jcmm.12223] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Accepted: 11/28/2013] [Indexed: 12/16/2022] Open
Abstract
The function of microRNAs (miRNAs) during alcoholic liver disease (ALD) has recently become of great interest in biological research. Studies have shown that ALD associated miRNAs play a crucial role in the regulation of liver-inflammatory agents such as tumour necrosis factor-alpha (TNF-α), one of the key inflammatory agents responsible for liver fibrosis (liver scarring) and the critical contributor of alcoholic liver disease. Lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, is responsible for TNF-α release by Kupffer cells. miRNAs are the critical mediators of LPS signalling in Kupffer cells, hepatocytes and hepatic stellate cells. Certain miRNAs, in particular miR-155 and miR-21, show a positive correlation in up-regulation of LPS signalling when they are exposed to ethanol. ALD is related to enhanced gut permeability that allows the levels of LPS to increase, leads to increased secretion of TNF-α by the Kupffer cells and subsequently promotes alcoholic liver injury through specific miRNAs. Meanwhile, two of the most frequently dysregulated miRNAs in steatohepatitis, miR-122 and miR-34a are the critical mediators in ethanol/LPS activated survival signalling during ALD. In this review, we summarize recent findings regarding the experimental and clinical aspects of functions of specific microRNAs, focusing mainly on inflammation and cell survival after ethanol/LPS treatment, and advances on the role of circulating miRNAs in human alcoholic disorders.
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Affiliation(s)
- Kelly McDaniel
- Research, Central Texas Veterans Health Care System, Temple, TX, USA; Department of Medicine, Scott & White Digestive Disease Research Center, Texas A&M University Health Science Center and Scott & White Healthcare, Temple, TX, USA; Academic Operations, Scott & White Hospital, Temple, TX, USA
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Kupffer Cells in Health and Disease. MACROPHAGES: BIOLOGY AND ROLE IN THE PATHOLOGY OF DISEASES 2014. [PMCID: PMC7121975 DOI: 10.1007/978-1-4939-1311-4_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Kupffer cells (KC), the resident macrophages of the liver, represent the largest population of mononuclear phagocytes in the body. Phenotypic, developmental, and functional aspects of these cells in steady state and in different diseases are the focus of this review. Recently it has become evident that KC precursors seed the liver already early in fetal development, and the population can be maintained independently from circulating monocytes. However, inflammatory conditions allow rapid differentiation of monocytes into mature cells that are indistinguishable from genuine KC. KC are located in the lumen of sinusoids that receive blood both from the portal vein, carrying nutrients and microbial products from the gut, and from the hepatic artery. This positions KC ideally for their prime function, namely surveillance and clearance of the circulation. As such, they are important in iron recycling by phagocytosing effete erythrocytes, for instance. The immunophenotype of KC, characterized by a wide variety of endocytic receptors, is indicative of this scavenger function. In maintaining homeostasis, KC have an ambivalent response to exogenous triggers. On the one hand, their surveillance function requires alert responses to potentially hazardous substances. On the other hand, continuous exposure of the cells to the trigger-rich content of blood originating from the gut dampens their responsiveness to further stimuli. This ambivalence is also reflected in their diverse roles in disease pathogenesis. For the latter, we sketch the contribution of KC by giving examples of their role in metabolic disease, infections, and liver injury.
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27
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Liangpunsakul S, Ross RA, Crabb DW. Activation of carbohydrate response element-binding protein by ethanol. J Investig Med 2013; 61:270-7. [PMID: 23266705 DOI: 10.2310/jim.0b013e31827c2795] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Carbohydrate response element-binding protein (ChREBP) is a transcription factor involved in hepatic lipogenesis. Its function is in part under the control of AMP-activated protein kinase (AMPK) and protein phosphatase 2A (PP2A). Given known effects of ethanol on AMPK and PP2A, it is plausible that ethanol might enhance fatty acid synthesis by increasing the activity of ChREBP. We hypothesized that another potential pathway of ethanol-induced hepatic steatosis is mediated by activation of ChREBP. METHODS The effects of ethanol on ChREBP were assessed in hepatoma cells and in C57BL/6J mice fed with the Lieber-DeCarli diet. RESULTS When the cells were exposed to ethanol (50 mM) for 24 hours, the activity of a liver pyruvate kinase (LPK) promoter-luciferase reporter was increased by ∼4-fold. Ethanol feeding of mice resulted in the translocation of ChREBP from cytosol to the nucleus. Protein phosphatase 2A activity was increased in the liver of ethanol-fed mice by 22%. We found no difference in the levels of hepatic Xu-5-P between ethanol-fed mice and controls. Transfection of a constitutively active AMPK expression plasmid suppressed the basal activity of the LPK luciferase reporter and abolished the effect of ethanol on the reporter activity. However, transfection of rat hepatoma cells with a dominant-negative AMPK expression plasmid induced basal LPK luciferase activity by only ∼20%. The effect of ethanol on ChREBP was attenuated in the presence of okadaic acid, an inhibitor of PP2A. CONCLUSIONS The effects of ethanol on AMPK and PP2A may result in activation of ChREBP, providing another potential mechanism for ethanol-induced hepatic steatosis. However, additional okadaic acid-insensitive effects appear to be important as well.
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Affiliation(s)
- Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
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Ippolito JA, Curtis BJ, Choudhry MA, Kovacs EJ. Alcohol and immunology: Summary of the 2012 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 2013; 47:589-93. [PMID: 24169087 DOI: 10.1016/j.alcohol.2013.09.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Accepted: 09/19/2013] [Indexed: 02/08/2023]
Abstract
On October 27, 2012, the 17th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held at the Grand Wailea Hotel in Maui, Hawaii as a satellite meeting to the 2012 Society of Leukocyte Biology conference. This year's meeting focused on the influence of alcohol on signal transduction pathways in various disease and injury models. Three plenary sessions were held where invited speakers shared their research on alcohol-mediated alterations of cell signaling components, immune cell subsets, and inflammation. These studies suggested alcohol has a negative effect on cell signaling machinery and immune cell homeostasis, resulting in disease, disease progression, and increased mortality. Researchers also identified tissue-specific alcohol-linked elevations in markers of inflammation, including cold-shock proteins and microRNAs. Additionally, one study revealed the effects of alcohol on immune cell subsets in a model of allergic asthma.
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Ge N, Liang H, Liu Y, Ma AG, Han L. Protective effect of Aplysin on hepatic injury in ethanol-treated rats. Food Chem Toxicol 2013; 62:361-72. [DOI: 10.1016/j.fct.2013.08.071] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2013] [Revised: 08/16/2013] [Accepted: 08/25/2013] [Indexed: 01/01/2023]
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Brandon-Warner E, Schrum LW, Schmidt CM, McKillop IH. Rodent models of alcoholic liver disease: of mice and men. Alcohol 2012; 46:715-25. [PMID: 22960051 DOI: 10.1016/j.alcohol.2012.08.004] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Revised: 07/18/2012] [Accepted: 08/14/2012] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) is a major cause of acute and chronic liver disease worldwide. The progressive nature of ALD is well described; however, the complex interactions under which these pathologies evolve remain to be fully elucidated. Clinically there are no clear biomarkers or universally accepted, effective treatment strategies for ALD. Experimental models of ALD are an important component in identifying underlying mechanisms of alcohol-induced injury to develop better diagnostic markers, predictors of disease progression, and therapeutic targets to manage, halt, or reverse disease progression. Rodents remain the most accessible model for studying ALD pathology. Effective rodent models must mimic the natural history of ALD while allowing examination of complex interactions between multiple hepatic, and non-hepatic, cell types in the setting of altered metabolic or oxidative/nitrosative stress, inflammatory responses, and sensitivity to cytotoxic stress. Additionally, mode and duration of alcohol delivery influence hepatic response and present unique challenges in understanding disease pathology. This review provides an overview of rodent models of ALD, their strengths and weaknesses relative to human disease states, and provides insight of the potential to develop novel rodent models to simulate the course of human ALD.
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Abstract
INTRODUCTION Surgical site infections (SSI) are a source of significant postoperative morbidity and cost. Although immediate breast reconstruction after mastectomy has become routine, the data regarding the incidence of SSI in immediate breast reconstruction is highly variable and series dependent. METHODS Using the National Surgical Quality Improvement Program database, all female patients undergoing mastectomy, with or without immediate reconstruction, from 2005 to 2009 were identified. Only "clean" procedures were included. The primary outcome was incidence of SSI within 30 days of operation. Stepwise logistic regression analysis was used to identify risk factors associated with SSI. RESULTS A total of 48,393 mastectomies were performed during the study period, of which 9315 (19.2%) had immediate breast reconstruction. The incidence of SSI was 3.5% (330/9315) (95% CI [confidence interval]: 3.2%-4%) in patients undergoing mastectomy with reconstruction and 2.5% (966/39,078) (95% CI: 2.3%-2.6%) in patients undergoing mastectomy without reconstruction (P < 0.001). Independent risk factors for SSI include increased preoperative body mass index (BMI), heavy alcohol use, ASA (American Society of Anesthesiologists) score greater than 2, flap failure, and operative time of 6 hours or longer. CONCLUSIONS Immediate breast reconstruction is associated with a statistically significant increase in risk of SSI in patients undergoing mastectomy (3.5% vs 2.5%). However, this difference was not considered to be clinically significant. In this large series, increased BMI, alcohol use, ASA class greater than 2, flap failure, and prolonged operative time were associated with increased risk of SSI.
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Levin I, Petrasek J, Szabo G. The presence of p47phox in liver parenchymal cells is a key mediator in the pathogenesis of alcoholic liver steatosis. Alcohol Clin Exp Res 2012; 36:1397-406. [PMID: 22376231 PMCID: PMC4120658 DOI: 10.1111/j.1530-0277.2012.01739.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2011] [Accepted: 11/30/2011] [Indexed: 01/01/2023]
Abstract
BACKGROUND Reactive oxygen species contribute to steatosis and inflammation in alcoholic liver disease (ALD). Here, we evaluated the selective contribution of p47phox, a critical subunit of nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase complex, in liver parenchymal cells and in bone marrow (BM)-derived cells. METHODS Female C57Bl/6 wild type [WT], total body p47phox-deficient knockout [KO] or p47phox chimera mice generated by BM transplantation of p47phox-KO-BM into irradiated WT mice (WT/p47phox-KO-BM mice) received 5% Lieber-DeCarli alcohol or control (pair feeding) diet for 4 weeks. RESULTS Alcohol-induced liver steatosis as measured by Oil Red O staining and serum triglyceride up-regulation were prevented in p47phox-KO mice but not in WT/p47phox-KO-BM chimeras compared to WT controls. Serum alanine aminotransferase (ALT) was significantly increased in alcohol-fed WT mice but not in p47phox-KO mice compared to pair-fed controls. There was no protection from alcohol-induced increase in ALT and liver damage in the WT/p47phox-KO-BM mice. Alcohol-induced liver steatosis was accompanied by up-regulation of the lipid droplet-stabilizing protein, adipocyte differentiation-related protein (ADRP), and the fatty acid synthesis-associated genes, fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACACA). Total body deficiency in p47phox but not selective absence of p47phox in BM-derived cells prevented alcohol-induced up-regulation of ADRP, FASN, and ACACA in the liver. Finally, alcohol-induced activation and DNA binding of nuclear factor κB (NF-κB), a master regulator of inflammation, were significantly increased after alcohol feeding in WT but not in p47phox-KO mice. Selective deficiency of p47phox in BM-derived cells (WT/p47phox-KO-BM chimera) failed to prevent NF-κB induction after alcohol feeding. CONCLUSIONS Total body deficiency in p47phox subunit of NADPH oxidase complex protects mice from alcohol-induced liver steatosis via mechanisms involving ADRP, FASN, and ACACA as well as from alcohol-induced NF-κB activation. In contrast, selective absence of p47phox in BM-derived cells fails to provide protection via these mechanisms. These results suggest that p47phox in parenchymal cells plays a critical role in the pathogenesis of ALD.
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Affiliation(s)
- Ivan Levin
- Department of Medicine, University of Massachusetts Medical School, Worcester, 01605, USA
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Nath B, Szabo G. Hypoxia and hypoxia inducible factors: diverse roles in liver diseases. HEPATOLOGY (BALTIMORE, MD.) 2012. [PMID: 22120903 DOI: 10.1002/hep.25497]] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The hypoxia inducible factors (HIFs) are a family of evolutionarily conserved transcriptional regulators that affect a homeostatic response to low oxygen tension and have been identified as key mediators of angiogenesis, inflammation, and metabolism. In this review we summarize the evidence for a role of HIFs across a range of hepatic pathophysiology. We describe regulation of the HIFs and review investigations that demonstrate a role for HIFs in the development of liver fibrosis, activation of innate immune pathways, hepatocellular carcinoma, as well as other liver diseases in both human disease as well as murine models.
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Affiliation(s)
- Bharath Nath
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Abstract
The liver is necessary for survival. Its strategic localisation, blood flow and prominent role in the metabolism of xenobiotics render this organ particularly susceptible to injury by chemicals to which we are ubiquitously exposed. The pathogenesis of most chemical-induced liver injuries is initiated by the metabolic conversion of chemicals into reactive intermediate species, such as electrophilic compounds or free radicals, which can potentially alter the structure and function of cellular macromolecules. Many reactive intermediate species can produce oxidative stress, which can be equally detrimental to the cell. When protective defences are overwhelmed by excess toxicant insult, the effects of reactive intermediate species lead to deregulation of cell signalling pathways and dysfunction of biomolecules, leading to failure of target organelles and eventual cell death. A myriad of genetic factors determine the susceptibility of specific individuals to chemical-induced liver injury. Environmental factors, lifestyle choices and pre-existing pathological conditions also have roles in the pathogenesis of chemical liver injury. Research aimed at elucidating the molecular mechanism of the pathogenesis of chemical-induced liver diseases is fundamental for preventing or devising new modalities of treatment for liver injury by chemicals.
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Affiliation(s)
- Xinsheng Gu
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA
| | - Jose E. Manautou
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA
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Abstract
Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The hypoxia inducible factors (HIFs) are a family of evolutionarily conserved transcriptional regulators that affect a homeostatic response to low oxygen tension and have been identified as key mediators of angiogenesis, inflammation, and metabolism. In this review we summarize the evidence for a role of HIFs across a range of hepatic pathophysiology. We describe regulation of the HIFs and review investigations that demonstrate a role for HIFs in the development of liver fibrosis, activation of innate immune pathways, hepatocellular carcinoma, as well as other liver diseases in both human disease as well as murine models.
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Affiliation(s)
- Bharath Nath
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Effect of sweet grass extract against oxidative stress in rat liver and serum. Food Chem Toxicol 2012; 50:135-40. [DOI: 10.1016/j.fct.2011.09.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2011] [Revised: 09/14/2011] [Accepted: 09/14/2011] [Indexed: 11/17/2022]
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Ganz M, Csak T, Nath B, Szabo G. Lipopolysaccharide induces and activates the Nalp3 inflammasome in the liver. World J Gastroenterol 2011; 17:4772-8. [PMID: 22147977 PMCID: PMC3229625 DOI: 10.3748/wjg.v17.i43.4772] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2010] [Revised: 05/26/2011] [Accepted: 05/30/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the activation of the Nalp3 inflammasome and its downstream targets following lipopolysaccharide (LPS)-induced stimulation in the liver.
METHODS: Six-to-eight-week-old C57BL/6 chow fed mice were injected intraperitoneally with 0.5 μg/g bodyweight LPS and sacrificed 2, 4, 6, 18 or 24 h later. LPS-induced liver damage was confirmed by a biochemical assay to detect alanine aminotransferase (ALT) levels. To determine if LPS stimulation in the liver led to activation of the inflammasome, real-time quantitative polymerase chain reaction was used to evaluate the mRNA expression of components of the Nalp3 inflammasome. Enzyme-linked immunosorbent assays were used to determine the protein expression levels of several downstream targets of the Nalp3 inflammasome, including caspase-1 and two cytokine targets of caspase-1, interleukin (IL)-1β and IL-18.
RESULTS: We found that LPS injection resulted in liver damage as indicated by elevated ALT levels. This was associated with a significant increase in both mRNA and protein levels of the proinflammatory cytokine tumor necrosis factor (TNF)-α in the liver, as well as increased levels of TNFs in serum. We showed that LPS stimulation led to upregulation of mRNA levels in the liver for all the receptor components of the inflammasome, including Nalp3, Nalp1, pannexin-1 and the adaptor molecule apoptosis-associated speck-like, caspase recruitment domain-domain containing protein. We also found increased levels of mRNA and protein for caspase-1, a downstream target of the inflammasome. In addition, LPS challenge led to increased levels of both mRNA and protein in the liver for two cytokine targets of caspase-1, IL-1β and IL-18. Interestingly, substantial baseline expression of pre-IL-1β and pre-IL-18 was found in the liver. Inflammasome and caspase-1 activation was indicated by the significant increase in the active forms of IL-1β and IL-18 after LPS stimulation.
CONCLUSION: Our results show that the Nalp3 inflammasome is upregulated and activated in the liver in response to LPS stimulation.
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Li G, Ye Y, Kang J, Yao X, Zhang Y, Jiang W, Gao M, Dai Y, Xin Y, Wang Q, Yin Z, Luo L. l-Theanine prevents alcoholic liver injury through enhancing the antioxidant capability of hepatocytes. Food Chem Toxicol 2011; 50:363-72. [PMID: 22019691 DOI: 10.1016/j.fct.2011.10.036] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2011] [Revised: 10/03/2011] [Accepted: 10/05/2011] [Indexed: 12/17/2022]
Abstract
l-Theanine is a unique amino acid in green tea. We here evaluated the protective effects of l-theanine on ethanol-induced liver injury in vitro and in vivo. Our results revealed that l-theanine significantly protected hepatocytes against ethanol-induced cell cytotoxicity which displayed by decrease of viability and increase of LDH and AST. Furthermore, the experiments of DAPI staining, pro-caspase3 level and PARP cleavage determination indicated that l-theanine inhibited ethanol-induced L02 cell apoptosis. Mechanically, l-theanine inhibited loss of mitochondrial membrane potential and prevented cytochrome c release from mitochondria in ethanol-treated L02 cells. l-Theanine also prevented ethanol-triggered ROS and MDA generation in L02 cells. l-Theanine restored the antioxidant capability of hepatocytes including GSH content and SOD activity which were reduced by ethanol. In vivo experiments showed that l-theanine significantly inhibited ethanol-stimulated the increase of ALT, AST, TG and MDA in mice. Histopathological examination demonstrated that l-theanine pretreated to mice apparently diminished ethanol-induced fat droplets. In accordance with the in vitro study, l-theanine significantly inhibited ethanol-induced reduction of mouse antioxidant capability which included the activities of SOD, CAT and GR, and level of GSH. These results indicated that l-theanine prevented ethanol-induced liver injury through enhancing hepatocyte antioxidant abilities.
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Affiliation(s)
- Guilan Li
- Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210046, People's Republic of China
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Seth D, Haber PS, Syn WK, Diehl AM, Day CP. Pathogenesis of alcohol-induced liver disease: classical concepts and recent advances. J Gastroenterol Hepatol 2011; 26:1089-105. [PMID: 21545524 DOI: 10.1111/j.1440-1746.2011.06756.x] [Citation(s) in RCA: 112] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) is a primary consequence of heavy and prolonged drinking. ALD contributes to the bulk of liver disease burden worldwide. Progression of ALD is a multifactorial and multistep process that includes many genetic and environmental risk factors. The molecular pathogenesis of ALD involves alcohol metabolism and secondary mechanisms such as oxidative stress, endotoxin, cytokines and immune regulators. The histopathological manifestation of ALD occurs as an outcome of complex but controlled interactions between hepatic cell types. Hepatic stellate cells (HSCs) are the key drivers of fibrogenesis, but transformation of hepatocytes to myofibroblastoids also implicate parenchymal cells as playing an active role in hepatic fibrogenesis. Recent discoveries indicate that lipogenesis during the early stages of ALD is a risk for advancement to cirrhosis. Other recently identified novel molecules and physiological/cell signaling pathways include fibrinolysis, osteopontin, transforming growth factor-β-SMAD and hedgehog signaling, and involvement of novel cytokines in hepatic fibrogenesis. The observation that ALD and non-alcoholic steatohepatitis share common pathways and genetic polymorphisms suggests operation of parallel pathogenic mechanisms. Future research involving genomics, epigenomics, deep sequencing and non-coding regulatory elements holds promise to identify novel diagnostic and therapeutic targets for ALD. There is also a need for adequate animal models to study pathogenic mechanisms at the molecular level and targeted therapy.
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Affiliation(s)
- Devanshi Seth
- Drug Health Services, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
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Nath B, Levin I, Csak T, Petrasek J, Mueller C, Kodys K, Catalano D, Mandrekar P, Szabo G. Hepatocyte-specific hypoxia-inducible factor-1α is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice. Hepatology 2011; 53:1526-37. [PMID: 21520168 PMCID: PMC3104403 DOI: 10.1002/hep.24256] [Citation(s) in RCA: 164] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
UNLABELLED Chronic alcohol causes hepatic steatosis and liver hypoxia. Hypoxia-regulated hypoxia-inducible factor 1-α, (HIF-1α) may regulate liporegulatory genes, but the relationship of HIF-1 to steatosis remains unknown. We investigated HIF-1α in alcohol-induced hepatic lipid accumulation. Alcohol administration resulted in steatosis, increased liver triglyceride levels, and increased serum alanine aminotransferase (ALT) levels, suggesting liver injury in wild-type (WT) mice. There was increased hepatic HIF-1α messenger RNA (mRNA), protein, and DNA-binding activity in alcohol-fed mice compared with controls. Mice engineered with hepatocyte-specific HIF-1 activation (HIF1dPA) had increased HIF-1α mRNA, protein, and DNA-binding activity, and alcohol feeding in HIF1dPA mice increased hepatomegaly and hepatic triglyceride compared with WT mice. In contrast, hepatocyte-specific deletion of HIF-1α [HIF-1α(Hep(-/-) )], protected mice from alcohol- and lipopolysaccharide (LPS)-induced liver damage, serum ALT elevation, hepatomegaly, and lipid accumulation. HIF-1α(Hep(-/-) ), WT, and HIF1dPA mice had equally suppressed levels of peroxisome proliferator-activated receptor α mRNA after chronic ethanol, whereas the HIF target, adipocyte differentiation-related protein, was up-regulated in WT mice but not HIF-1α(Hep(-/-) ) ethanol-fed/LPS-challenged mice. The chemokine monocyte chemoattractant protein-1 (MCP-1) was cooperatively induced by alcohol feeding and LPS in WT but not HIF-1α(Hep(-/-) ) mice. Using Huh7 hepatoma cells in vitro, we found that MCP-1 treatment induced lipid accumulation and increased HIF-1α protein expression as well as DNA-binding activity. Small interfering RNA inhibition of HIF-1α prevented MCP-1-induced lipid accumulation, suggesting a mechanistic role for HIF-1α in hepatocyte lipid accumulation. CONCLUSION Alcohol feeding results in lipid accumulation in hepatocytes involving HIF-1α activation. The alcohol-induced chemokine MCP-1 triggers lipid accumulation in hepatocytes via HIF-1α activation, suggesting a mechanistic link between inflammation and hepatic steatosis in alcoholic liver disease.
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Affiliation(s)
- Bharath Nath
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605 USA
| | - Ivan Levin
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605 USA
| | - Timea Csak
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605 USA
| | - Jan Petrasek
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605 USA
| | - Christian Mueller
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605 USA
| | - Karen Kodys
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605 USA
| | - Donna Catalano
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605 USA
| | - Pranoti Mandrekar
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605 USA
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605 USA
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Gao B, Seki E, Brenner DA, Friedman S, Cohen JI, Nagy L, Szabo G, Zakhari S. Innate immunity in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 2011; 300:G516-25. [PMID: 21252049 PMCID: PMC3774265 DOI: 10.1152/ajpgi.00537.2010] [Citation(s) in RCA: 181] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2010] [Accepted: 01/12/2011] [Indexed: 02/06/2023]
Abstract
Excessive alcohol consumption is a leading cause of chronic liver disease in the Western world. Alcohol-induced hepatotoxicity and oxidative stress are important mechanisms contributing to the pathogenesis of alcoholic liver disease. However, emerging evidence suggests that activation of innate immunity involving TLR4 and complement also plays an important role in initiating alcoholic steatohepatitis and fibrosis, but the role of adaptive immunity in the pathogenesis of alcoholic liver disease remains obscure. Activation of a TLR4-mediated MyD88-independent (TRIF/IRF-3) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis, whereas activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis. Alcohol consumption activates the complement system in the liver by yet unidentified mechanisms, leading to alcoholic steatohepatitis. In contrast to activation of TLR4 and complement, alcohol consumption can inhibit natural killer cells, another important innate immunity component, contributing to alcohol-mediated acceleration of viral infection and liver fibrosis in patients with chronic viral hepatitis. Understanding of the role of innate immunity in the pathogenesis of alcoholic liver disease may help us identify novel therapeutic targets to treat this disease.
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Affiliation(s)
- Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA.
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Continuous versus discontinuous drinking of an ethanol liquid diet in peripubertal rats: effect on 24-h variation of lymph node and splenic mitogenic responses and lymphocyte subset populations. Alcohol 2011; 45:183-92. [PMID: 20843641 DOI: 10.1016/j.alcohol.2010.08.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2009] [Revised: 08/08/2010] [Accepted: 08/09/2010] [Indexed: 11/22/2022]
Abstract
Excessive alcohol consumption continues to be a major public health problem, particularly in the adolescent and young adult populations. Generally, such a behavior tends to be confined to the weekends, to attain frequently binge drinking. This study in peripubertal male rats compares the effect of the discontinuous feeding of a liquid diet containing a moderate amount of ethanol (6.2% wt/vol) to that of continuous ethanol administration or a control diet, taking as end points the 24-h variations of plasma prolactin levels and mitogenic responses and lymphocyte subset populations in submaxillary lymph nodes and spleen. Animals received the ethanol liquid diet starting on day 35 of life, the diet being similar to that given to controls except for that maltose was isocalorically replaced by ethanol. Ethanol provided 36% of the total caloric content. Every week, the discontinuous ethanol group received the ethanol diet for 3 days and the control liquid diet for the remaining 4 days. After 4 weeks, rats were killed at six time intervals, beginning at 0900 h. A significant decrease of splenic cells' response to concanavalin A, and of lymph node and splenic cells' response to lipopolysaccharide was found in rats under the discontinuous ethanol regime, when compared with control- or ethanol-chronic rats. Under discontinuous ethanol feeding, mean values of lymph node and splenic CD8(+) and CD4(+)-CD8(+) cells decreased, whereas those of lymph node and splenic T cells, and splenic B cells, augmented. In rats chronically fed with ethanol, splenic mean levels of CD8(+) and CD4(+)-CD8(+) cells augmented. Both modalities of ethanol administration disrupted the 24 h variation in immune function seen in controls. Mean plasma prolactin levels increased by 3.6-fold and 8.5-fold in rats chronically or discontinuously fed with alcohol, respectively. The immune parameters examined in an additional group of rats fed regular chow and water ad libitum did not differ significantly from control liquid diet. The results support the view that the discontinuous drinking of a moderate amount of ethanol can be more harmful for the immune system than a continuous ethanol intake, presumably by inducing a greater stress as indicated by the augmented plasma prolactin levels observed.
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Sarc L, Wraber B, Lipnik-Stangelj M. Ethanol and acetaldehyde disturb TNF-alpha and IL-6 production in cultured astrocytes. Hum Exp Toxicol 2010; 30:1256-65. [PMID: 21056952 DOI: 10.1177/0960327110388533] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Ethanol disturbs astroglial growth and differentiation and causes functional alterations. Furthermore, many signalling molecules produced by astrocytes contribute to these processes. The aim of the present study was to investigate the influence of ethanol and its primary metabolite, acetaldehyde, on TNF-alpha and IL-6 production in a rat cortical astrocyte primary culture. We are the first to report that both ethanol and acetaldehyde can modulate TNF-alpha and IL-6 secretion from cultured astrocytes. Long-term exposure (7 days) to ethanol and acetaldehyde was more toxic than an acute (24 hours) exposure. However, both compounds showed a biphasic, hormestic effect on the IL-6 secretion after the acute as well as the long-term exposure, and the maximum stimulation was reached for 50-mM ethanol and 1-mM acetaldehyde after 7-day exposure. In contrast, both compounds reduced the TNF-alpha secretion, where the effect was concentration-dependent. The catalase inhibitor 2-amino-1,2,4 triazole significantly reduced the ethanol toxicity in the cultured astrocytes after the acute as well as the long-term exposure. In conclusion, both ethanol and acetaldehyde affect the production of IL-6 and TNF-alpha in cultured astrocytes. The effect depends on the concentration of the compounds and the duration of the exposure. Acetaldehyde is a more potent toxin than ethanol, and ethanol's toxicity in the brain is at least partially due to its primary metabolite, acetaldehyde.
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Affiliation(s)
- Lucija Sarc
- Poison Control Centre, University Medical Centre, Ljubljana, Slovenia
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Nath B, Li Y, Carroll JE, Szabo G, Tseng JF, Shah SA. Alcohol exposure as a risk factor for adverse outcomes in elective surgery. J Gastrointest Surg 2010; 14:1732-41. [PMID: 20839071 DOI: 10.1007/s11605-010-1350-4] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2010] [Accepted: 08/23/2010] [Indexed: 01/31/2023]
Abstract
BACKGROUND AND AIMS Alcohol consumption is a well-documented determinant of adverse perioperative outcome. We sought to determine the effect of active alcohol consumption following elective surgery. METHODS We queried discharge records from the American College of Surgeons' National Surgical Quality Improvement Program (NSQIP, 2005-2007) for all elective adult admissions. The 7,631 (2.5%) patients with documented alcohol use (active alcohol use of at least two drinks per day within 2 weeks of surgery; ETOH use) underwent elective surgery; 301,994 (97.5%) patients denied ETOH use. Multivariate analysis was performed with adjustments for demographic and comorbid factors. Primary outcome measures included length of stay (LOS), postoperative complications, and death. RESULTS ETOH use associated with elective surgery decreased over the course of the study (p < 0.0001). ETOH use was an independent predictor of pneumonia (OR 1.98, 95% CI 1.84-2.13), sepsis (OR 1.19, 95% CI 1.03-1.37), superficial surgical site infection (SSI; OR 1.15, 95% CI 1.02-1.31), wound disruption (OR 1.41, 95% CI 1.11-1.80), and prolonged LOS (OR 1.17, 95% CI 1.08-1.26). Except for SSI, these complications were independent risk factors for postoperative mortality. ETOH use was associated with earlier time to wound disruption (9 vs. 11 days; p = 0.04), longer median hospital stays (5 vs. 3 days; p < 0.0001), and longer LOS after operation (4 vs. 3 days; p < 0.0001). CONCLUSIONS Active alcohol consumption is a significant determinant of adverse outcomes in elective surgery; patients with ETOH use who are scheduled to undergo elective surgery should be appropriately educated and counseled.
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Affiliation(s)
- Bharath Nath
- Department of Surgery, Surgical Outcomes Analysis & Research, University of Massachusetts Medical School, 55 Lake Avenue North, S6-432, Worcester, MA 01655, USA
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Szabo G. The 40th anniversary of the National Institute on Alcoholism and Alcohol Abuse: the impact on liver disease. Hepatology 2010; 52:10-2. [PMID: 20578124 DOI: 10.1002/hep.23790] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
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Bardag-Gorce F, Oliva J, Lin A, Li J, French BA, French SW. SAMe prevents the up regulation of toll-like receptor signaling in Mallory-Denk body forming hepatocytes. Exp Mol Pathol 2010; 88:376-9. [PMID: 20206621 PMCID: PMC2901103 DOI: 10.1016/j.yexmp.2010.02.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2010] [Accepted: 02/18/2010] [Indexed: 01/22/2023]
Abstract
Mallory-Denk body (MDB) formation is a component of alcoholic and non alcoholic hepatitis. In the present study, the role of the toll-like receptor (TLR) signaling pathway was investigated in the mechanism of MDB formation in the DDC-fed mouse model. Microarray analysis data mining, performed on the livers of drug-primed mice refed DDC, showed that TLR2/4 gene expression was significantly up regulated by DDC refeeding. SAMe supplementation prevented this up regulation and prevented the formation of MDBs. qRT-PCR analysis confirmed these results. TLR2/4 activates the adapter protein MyD88. The levels of MyD88 were increased by DDC refeeding. The increase of MyD88 was also prevented by SAMe supplementation. Results showed that MyD88-independent TLR3/4-TRIF-IRF3 pathway was not up regulated in the liver of DDC refed mice. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is the downstream protein recruited by the MyD88/IRAK protein complex, and is involved in the regulation of innate immune responses. Results showed a significant increase in the levels of TRAF-6. TRAF-6 activation leads to activation of NFkB and the mitogen-activated protein kinase (MAPK) cascade. The TRAF-6 increase was ameliorated by SAMe supplementation. These results suggest that DDC induces MDB formation through the TLR2/4 and MyD88-dependent signaling pathway. In conclusion, SAMe blocked the over-expression of TLR2/4, and their downstream signaling components MyD88 and TRAF-6. SAMe prevented the DDC-induced up regulation of the TLR signaling pathways, probably by preventing the up regulation of INF-gamma receptors by DDC feeding. INFgamma stimulates the up regulation of TLR2. The ability of SAMe feeding to prevent TLR signaling up regulation has not been previously described.
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Seth D, D'Souza El-Guindy NB, Apte M, Mari M, Dooley S, Neuman M, Haber PS, Kundu GC, Darwanto A, de Villiers WJ, Vonlaufen A, Xu Z, Phillips P, Yang S, Goldstein D, Pirola RM, Wilson JS, Moles A, Fernández A, Colell A, García-Ruiz C, Fernández-Checa JC, Meyer C, Meindl-Beinker NM. Alcohol, signaling, and ECM turnover. Alcohol Clin Exp Res 2010; 34:4-18. [PMID: 19860812 DOI: 10.1111/j.1530-0277.2009.01060.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
Abstract
Alcohol is recognized as a direct hepatotoxin, but the precise molecular pathways that are important for the initiation and progression of alcohol-induced tissue injury are not completely understood. The current understanding of alcohol toxicity to organs suggests that alcohol initiates injury by generation of oxidative and nonoxidative ethanol metabolites and via translocation of gut-derived endotoxin. These processes lead to cellular injury and stimulation of the inflammatory responses mediated through a variety of molecules. With continuing alcohol abuse, the injury progresses through impairment of tissue regeneration and extracellular matrix (ECM) turnover, leading to fibrogenesis and cirrhosis. Several cell types are involved in this process, the predominant being stellate cells, macrophages, and parenchymal cells. In response to alcohol, growth factors and cytokines activate many signaling cascades that regulate fibrogenesis. This mini-review brings together research focusing on the underlying mechanisms of alcohol-mediated injury in a number of organs. It highlights the various processes and molecules that are likely involved in inflammation, immune modulation, susceptibility to infection, ECM turnover and fibrogenesis in the liver, pancreas, and lung triggered by alcohol abuse.
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Affiliation(s)
- Devanshi Seth
- Drug Health Services & Centenary Institute, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
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