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Baky NAA, Fouad LM, Ahmed KA, Alzokaky AA. Mechanistic insight into the hepatoprotective effect of Moringa oleifera Lam leaf extract and telmisartan against carbon tetrachloride-induced liver fibrosis: plausible roles of TGF-β1/SMAD3/SMAD7 and HDAC2/NF-κB/PPARγ pathways. Drug Chem Toxicol 2025; 48:84-97. [PMID: 38835191 DOI: 10.1080/01480545.2024.2358066] [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: 12/20/2023] [Accepted: 05/16/2024] [Indexed: 06/06/2024]
Abstract
The increasing prevalence and limited therapeutic options for liver fibrosis necessitates more medical attention. Our study aims to investigate the potential molecular targets by which Moringa oleifera Lam leaf extract (Mor) and/or telmisartan (Telm) alleviate carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Liver fibrosis was induced in male Sprague-Dawley rats by intraperitoneal injection of 50% CCl4 (1 ml/kg) every 72 hours, for 8 weeks. Intoxicated rats with CCl4 were simultaneously orally administrated Mor (400 mg/kg/day for 8 weeks) and/or Telm (10 mg/kg/day for 8 weeks). Treatment of CCl4-intoxicated rats with Mor/Telm significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities compared to CCl4 intoxicated group (P < 0.001). Additionally, Mor/Telm treatment significantly reduced the level of hepatic inflammatory, profibrotic, and apoptotic markers including; nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), transforming growth factor-βeta1 (TGF-β1), and caspase-3. Interestingly, co-treatment of CCl4-intoxicated rats with Mor/Telm downregulated m-RNA expression of histone deacetylase 2 (HDAC2) (71.8%), and reduced protein expression of mothers against decapentaplegic homolog 3 (p-SMAD3) (70.6%) compared to untreated animals. Mor/Telm regimen also elevated p-SMAD7 protein expression as well as m-RNA expression of peroxisome proliferator-activated receptor γ (PPARγ) (3.6 and 3.1 fold, respectively p < 0.05) compared to CCl4 intoxicated group. Histopathological picture of the liver tissue intoxicated with CCl4 revealed marked improvement by Mor/Telm co-treatment. Conclusively, this study substantiated the hepatoprotective effect of Mor/Telm regimen against CCl4-induced liver fibrosis through suppression of TGF-β1/SMAD3, and HDAC2/NF-κB signaling pathways and up-regulation of SMAD7 and PPARγ expression.
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Affiliation(s)
- Nayira A Abdel Baky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Lamiaa M Fouad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Kawkab A Ahmed
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt
| | - Amany A Alzokaky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University, New Damietta, Egypt
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You JB, Cao Y, You QY, Liu ZY, Wang XC, Ling H, Sha JM, Tao H. The landscape of histone modification in organ fibrosis. Eur J Pharmacol 2024; 977:176748. [PMID: 38897443 DOI: 10.1016/j.ejphar.2024.176748] [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: 04/12/2024] [Revised: 06/05/2024] [Accepted: 06/16/2024] [Indexed: 06/21/2024]
Abstract
An increase in fibrous connective tissue and a decrease in parenchymal cells in organ tissues are the primary pathological alterations linked to organ fibrosis. If fibrosis is not treated, organ structure is destroyed, function can decline, or even fail, posing a serious risk to human life and health. Numerous organs develop fibrosis, and organ fibroproliferative illnesses account for almost 45% of patient deaths from various diseases in the industrialized world, as well as a major cause of disability and mortality in many other diseases. Recently, it has become evident that histone modification is an important way to regulate gene expression in organ fibrosis. Histone modifications alter the structure of chromatin, thereby affecting gene accessibility. Histone acetylation modifications relax chromatin, making it easier for gene transcription factors to access DNA, thereby promoting gene transcription. In addition, histone modifications recruit other proteins to interact with chromatin to form complexes that further regulate gene expression. Histone methylation modifications recruit methylation-reading proteins that recognize methylation marks and alter gene expression status. It not only affects the normal physiological function of cells, but also plays an important role in organ fibrosis. This article reviews the important role played by histone modifications in organ fibrosis and potential therapeutic approaches.
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Affiliation(s)
- Jun-Bo You
- Department of Thoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, PR China
| | - Yi Cao
- Department of Pharmacy, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, PR China
| | - Qing-Ye You
- Anhui Women and Children's Medical Center, Hefei, 230001, PR China
| | - Zhi-Yan Liu
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, PR China
| | - Xian-Chen Wang
- Department of Thoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, PR China
| | - Hui Ling
- Department of Thoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, PR China
| | - Ji-Ming Sha
- Department of Thoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, PR China.
| | - Hui Tao
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, PR China.
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Samuvel DJ, Lemasters JJ, Chou CJ, Zhong Z. LP340, a novel histone deacetylase inhibitor, decreases liver injury and fibrosis in mice: role of oxidative stress and microRNA-23a. Front Pharmacol 2024; 15:1386238. [PMID: 38828459 PMCID: PMC11140137 DOI: 10.3389/fphar.2024.1386238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/24/2024] [Indexed: 06/05/2024] Open
Abstract
Effective therapy for liver fibrosis is lacking. Here, we examined whether LP340, the lead candidate of a new-generation of hydrazide-based HDAC1,2,3 inhibitors (HDACi), decreases liver fibrosis. Liver fibrosis was induced by CCl4 treatment and bile duct ligation (BDL) in mice. At 6 weeks after CCl4, serum alanine aminotransferase increased, and necrotic cell death and leukocyte infiltration occurred in the liver. Tumor necrosis factor-α and myeloperoxidase markedly increased, indicating inflammation. After 6 weeks, α-smooth muscle actin (αSMA) and collagen-1 expression increased by 80% and 575%, respectively, indicating hepatic stellate cell (HSC) activation and fibrogenesis. Fibrosis detected by trichrome and Sirius-red staining occurred primarily in pericentral regions with some bridging fibrosis in liver sections. 4-Hydroxynonenal adducts (indicator of oxidative stress), profibrotic cytokine transforming growth factor-β (TGFβ), and TGFβ downstream signaling molecules phospho-Smad2/3 also markedly increased. LP340 attenuated indices of liver injury, inflammation, and fibrosis markedly. Moreover, Ski-related novel protein-N (SnoN), an endogenous inhibitor of TGFβ signaling, decreased, whereas SnoN expression suppressor microRNA-23a (miR23a) increased markedly. LP340 (0.05 mg/kg, ig., daily during the last 2 weeks of CCl4 treatment) decreased 4-hydroxynonenal adducts and miR23a production, blunted SnoN decreases, and inhibited the TGFβ/Smad signaling. By contrast, LP340 had no effect on matrix metalloproteinase-9 expression. LP340 increased histone-3 acetylation but not tubulin acetylation, indicating that LP340 inhibited Class-I but not Class-II HDAC in vivo. After BDL, focal necrosis, inflammation, ductular reactions, and portal and bridging fibrosis occurred at 2 weeks, and αSMA and collagen-1 expression increased by 256% and 560%, respectively. LP340 attenuated liver injury, ductular reactions, inflammation, and liver fibrosis. LP340 also decreased 4-hydroxynonenal adducts and miR23a production, prevented SnoN decreases, and inhibited the TGFβ/Smad signaling after BDL. In vitro, LP340 inhibited immortal human hepatic stellate cells (hTERT-HSC) activation in culture (αSMA and collagen-1 expression) as well as miR23a production, demonstrating its direct inhibitory effects on HSC. In conclusions, LP340 is a promising therapy for both portal and pericentral liver fibrosis, and it works by inhibiting oxidative stress and decreasing miR23a.
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Affiliation(s)
- Devadoss J. Samuvel
- Departments of Drug Discovery and Biomedical Sciences, Charleston, SC, United States
| | - John J. Lemasters
- Departments of Drug Discovery and Biomedical Sciences, Charleston, SC, United States
- Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States
| | - C. James Chou
- Departments of Drug Discovery and Biomedical Sciences, Charleston, SC, United States
- Lydex Pharmaceuticals, Mount Pleasant, SC, United States
| | - Zhi Zhong
- Departments of Drug Discovery and Biomedical Sciences, Charleston, SC, United States
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Wang Y, Chen S, Bao S, Yao L, Wen Z, Xu L, Chen X, Guo S, Pang H, Zhou Y, Zhou P. Deciphering the fibrotic process: mechanism of chronic radiation skin injury fibrosis. Front Immunol 2024; 15:1338922. [PMID: 38426100 PMCID: PMC10902513 DOI: 10.3389/fimmu.2024.1338922] [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: 11/16/2023] [Accepted: 02/02/2024] [Indexed: 03/02/2024] Open
Abstract
This review explores the mechanisms of chronic radiation-induced skin injury fibrosis, focusing on the transition from acute radiation damage to a chronic fibrotic state. It reviewed the cellular and molecular responses of the skin to radiation, highlighting the role of myofibroblasts and the significant impact of Transforming Growth Factor-beta (TGF-β) in promoting fibroblast-to-myofibroblast transformation. The review delves into the epigenetic regulation of fibrotic gene expression, the contribution of extracellular matrix proteins to the fibrotic microenvironment, and the regulation of the immune system in the context of fibrosis. Additionally, it discusses the potential of biomaterials and artificial intelligence in medical research to advance the understanding and treatment of radiation-induced skin fibrosis, suggesting future directions involving bioinformatics and personalized therapeutic strategies to enhance patient quality of life.
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Affiliation(s)
- Yiren Wang
- School of Nursing, Southwest Medical University, Luzhou, China
- Wound Healing Basic Research and Clinical Application Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Shouying Chen
- School of Nursing, Southwest Medical University, Luzhou, China
- Wound Healing Basic Research and Clinical Application Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Shuilan Bao
- School of Nursing, Southwest Medical University, Luzhou, China
- Wound Healing Basic Research and Clinical Application Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Li Yao
- School of Nursing, Southwest Medical University, Luzhou, China
- Wound Healing Basic Research and Clinical Application Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Zhongjian Wen
- School of Nursing, Southwest Medical University, Luzhou, China
- Wound Healing Basic Research and Clinical Application Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Lixia Xu
- School of Nursing, Southwest Medical University, Luzhou, China
| | - Xiaoman Chen
- School of Nursing, Southwest Medical University, Luzhou, China
| | - Shengmin Guo
- Department of Nursing, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Haowen Pang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yun Zhou
- School of Medical Information and Engineering, Southwest Medical University, Luzhou, China
| | - Ping Zhou
- Wound Healing Basic Research and Clinical Application Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
- Department of Radiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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Jain I, Brougham-Cook A, Underhill GH. Effect of distinct ECM microenvironments on the genome-wide chromatin accessibility and gene expression responses of hepatic stellate cells. Acta Biomater 2023; 167:278-292. [PMID: 37343907 PMCID: PMC10527607 DOI: 10.1016/j.actbio.2023.06.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 05/25/2023] [Accepted: 06/14/2023] [Indexed: 06/23/2023]
Abstract
Hepatic stellate cells (HSCs) are one of the primary drivers of liver fibrosis in non-alcoholic fatty liver disease. Although HSC activation in liver disease is associated with changes in extracellular matrix (ECM) deposition and remodeling, it remains unclear how ECM regulates the phenotypic state transitions of HSCs. Using high-throughput cellular microarrays, coupled with genome-wide ATAC and RNA sequencing within engineered ECM microenvironments, we investigated the effect of ECM and substrate stiffness on chromatin accessibility and resulting gene expression in activated primary human HSCs. Cell microarrays demonstrated the cooperative effects of stiffness and ECM composition on H3K4 and H3K9 methylation/acetylation. ATAC sequencing revealed higher chromatin accessibility in HSCs on 1kPa compared to 25kPa substrates for all ECM conditions. Gene set enrichment analysis using RNA sequencing data of HSCs in defined ECM microenvironments demonstrated higher enrichment of NAFLD and fibrosis-related genes in pre-activated HSCs on 1kPa relative to 25kPa. Overall, these findings are indicative of a microenvironmental adaptation response in HSCs, and the acquisition of a persistent activation state. Combined ATAC/RNA sequencing analyses enabled identification of candidate regulatory factors, including HSD11B1 and CEBPb. siRNA-mediated knockdown of HSD11b1 and CEBPb demonstrated microenvironmental controlled reduction in fibrogenic markers in HSCs. STATEMENT OF SIGNIFICANCE: Hepatic stellate cells (HSCs) are one of the primary drivers of liver fibrosis in non-alcoholic fatty liver disease. Although HSC activation in liver disease is associated with changes in extracellular matrix (ECM) deposition and remodeling, it remains unclear how ECM regulates the phenotypic state transitions of HSCs. Using high-throughput cellular microarrays, coupled with genome-wide ATAC and RNA sequencing within engineered ECM microenvironments, we investigated the effect of ECM and substrate stiffness on chromatin accessibility and resulting gene expression in activated primary human HSCs. Overall, these findings were indicative of a microenvironmental adaptation response in HSCs, and the acquisition of a persistent activation state. Combined ATAC/RNA sequencing analyses enabled identification of candidate regulatory factors, including HSD11B1 and CEBPb. siRNA-mediated knockdown of HSD11b1 and CEBPb demonstrated microenvironmental controlled reduction in fibrogenic markers in HSCs.
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Affiliation(s)
- Ishita Jain
- University of Illinois at Urbana Champaign, Urbana, USA
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Liu Y, Wen D, Ho C, Yu L, Zheng D, O'Reilly S, Gao Y, Li Q, Zhang Y. Epigenetics as a versatile regulator of fibrosis. J Transl Med 2023; 21:164. [PMID: 36864460 PMCID: PMC9983257 DOI: 10.1186/s12967-023-04018-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 02/23/2023] [Indexed: 03/04/2023] Open
Abstract
Fibrosis, a process caused by excessive deposition of extracellular matrix (ECM), is a common cause and outcome of organ failure and even death. Researchers have made many efforts to understand the mechanism of fibrogenesis and to develop therapeutic strategies; yet, the outcome remains unsatisfactory. In recent years, advances in epigenetics, including chromatin remodeling, histone modification, DNA methylation, and noncoding RNA (ncRNA), have provided more insights into the fibrotic process and have suggested the possibility of novel therapy for organ fibrosis. In this review, we summarize the current research on the epigenetic mechanisms involved in organ fibrosis and their possible clinical applications.
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Affiliation(s)
- Yangdan Liu
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Dongsheng Wen
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Chiakang Ho
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Li Yu
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Danning Zheng
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China
| | | | - Ya Gao
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China.
| | - Qingfeng Li
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China.
| | - Yifan Zhang
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China.
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Alpoim-Moreira J, Fernandes C, Pimenta J, Bliebernicht M, Rebordão MR, Castelo-Branco P, Szóstek-Mioduchowska A, Skarzynski DJ, Ferreira-Dias G. Metallopeptidades 2 and 9 genes epigenetically modulate equine endometrial fibrosis. Front Vet Sci 2022; 9:970003. [PMID: 36032279 PMCID: PMC9412240 DOI: 10.3389/fvets.2022.970003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/22/2022] [Indexed: 12/13/2022] Open
Abstract
Endometrium type I (COL1) and III (COL3) collagen accumulation, periglandular fibrosis and mare infertility characterize endometrosis. Metalloproteinase-2 (MMP-2), MMP-9 and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) are involved in collagen turnover. Since epigenetic changes may control fibroproliferative diseases, we hypothesized that epigenetic mechanisms could modulate equine endometrosis. Epigenetic changes can be reversed and therefore extremely promising for therapeutic use. Methylation pattern analysis of a particular gene zone is used to detect epigenetic changes. DNA methylation commonly mediates gene repression. Thus, this study aimed to evaluate if the transcription of some genes involved in equine endometrosis was altered with endometrial fibrosis, and if the observed changes were epigenetically modulated, through DNA methylation analysis. Endometrial biopsies collected from cyclic mares were histologically classified (Kenney and Doig category I, n = 6; category IIA, n = 6; category IIB, n = 6 and category III, n = 6). Transcription of COL1A1, COL1A2, COL3A1, MMP2, MMP9, TIMP1, and TIMP2 genes and DNA methylation pattern by pyrosequencing of COL1A1, MMP2, MMP9, TIMP1 genes were evaluated. Both MMP2 and MMP9 transcripts decreased with fibrosis, when compared with healthy endometrium (category I) (P < 0.05). TIMP1 transcripts were higher in category III, when compared to category I endometrium (P < 0.05). No differences were found for COL1A1, COL1A2, COL3A1 and TIMP2 transcripts between endometrial categories. There were higher methylation levels of (i) COL1A1 in category IIB (P < 0.05) and III (P < 0.01), when compared to category I; (ii) MMP2 in category III, when compared to category I (P < 0.001) and IIA (P < 0.05); and (iii) MMP9 in category III, when compared to category I and IIA (P < 0.05). No differences in TIMP1 methylation levels were observed between endometrial categories. The hypermethylation of MMP2 and MMP9, but not of COL1A1 genes, occurred simultaneously with a decrease in their mRNA levels, with endometrial fibrosis, suggesting that this hypermethylation is responsible for repressing their transcription. Our results show that endometrosis is epigenetically modulated by anti-fibrotic genes (MMP2 and MMP9) inhibition, rather than fibrotic genes activation and therefore, might be promising targets for therapeutic use.
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Affiliation(s)
- Joana Alpoim-Moreira
- CIISA - Center for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Lisbon, Portugal
| | - Carina Fernandes
- CIISA - Center for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Lisbon, Portugal
| | - Jorge Pimenta
- CIISA - Center for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal
- Unidade Estratégica de Investigação e Serviços de Biotecnologia e Recursos Genéticos (UEISBR), Instituto Nacional de Investigação Agrária e Veterinária, I. P. (INIAV), Vairão, Portugal
| | | | - Maria Rosa Rebordão
- CIISA - Center for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Lisbon, Portugal
- Polytechnic of Coimbra, Coimbra Agriculture School, Coimbra, Portugal
| | - Pedro Castelo-Branco
- Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Faro, Portugal
- Algarve Biomedical Center Research Institute (ABC-RI), Faro, Portugal
| | | | | | - Graça Ferreira-Dias
- CIISA - Center for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Lisbon, Portugal
- *Correspondence: Graça Ferreira-Dias
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Avci E, Sarvari P, Savai R, Seeger W, Pullamsetti SS. Epigenetic Mechanisms in Parenchymal Lung Diseases: Bystanders or Therapeutic Targets? Int J Mol Sci 2022; 23:ijms23010546. [PMID: 35008971 PMCID: PMC8745712 DOI: 10.3390/ijms23010546] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 12/17/2022] Open
Abstract
Epigenetic responses due to environmental changes alter chromatin structure, which in turn modifies the phenotype, gene expression profile, and activity of each cell type that has a role in the pathophysiology of a disease. Pulmonary diseases are one of the major causes of death in the world, including lung cancer, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), lung tuberculosis, pulmonary embolism, and asthma. Several lines of evidence indicate that epigenetic modifications may be one of the main factors to explain the increasing incidence and prevalence of lung diseases including IPF and COPD. Interestingly, isolated fibroblasts and smooth muscle cells from patients with pulmonary diseases such as IPF and PH that were cultured ex vivo maintained the disease phenotype. The cells often show a hyper-proliferative, apoptosis-resistant phenotype with increased expression of extracellular matrix (ECM) and activated focal adhesions suggesting the presence of an epigenetically imprinted phenotype. Moreover, many abnormalities observed in molecular processes in IPF patients are shown to be epigenetically regulated, such as innate immunity, cellular senescence, and apoptotic cell death. DNA methylation, histone modification, and microRNA regulation constitute the most common epigenetic modification mechanisms.
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MESH Headings
- Animals
- Biomarkers
- Combined Modality Therapy
- DNA Methylation
- Diagnosis, Differential
- Disease Management
- Disease Susceptibility
- Epigenesis, Genetic
- Gene Expression Regulation
- Histones/metabolism
- Humans
- Idiopathic Pulmonary Fibrosis/diagnosis
- Idiopathic Pulmonary Fibrosis/etiology
- Idiopathic Pulmonary Fibrosis/metabolism
- Idiopathic Pulmonary Fibrosis/therapy
- Lung Diseases, Interstitial/diagnosis
- Lung Diseases, Interstitial/etiology
- Lung Diseases, Interstitial/metabolism
- Lung Diseases, Interstitial/therapy
- Pulmonary Disease, Chronic Obstructive/diagnosis
- Pulmonary Disease, Chronic Obstructive/etiology
- Pulmonary Disease, Chronic Obstructive/metabolism
- Pulmonary Disease, Chronic Obstructive/therapy
- Treatment Outcome
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Affiliation(s)
- Edibe Avci
- Department of Lung Development and Remodeling, Max-Planck Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany; (E.A.); (P.S.); (R.S.); (W.S.)
| | - Pouya Sarvari
- Department of Lung Development and Remodeling, Max-Planck Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany; (E.A.); (P.S.); (R.S.); (W.S.)
| | - Rajkumar Savai
- Department of Lung Development and Remodeling, Max-Planck Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany; (E.A.); (P.S.); (R.S.); (W.S.)
- Department of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany
- Institute for Lung Health (ILH), Justus Liebig University, 35392 Giessen, Germany
| | - Werner Seeger
- Department of Lung Development and Remodeling, Max-Planck Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany; (E.A.); (P.S.); (R.S.); (W.S.)
- Department of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany
- Institute for Lung Health (ILH), Justus Liebig University, 35392 Giessen, Germany
| | - Soni S. Pullamsetti
- Department of Lung Development and Remodeling, Max-Planck Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany; (E.A.); (P.S.); (R.S.); (W.S.)
- Department of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany
- Correspondence: ; Tel.: +49-603-270-5380; Fax: +49-603-270-5385
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9
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Serna-Salas SA, Arroyave-Ospina JC, Zhang M, Damba T, Buist-Homan M, Muñoz-Ortega MH, Ventura-Juárez J, Moshage H. α-1 Adrenergic receptor antagonist doxazosin reverses hepatic stellate cells activation via induction of senescence. Mech Ageing Dev 2021; 201:111617. [PMID: 34958827 DOI: 10.1016/j.mad.2021.111617] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 12/06/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Activated hepatic stellate cells (aHSCs) are the main effector cells during liver fibrogenesis. α-1 adrenergic antagonist doxazosin (DX) was shown to be anti-fibrotic in an in vivo model of liver fibrosis (LF), but the mechanism remains to be elucidated. Recent studies suggest that reversion of LF can be achieved by inducing cellular senescence characterized by irreversible cell-cycle arrest and acquisition of the senescence-associated secretory phenotype (SASP). AIM To elucidate the mechanism of the anti-fibrotic effect of DX and determine whether it induces senescence. METHODS Primary culture-activated rat HSCs were used. mRNA and protein expression were measured by qPCR and Western blot, respectively. Cell proliferation was assessed by BrdU incorporation and xCelligence analysis. TGF-β was used for maximal HSC activation. Norepinephrine (NE), PMA and m-3M3FBS were used to activate alpha-1 adrenergic signaling. RESULTS Expression of Col1α1 was significantly decreased by DX (10 µmol/L) at mRNA (-30 %) and protein level (-50 %) in TGF-β treated aHSCs. DX significantly reduced aHSCs proliferation and increased expression of senescence and SASP markers. PMA and m-3M3FBS reversed the effect of DX on senescence markers. CONCLUSION Doxazosin reverses the fibrogenic phenotype of aHSCs and induces the senescence phenotype.
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Affiliation(s)
- Sandra A Serna-Salas
- Dept. Morphology, Autonomous University of Aguascalientes, Aguascalientes, Mexico; Dept. Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Johanna C Arroyave-Ospina
- Dept. Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Mengfan Zhang
- Dept. Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Turtushikh Damba
- Dept. Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Manon Buist-Homan
- Dept. Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Dept. Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | | | | | - Han Moshage
- Dept. Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Dept. Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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10
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Liu YR, Wang JQ, Huang ZG, Chen RN, Cao X, Zhu DC, Yu HX, Wang XR, Zhou HY, Xia Q, Li J. Histone deacetylase‑2: A potential regulator and therapeutic target in liver disease (Review). Int J Mol Med 2021; 48:131. [PMID: 34013366 PMCID: PMC8136123 DOI: 10.3892/ijmm.2021.4964] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 04/12/2021] [Indexed: 12/12/2022] Open
Abstract
Histone acetyltransferases are responsible for histone acetylation, while histone deacetylases (HDACs) counteract histone acetylation. An unbalanced dynamic between histone acetylation and deacetylation may lead to aberrant chromatin landscape and chromosomal function. HDAC2, a member of class I HDAC family, serves a crucial role in the modulation of cell signaling, immune response and gene expression. HDAC2 has emerged as a promising therapeutic target for liver disease by regulating gene transcription, chromatin remodeling, signal transduction and nuclear reprogramming, thus receiving attention from researchers and clinicians. The present review introduces biological information of HDAC2 and its physiological and biochemical functions. Secondly, the functional roles of HDAC2 in liver disease are discussed in terms of hepatocyte apoptosis and proliferation, liver regeneration, hepatocellular carcinoma, liver fibrosis and non-alcoholic steatohepatitis. Moreover, abnormal expression of HDAC2 may be involved in the pathogenesis of liver disease, and its expression levels and pharmacological activity may represent potential biomarkers of liver disease. Finally, research on selective HDAC2 inhibitors and non-coding RNAs relevant to HDAC2 expression in liver disease is also reviewed. The aim of the present review was to improve understanding of the multifunctional role and potential regulatory mechanism of HDAC2 in liver disease.
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Affiliation(s)
- Ya-Ru Liu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Jie-Quan Wang
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230000, P.R. China
| | - Zhao-Gang Huang
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Ruo-Nan Chen
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Xi Cao
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Dong-Chun Zhu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Hai-Xia Yu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Xiu-Rong Wang
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Hai-Yun Zhou
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Quan Xia
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Jun Li
- The Key Laboratory of Anti‑inflammatory Immune Medicines, School of Pharmacy, Anhui Medical University, Ministry of Education, Hefei, Anhui 230032, P.R. China
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11
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Wang F, Malnassy G, Qiu W. The Epigenetic Regulation of Microenvironment in Hepatocellular Carcinoma. Front Oncol 2021; 11:653037. [PMID: 33791228 PMCID: PMC8005717 DOI: 10.3389/fonc.2021.653037] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 02/22/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly lethal and complex malignancy strongly influenced by the surrounding tumor microenvironment. The HCC microenvironment comprises hepatic stellate cells (HSCs), tumor-associated macrophages (TAMs), stromal and endothelial cells, and the underlying extracellular matrix (ECM). Emerging evidence demonstrates that epigenetic regulation plays a crucial role in altering numerous components of the HCC tumor microenvironment. In this review, we summarize the current understanding of the mechanisms of epigenetic regulation of the microenvironment in HCC. We review recent studies demonstrating how specific epigenetic mechanisms (DNA methylation, histone regulation, and non-coding RNAs mediated regulation) in HSCs, TAMs, and ECM, and how they contribute to HCC development, so as to gain new insights into the treatment of HCC via regulating epigenetic regulation in the tumor microenvironment.
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Affiliation(s)
- Fang Wang
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States.,Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States
| | - Greg Malnassy
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States.,Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States
| | - Wei Qiu
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States.,Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States
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12
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Ganguly N, Chakrabarti S. Role of long non‑coding RNAs and related epigenetic mechanisms in liver fibrosis (Review). Int J Mol Med 2021; 47:23. [PMID: 33495817 PMCID: PMC7846421 DOI: 10.3892/ijmm.2021.4856] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 10/29/2020] [Indexed: 02/07/2023] Open
Abstract
Liver fibrosis is one of the major liver pathologies affecting patients worldwide. It results from an improper tissue repair process following liver injury or inflammation. If left untreated, it ultimately leads to liver cirrhosis and liver failure. Long non‑coding RNAs (lncRNAs) have been implicated in a wide variety of diseases. They can regulate gene expression and modulate signaling. Some of the lncRNAs promote, while others inhibit liver fibrosis. Similarly, other epigenetic processes, such as methylation and acetylation regulate gene transcription and can modulate gene expression. Notably, there are several regulatory associations of lncRNAs with other epigenetic processes. A major mechanism of action of long non‑coding RNAs is to competitively bind to their target microRNAs (miRNAs or miRs), which in turn affects miRNA availability and bioactivity. In the present review, the role of lncRNAs and related epigenetic processes contributing to liver fibrosis is discussed. Finally, various potential therapeutic approaches targeting lncRNAs and related epigenetic processes, which are being considered as possible future treatment targets for liver fibrosis are identified.
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Affiliation(s)
- Niladri Ganguly
- Department of Pathology and Laboratory Medicine, University of Western Ontario, London, ON N6A 5C1, Canada
| | - Subrata Chakrabarti
- Department of Pathology and Laboratory Medicine, University of Western Ontario, London, ON N6A 5C1, Canada
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13
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Lee Y, Shin MH, Kim MK, Park CH, Shin HS, Lee DH, Chung JH. Ultraviolet irradiation-induced inhibition of histone deacetylase 4 increases the expression of matrix metalloproteinase-1 but decreases that of type I procollagen via activating JNK in human dermal fibroblasts. J Dermatol Sci 2020; 101:107-114. [PMID: 33309320 DOI: 10.1016/j.jdermsci.2020.11.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/23/2020] [Accepted: 11/30/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Ultraviolet (UV) irradiation is the main contributing factor for skin aging. UV irradiation induces epigenetic changes in skin. It increases the activity of histone acetylases (HATs) but decreases that of histone deacetylases (HDACs). OBJECTIVE We aimed to investigate alterations in all classes of HDACs and sirtuins (SIRTs) in response to UV irradiation, and determine the HDACs regulating the expressions of matrix metalloproteinase 1 (MMP-1) and type I procollagen. METHODS Primary human dermal fibroblasts were UV irradiated. HDAC4 was knocked-down or overexpressed to investigate its effect on the expression of MMP-1 and type I procollagen. The mRNA and protein levels were analyzed by quantitative real-time polymerase chain reaction and western blotting. RESULTS Among 11 HDACs and 7 SIRTs, we found that the expression of HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC11, SIRT2, and SIRT3 were significantly and consistently reduced by UV at both mRNA and protein levels. Among these, the reduction of HDAC4 was responsible for the basal and UV-induced increase in the expression of MMP-1 and decrease in that of type I procollagen. Furthermore, the reduced HDAC4 could activate c-Jun N-terminal kinase (JNK), resulting in an increase in MMP-1 and decrease in type I procollagen. CONCLUSIONS UV treatment decreases the expression of HDACs and SIRTs in dermal fibroblasts; in particular, the UV-induced reduction in the expression of HDAC4 might play an important role in regulating the expression of MMP-1 and type I procollagen.
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Affiliation(s)
- Yuri Lee
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea
| | - Mi Hee Shin
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea
| | - Min-Kyoung Kim
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea
| | - Chi-Hyun Park
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea
| | - Hye Sun Shin
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea
| | - Dong Hun Lee
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
| | - Jin Ho Chung
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea; Institute on Aging, Seoul National University, Seoul, Republic of Korea.
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14
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Claveria-Cabello A, Colyn L, Arechederra M, Urman JM, Berasain C, Avila MA, Fernandez-Barrena MG. Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target? Cells 2020; 9:cells9102321. [PMID: 33086678 PMCID: PMC7589994 DOI: 10.3390/cells9102321] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/15/2020] [Accepted: 10/17/2020] [Indexed: 12/13/2022] Open
Abstract
Chronic liver diseases (CLD) represent a worldwide health problem. While CLDs may have diverse etiologies, a common pathogenic denominator is the presence of liver fibrosis. Cirrhosis, the end-stage of CLD, is characterized by extensive fibrosis and is markedly associated with the development of hepatocellular carcinoma. The most important event in hepatic fibrogenesis is the activation of hepatic stellate cells (HSC) following liver injury. Activated HSCs acquire a myofibroblast-like phenotype becoming proliferative, fibrogenic, and contractile cells. While transient activation of HSCs is part of the physiological mechanisms of tissue repair, protracted activation of a wound healing reaction leads to organ fibrosis. The phenotypic changes of activated HSCs involve epigenetic mechanisms mediated by non-coding RNAs (ncRNA) as well as by changes in DNA methylation and histone modifications. During CLD these epigenetic mechanisms become deregulated, with alterations in the expression and activity of epigenetic modulators. Here we provide an overview of the epigenetic alterations involved in fibrogenic HSCs transdifferentiation with particular focus on histones acetylation changes. We also discuss recent studies supporting the promising therapeutic potential of histone deacetylase inhibitors in liver fibrosis.
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Affiliation(s)
- Alex Claveria-Cabello
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (M.A.); (C.B.)
| | - Leticia Colyn
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (M.A.); (C.B.)
| | - Maria Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (M.A.); (C.B.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
| | - Jesus M. Urman
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
- Department of Gastroenterology and Hepatology, Navarra University Hospital Complex, 31008 Pamplona, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (M.A.); (C.B.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
| | - Matias A. Avila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (M.A.); (C.B.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
- Correspondence: (M.A.A.); (M.G.F.-B.); Tel.: +34-94-819-4700 (M.A.A.); +34-94-819-4700 (M.G.F.-B.)
| | - Maite G. Fernandez-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (A.C.-C.); (L.C.); (M.A.); (C.B.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain;
- Correspondence: (M.A.A.); (M.G.F.-B.); Tel.: +34-94-819-4700 (M.A.A.); +34-94-819-4700 (M.G.F.-B.)
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15
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Chen L, Huang W, Wang L, Zhang Z, Zhang F, Zheng S, Kong D. The effects of epigenetic modification on the occurrence and progression of liver diseases and the involved mechanism. Expert Rev Gastroenterol Hepatol 2020; 14:259-270. [PMID: 32124651 DOI: 10.1080/17474124.2020.1736042] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Epigenetic modification is a type of gene expression and regulation that does not involve changes in DNA sequences. An increasing number of studies have proven that epigenetic modifications play an important role in the occurrence and progression of liver diseases through the gene regulation and protein expressions of hepatocellular lipid metabolism, inflammatory reaction, cell proliferation, and activation, etc.Areas covered: In this study, we elaborated and analyzed the underlying functional mechanism of epigenetic modification in alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), liver fibrosis (LF), viral hepatitis, hepatocellular carcinoma (HCC), and research progress of recent years.Expert opinion: The further understanding of epigenetic mechanisms that can regulate gene expression and cell phenotype leads to new insights in epigenetic control of chronic liver disease. Currently, hepatologists are exploring the role of DNA methylation, histone/chromatin modification, and non-coding RNA in specific liver pathology. These findings have led to advances in direct epigenetic biomarker testing of patient tissue or body fluid specimens, as well as quantitative analysis. Based on these findings, drug validation of some targets involved in the epigenetic mechanism of liver disease is gradually being carried out clinically.
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Affiliation(s)
- Liping Chen
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Weifang Huang
- Department of Pharmacology, School of Integral Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ling Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Desong Kong
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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16
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Lyu X, Hu M, Peng J, Zhang X, Sanders YY. HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis. Ther Adv Chronic Dis 2019; 10:2040622319862697. [PMID: 31367296 PMCID: PMC6643173 DOI: 10.1177/2040622319862697] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 06/17/2019] [Indexed: 12/14/2022] Open
Abstract
Fibrosis usually results from dysregulated wound repair and is characterized by
excessive scar tissue. It is a complex process with unclear mechanisms.
Accumulating evidence indicates that epigenetic alterations, including histone
acetylation, play a pivotal role in this process. Histone acetylation is
governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs).
HDACs are enzymes that remove the acetyl groups from both histone and nonhistone
proteins. Aberrant HDAC activities are observed in fibrotic diseases, including
cardiac and pulmonary fibrosis. HDAC inhibitors (HDACIs) are molecules that
block HDAC functions. HDACIs have been studied extensively in a variety of
tumors. Currently, there are four HDACIs approved by the US Food and Drug
Administration for cancer treatment yet none for fibrotic diseases. Emerging
evidence from in vitro and in vivo preclinical
studies has presented beneficial effects of HDACIs in preventing or reversing
fibrogenesis. In this review, we summarize the latest findings of the roles of
HDACs in the pathogenesis of cardiac and pulmonary fibrosis and highlight the
potential applications of HDACIs in these two fibrotic diseases.
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Affiliation(s)
- Xing Lyu
- Laboratory of Clinical Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Min Hu
- Laboratory of Clinical Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jieting Peng
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiangyu Zhang
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Yan Y Sanders
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, 901 19 Street South, BMRII Room 408, Birmingham, AL 35294, USA
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17
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Barcena-Varela M, Colyn L, Fernandez-Barrena MG. Epigenetic Mechanisms in Hepatic Stellate Cell Activation During Liver Fibrosis and Carcinogenesis. Int J Mol Sci 2019; 20:E2507. [PMID: 31117267 PMCID: PMC6566358 DOI: 10.3390/ijms20102507] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 05/17/2019] [Accepted: 05/19/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is an essential component of chronic liver disease (CLD) and hepatocarcinogenesis. The fibrotic stroma is a consequence of sustained liver damage combined with exacerbated extracellular matrix (ECM) accumulation. In this context, activation of hepatic stellate cells (HSCs) plays a key role in both initiation and perpetuation of fibrogenesis. These cells suffer profound remodeling of gene expression in this process. This review is focused on the epigenetic alterations participating in the transdifferentiation of HSCs from the quiescent to activated state. Recent advances in the field of DNA methylation and post-translational modifications (PTM) of histones (acetylation and methylation) patterns are discussed here, together with altered expression and activity of epigenetic remodelers. We also consider recent advances in translational approaches, including the use of epigenetic marks as biomarkers and the promising antifibrotic properties of epigenetic drugs that are currently being used in patients.
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Affiliation(s)
| | - Leticia Colyn
- Hepatology Program, CIMA, University of Navarra, 31180 Pamplona, Spain.
| | - Maite G Fernandez-Barrena
- Hepatology Program, CIMA, University of Navarra, 31180 Pamplona, Spain.
- CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.
- Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, 31180 Pamplona, Spain.
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18
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Yin L, Li F, Li J, Yang X, Xie X, Xue L, Li Y, Zhang C. Chronic Intermittent Ethanol Exposure Induces Upregulation of Matrix Metalloproteinase-9 in the Rat Medial Prefrontal Cortex and Hippocampus. Neurochem Res 2019; 44:1593-1601. [PMID: 30915602 DOI: 10.1007/s11064-019-02783-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 03/15/2019] [Accepted: 03/18/2019] [Indexed: 12/17/2022]
Abstract
Matrix metalloproteinase-9 (MMP-9, Gelatinase B), an extracellular-acting Zn2+-dependent endopeptidase, are involved in brain pathologies including ischemia, glioma, and epilepsy. Recent studies suggested that MMP-9 plays an important role in neuronal plasticity, specifically in learning and memory. To determine whether and how MMP-9 plays role in alcohol-related behaviors, male Sprague-Dawley (SD) rats were subjected to chronic intermittent ethanol (CIE) exposure for 4 weeks, following which we collected tissue samples from the hippocampus, medial prefrontal cortex (mPFC), and amygdala at different stages (acute and chronic exposure) during alcohol exposure. Real-time PCR and western blot assays were used to detect changes in the mRNA and protein expression of MMP-9. Our results indicated that both acute and chronic alcohol exposure induced up-regulation of MMP-9 mRNA levels in the hippocampus and mPFC, but not in the amygdala. Furthermore, acute and chronic alcohol exposure up regulated the expression of total MMP-9 and active MMP-9 in these two brain regions. Moreover, the increase of active MMP-9 expression was larger than those in total MMP-9 expression. Immunoprecipitation analyses identified potential MMP-9-interacting proteins, including Itgb1, Src, Eef1a2, tubulin, actin, and histone H2B. These results demonstrate that both acute and CIE exposure induced increases in MMP-9 expression in the mPFC and hippocampus, suggesting that MMP-9 plays a key role in chronic alcohol exposure and dependence.
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Affiliation(s)
- Litian Yin
- Key Laboratory for Cellular Physiology of Ministry of Education, Department of Physiology, National Key Disciplines, Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
| | - Fengqing Li
- Key Laboratory for Cellular Physiology of Ministry of Education, Department of Physiology, National Key Disciplines, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Jue Li
- School of Clinic, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Xiaorong Yang
- Key Laboratory for Cellular Physiology of Ministry of Education, Department of Physiology, National Key Disciplines, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Xiaoyan Xie
- Key Laboratory for Cellular Physiology of Ministry of Education, Department of Physiology, National Key Disciplines, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Linyuan Xue
- Key Laboratory for Cellular Physiology of Ministry of Education, Department of Physiology, National Key Disciplines, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Yanli Li
- Key Laboratory for Cellular Physiology of Ministry of Education, Department of Physiology, National Key Disciplines, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Ce Zhang
- Key Laboratory for Cellular Physiology of Ministry of Education, Department of Physiology, National Key Disciplines, Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
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19
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Reactive Oxygen Species Drive Epigenetic Changes in Radiation-Induced Fibrosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:4278658. [PMID: 30881591 PMCID: PMC6381575 DOI: 10.1155/2019/4278658] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/06/2018] [Accepted: 12/12/2018] [Indexed: 12/14/2022]
Abstract
Radiation-induced fibrosis (RIF) develops months to years after initial radiation exposure. RIF occurs when normal fibroblasts differentiate into myofibroblasts and lay down aberrant amounts of extracellular matrix proteins. One of the main drivers for developing RIF is reactive oxygen species (ROS) generated immediately after radiation exposure. Generation of ROS is known to induce epigenetic changes and cause differentiation of fibroblasts to myofibroblasts. Several antioxidant compounds have been shown to prevent radiation-induced epigenetic changes and the development of RIF. Therefore, reviewing the ROS-linked epigenetic changes in irradiated fibroblast cells is essential to understand the development and prevention of RIF.
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20
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Zheng H, You Y, Hua M, Wu P, Liu Y, Chen Z, Zhang L, Wei H, Li Y, Luo M, Zeng Y, Liu Y, Luo DX, Zhang J, Feng M, Hu R, Pandol SJ, Han YP. Chlorophyllin Modulates Gut Microbiota and Inhibits Intestinal Inflammation to Ameliorate Hepatic Fibrosis in Mice. Front Physiol 2018; 9:1671. [PMID: 30564133 PMCID: PMC6288434 DOI: 10.3389/fphys.2018.01671] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Accepted: 11/07/2018] [Indexed: 12/24/2022] Open
Abstract
Liver fibrosis is an abnormal wound healing response and a common consequence of chronic liver diseases from infection or alcohol/xenobiotic exposure. At the cellular level, liver fibrosis is mediated by trans-differentiation of hepatic stellate cells (HSCs), which is driven by persistent hepatic and systemic inflammation. However, impaired enterohepatic circulation and gut dysbiosis may indirectly contribute to the liver fibrogenesis. The composition of the gut microbiota depends on diet composition and host factors. In this study, we examined chlorophyllin, derived from green pigment chlorophyll, on gut microbiota, the intestinal mucosal barrier, and liver fibrosis. BALB/c mice received carbon tetrachloride through intraperitoneal injection to induce liver fibrosis and chlorophyllin was administrated in drinking water. The effects of chlorophyllin on liver fibrosis were evaluated for (1) survival rate, (2) hepatic morphologic analysis, (3) inflammatory factors in both the small intestine and liver, and (4) gut microbiota. Our results indicate that oral administration of chlorophyllin could attenuate intestinal and hepatic inflammation and ameliorate liver fibrosis. Importantly, oral administration of chlorophyllin promptly rebalanced the gut microbiota, exhibiting down-regulation of the phylum Firmicutes and up-regulation of the phylum Bacteroidetes. In vitro experiments on intestinal epithelial cells showed that chlorophyllin exposure could inhibit NF-κB pathway via IKK-phosphorylation suppression. In conclusion, this study demonstrates potential application of chlorophyllin to regulate the intestinal microbiota and ameliorate hepatic fibrosis.
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Affiliation(s)
- Han Zheng
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, The Center for Growth, Metabolism and Aging, The College of Life Sciences, Sichuan University, Chengdu, China
| | - Yang You
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, The Center for Growth, Metabolism and Aging, The College of Life Sciences, Sichuan University, Chengdu, China
| | - Meiyun Hua
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, The Center for Growth, Metabolism and Aging, The College of Life Sciences, Sichuan University, Chengdu, China
| | - Pengfei Wu
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, The Center for Growth, Metabolism and Aging, The College of Life Sciences, Sichuan University, Chengdu, China
| | - Yu Liu
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, The Center for Growth, Metabolism and Aging, The College of Life Sciences, Sichuan University, Chengdu, China
| | - Zishuo Chen
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, The Center for Growth, Metabolism and Aging, The College of Life Sciences, Sichuan University, Chengdu, China
| | - Li Zhang
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, The Center for Growth, Metabolism and Aging, The College of Life Sciences, Sichuan University, Chengdu, China
| | - Haoche Wei
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, The Center for Growth, Metabolism and Aging, The College of Life Sciences, Sichuan University, Chengdu, China
| | - Yan Li
- Chengdu Tongde Pharmaceutical Ltd., Chengdu, China
| | - Mei Luo
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, The Center for Growth, Metabolism and Aging, The College of Life Sciences, Sichuan University, Chengdu, China.,Public Health and Clinical Center of Chengdu, Chengdu, China
| | - Yilan Zeng
- Public Health and Clinical Center of Chengdu, Chengdu, China
| | - Yong Liu
- Public Health and Clinical Center of Chengdu, Chengdu, China
| | - Dong-Xia Luo
- Public Health and Clinical Center of Chengdu, Chengdu, China
| | - Jie Zhang
- Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Min Feng
- Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Richard Hu
- Olive View-UCL Medical Center, Los Angeles, CA, United States
| | | | - Yuan-Ping Han
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, The Center for Growth, Metabolism and Aging, The College of Life Sciences, Sichuan University, Chengdu, China
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21
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Wang Y, Zhao L, Jiao FZ, Zhang WB, Chen Q, Gong ZJ. Histone deacetylase inhibitor suberoylanilide hydroxamic acid alleviates liver fibrosis by suppressing the transforming growth factor-β1 signal pathway. Hepatobiliary Pancreat Dis Int 2018; 17:423-429. [PMID: 30249543 DOI: 10.1016/j.hbpd.2018.09.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 09/11/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Histone deacetylases (HDACs) inhibitors are new anti-fibrotic drugs that inhibit the activity of hepatic stellate cells. The present study focused on the anti-fibrotic function of HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) by suppressing transforming growth factor-β1 (TGF-β1) signaling. METHODS Male Sprague-Dawley rats were used to induce liver fibrosis with carbon tetrachloride (CCl4) and LX2 cell (human hepatic stellate cell line) was stimulated by TGF-β1. Both animals and cells were treated with SAHA. The Smad7 and connective tissue growth factor (CTGF) mRNA levels were detected by real-time polymerase chain reaction (PCR). Western blotting was used to examine the protein levels of CTGF, Histone H3 (H3), Smad7, Smad2/3, Acetyl-Histone H3 (AH3), HDAC2, α-smooth muscle actin (α-SMA), HDAC6, p-Smad2/3 and HDAC8. In addition, the TGF-β1 and liver enzyme levels from rat serum were detected. Histopathological changes were examined by hematoxylin and eosin (HE), Sirius red and Masson trichrome staining. The α-SMA expression was detected by immumohistochemical staining. RESULTS Compared with control group, the TGF-β1 and liver enzyme levels from rat serum, together with the mRNA levels of CTGF and protein levels of CTGF, HDAC2, α-SMA, HDAC6, p-Smad2/3 and HDAC8 were elevated in fibrotic rats (P < 0.01). But the Smad7 mRNA and AH3 protein levels were notably suppressed in the fibrotic rats (P < 0.01). Pathological examination showed the typical changes of liver fibrosis in the fibrotic rats. After the treatment with SAHA, the levels of liver enzymes, TGF-β1, CTGF, HDAC2, α-SMA, HDAC6, p-Smad2/3 and HDAC8 were reduced (P < 0.01) and Smad7 and AH3 protein contents were elevated in liver fibrotic rats (P < 0.01). Moreover, immumohistochemistry showed that SAHA significantly suppressed the α-SMA protein content in fibrotic liver (P < 0.01). CONCLUSION The HDAC inhibitor SAHA alleviated liver fibrosis by suppressing the TGF-β1 signaling.
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Affiliation(s)
- Yao Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Lei Zhao
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Fang-Zhou Jiao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Wen-Bin Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Qian Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Zuo-Jiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China.
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22
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Wu JC, Luo SZ, Liu T, Lu LG, Xu MY. linc-SCRG1 accelerates liver fibrosis by decreasing RNA-binding protein tristetraprolin. FASEB J 2018; 33:2105-2115. [PMID: 30226813 DOI: 10.1096/fj.201800098rr] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The biologic roles of long noncoding RNAs (lncRNAs) in liver fibrosis remained unknown. Through microarray analysis, linc-SCRG1 (a lncRNA with transcript length 3118 bp) was found up-regulated 13.62-fold in human cirrhotic tissues. Quantitative PCR verified that linc-SCRG1 increased along with liver fibrosis progression in human tissues and in activated LX2 cells induced by TGF-β1. Knockdown of linc-SCRG1 significantly reversed the effects of TGF-β1 on LX2, including inhibiting activation, promoting apoptosis, reducing proliferation, lessening invasion, and down-regulating genes [fibrosis-related mRNA: α-smooth muscle actin ( α-SMA), type I collagen, and B-cell lymphoma-2; invasion-related mRNA: matrix metallopeptidase-2 ( MMP-2), MMP-9, and MMP-13; inflammation-related mRNA: TNF-α, IL-6, and IL-10]. linc-SCRG1 had binding sites with tristetraprolin (TTP), a kind of RNA-binding protein, and specifically combined to TTP proteins. Overexpression of linc-SCRG1 would cause TTP mRNA unstably and proteins decreasing. TTP mRNA was proved having negative relevance with linc-SCRG1 and was gradually reduced during human liver fibrosis progression. Overexpressing TTP resulted in knockdown of lincSCRG1 and degraded downstream target genes ( MMP-2 and TNF-α) in activated LX2. Overexpressing TTP had the same effects as small interfering RNA-lincSCRG1 (si- lincSCRG1), whereas knockdown of TTP had reversal effects on si- lincSCRG1 in activated LX2. In summary, linc-SCRG1 reduced TTP and restricted its degradation of target genes TNF-α and MMP-2. Therefore, linc-SCRG1 had a repressing TTP-elicited inactivation effect on hepatic stellate cell (HSC) phenotypes. Inhibition of linc-SCRG1 may be a novel therapeutic approach to inactivate HSCs and extenuate human liver fibrosis.-Wu, J.-C., Luo, S.-Z., Liu, T., Lu, L.-G., Xu, M.-Y. linc-SCRG1 accelerates liver fibrosis by decreasing RNA-binding protein tristetraprolin.
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Affiliation(s)
- Jun-Cheng Wu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sheng-Zheng Luo
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ting Liu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lun-Gen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming-Yi Xu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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23
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Feng M, Ding J, Wang M, Zhang J, Zhu X, Guan W. Kupffer-derived matrix metalloproteinase-9 contributes to liver fibrosis resolution. Int J Biol Sci 2018; 14:1033-1040. [PMID: 29989076 PMCID: PMC6036732 DOI: 10.7150/ijbs.25589] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Accepted: 05/03/2018] [Indexed: 02/07/2023] Open
Abstract
Kupffer cells (KCs) contribute to liver fibrosis resolution by production of a large spectrum of matrix metalloproteinases (MMPs). MMP9 is a major MMP expressed by KCs. However, its role in liver fibrosis resolution remains unclear. In this study, rodent liver fibrosis was induced by intraperitoneal thioacetamide (TAA) and the resolution process was initiated by TAA withdrawal. The role of KC-derived MMP9 in fibrolysis was investigated by adoptive transfer of KCs with or without MMP9 following their depletion. The levels of serum alanine aminotransferase (ALT) and hepatic cytokines were measured during fibrosis regression. The mRNA levels of MMPs and tissue inhibitor of metalloproteinases (TIMPs) were analyzed as well. It was found that removing KCs delayed fibrosis resolution. Adoptive transfer of KCs from WT animals promoted liver fibrosis resolution, compared with transfer of KCs from MMP9-/- mice. Depletion of KCs also resulted in prolonged liver wound healing, which was reversed partially by transferred KCs from either WT or MMP9-/- mice. Likewise, the absence of KCs led to reduction in MMPs mRNA levels and elevation in TIMPs mRNA levels. The expression patterns of MMPs or TIMPs were restored by adoptive transfer of the wild-type but not MMP9-/- KCs. In addition, liver fibrosis resolution was accelerated in MMP9-/- mice by adoptive transferred KCs from WT animals, compared to the KCs from MMP9-/- mice. Overall, KC-derived MMP9 plays a critical role in fibrosis resolution, which might serve as the foundation for developing anti-fibrosis therapy.
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Affiliation(s)
- Min Feng
- Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Jie Ding
- Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Min Wang
- Department of General Surgery, the Affiliated Hospital of Yangzhou University Medical School, Yangzhou 225001, China
| | - Jie Zhang
- Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.,Department of General Surgery, the Affiliated Hospital of Yangzhou University Medical School, Yangzhou 225001, China
| | - Xinhua Zhu
- Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Wenxian Guan
- Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
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24
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Russell‐Hallinan A, Watson CJ, Baugh JA. Epigenetics of Aberrant Cardiac Wound Healing. Compr Physiol 2018; 8:451-491. [DOI: 10.1002/cphy.c170029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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25
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Duong TE, Hagood JS. Epigenetic Regulation of Myofibroblast Phenotypes in Fibrosis. CURRENT PATHOBIOLOGY REPORTS 2018; 6:79-96. [PMID: 30271681 DOI: 10.1007/s40139-018-0155-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Purpose of Review Myofibroblasts are the fundamental drivers of fibrosing disorders; there is great value in better defining epigenetic networks involved in myofibroblast behavior. Complex epigenetic paradigms, which are likely organ and/or disease specific, direct pathologic myofibroblast phenotypes. In this review, we highlight epigenetic regulators and the mechanisms through which they shape myofibroblast phenotype in fibrotic diseases of different organs. Recent Findings Hundreds of genes and their expression contribute to the myofibroblast transcriptional regime influencing myofibroblast phenotype. An increasingly large number of epigenetic modifications have been identified in the regulation of these signaling pathways driving myofibroblast activation and disease progression. Drugs that inhibit or reverse profibrotic epigenetic modifications have shown promise in vitro and in vivo; however, no current epigenetic therapies have been approved to treat fibrosis. Newly described epigenetic mechanisms will be mentioned, along with potential therapeutic targets and innovative strategies to further understand myofibroblast-directed fibrosis. Summary Epigenetic regulators that direct myofibroblast behavior and differentiation into pathologic myofibroblast phenotypes in fibrotic disorders comprise both overlapping and organ-specific epigenetic mechanisms.
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Affiliation(s)
- Thu Elizabeth Duong
- Division of Pediatric Respiratory Medicine, University of California-San Diego, La Jolla, California.,Division of Respiratory Medicine, Rady Children's Hospital of San Diego, San Diego, California
| | - James S Hagood
- Division of Pediatric Respiratory Medicine, University of California-San Diego, La Jolla, California.,Division of Respiratory Medicine, Rady Children's Hospital of San Diego, San Diego, California
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26
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Zhao SQ, Xue ZZ, Wang LZ. HMGB1, TGF-β and NF-κB are associated with chronic allograft nephropathy. Exp Ther Med 2017; 14:6138-6146. [PMID: 29285170 DOI: 10.3892/etm.2017.5319] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 03/03/2017] [Indexed: 12/18/2022] Open
Abstract
The present study aimed to investigate the association between high mobility group protein B1 (HMGB1), transforming growth factor-β1 (TGF-β1), nuclear factor-κB (NF-κB) and chronic allograft nephropathy (CAN) and to identify the clinical significance of HMGB1, TGF-β1, NF-κB on patients with CAN. Between September 2012 and November 2014, 27 patients with CAN diagnosed by biopsy were enrolled in the present study and a further 30 patients that underwent nephrectomy following trauma were selected as the control group. Immunohistochemical staining with HMGB1, TGF-β1 and NF-κB expression in the renal tissues, and western blot analysis were used to measure the relative expression of HMGB1, TGF-β1 and NF-κB. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to estimate the relative expression of HMGB1, TGF-β1 and NF-κB mRNA. Statistical analysis was used to calculate the association between HMGB1, TGF-β1 and NF-κB expression and CAN grade. Immunohistochemical staining demonstrated that HMGB1, TGF-β1 and NF-κB had markedly positive expression rates in renal tubular epithelial cell cytoplasm and membranes in CAN renal tissues, and the positive rates of HMGB1, TGF-β1 and NF-κB increased with the aggravation of CAN pathological grade (I, II and III). The results of western blot analysis indicated that the expression levels of HMGB1, TGF-β1 and NF-κB were significantly higher in the CAN group, compared with the normal group (P<0.05), and the expression levels increased with the progression of CAN grade. A positive association among HMGB1, TGF-β1 and NF-κB expression was identified. RT-qPCR analysis demonstrated that the expression of HMGB1, TGF-β1 and NF-κB mRNA in the CAN group was significantly higher than in the normal group (P<0.05), and the relative expression level of HMGB1, TGF-β1 and NF-κB mRNA not only increased with the aggravation of CAN grade, but was also positively associated with the expression of HMGB1, TGF-β1 and NF-κB, respectively. The abnormal expression of HMGB1, TGF-β1 and NF-κB is therefore, an important manifestation of CAN and the expression of HMGB1, TGF-β1 and NF-κB mRNA in the renal tissues are significantly associated with CAN pathological progression. HMGB1, TGF-β1 and NF-κB may form a signaling pathway that leads to the occurrence of CAN, which induces renal interstitial fibrosis.
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Affiliation(s)
- Shi-Qi Zhao
- Emergency Intensive Care Unit, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
| | - Zhen-Zhen Xue
- Emergency Intensive Care Unit, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
| | - Ling-Zhang Wang
- Emergency Intensive Care Unit, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
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27
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Li M, Zheng Y, Yuan H, Liu Y, Wen X. Effects of dynamic changes in histone acetylation and deacetylase activity on pulmonary fibrosis. Int Immunopharmacol 2017; 52:272-280. [PMID: 28961490 DOI: 10.1016/j.intimp.2017.09.020] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 09/10/2017] [Accepted: 09/19/2017] [Indexed: 11/24/2022]
Abstract
OBJECTIVE Histone deacetylases (HDACs) play an important role in dysregulation of histone acetylation/deacetylation, which is the main driving force of the progression of pulmonary fibrosis. Here we investigated the changes in histone acetylation/deacetylation, and the contribution of specific class I and class II HDACs in the progression of pulmonary fibrosis. METHODS Male C57BL/6J mice received a single dose of tracheal administration of bleomycin to establish the pulmonary fibrosis model. The changes in acetylation rate of histone 3 (H3) and histone 4 (H4), and the activity of HDAC2 and HDAC4 in the lung tissue during the progression from alveolitis to pulmonary fibrosis were measured. RESULTS The acetylation rate of H3/H4 significantly decreased during alveolitis and the early and middle stages of fibrosis, but restored in the late stage of fibrosis. Correlation analysis showed that H4 deacetylation affected both alveolitis and pulmonary fibrosis. H3 deacetylation only affected alveolitis. HDAC2 activity significantly increased in the middle and late stages of pulmonary fibrosis. There was no significant difference in HDAC4 activity between bleomycin and saline groups. However, HDAC4 activity changed significantly with the progression of the disease in bleomycin group. The changes in HDAC2 and HDAC4 activity were different. HDAC2 had long-lasting effects, while HDAC4 had transient effects. Correlation analysis showed that HDAC2 and HDAC4 activity was positively correlated with alveolitis score and fibrosis score. CONCLUSIONS The changes in histone acetylation may directly regulate the gene expression of inflammatory cytokines/fibronectin and thus affect the progression of pulmonary fibrosis. The injury-induced histone deacetylation switched into acetylation at the late stage of pulmonary fibrosis, which may be involved in the repair process. HDAC2 is mainly involved in the chronic progression of pulmonary fibrosis, and HDAC4 is mainly involved in early stress response to pulmonary fibrosis.
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Affiliation(s)
- Mingwei Li
- Department of Rheumatology and Immunology, Fu Xing Hospital, Capital Medical University, China
| | - Yi Zheng
- Department of Rheumatology and Immunology, Beijing Chao-Yang Hospital, Capital Medical University, China.
| | - Huihui Yuan
- Department of Immunology, School of Basic Medical Science, Capital Medical University, China
| | - Yuan Liu
- Department of Rheumatology, First Affiliated Hospital of Baotou Medical College, Baotou, Inner Mongolia 014010, China
| | - Xiaohong Wen
- Department of Rheumatology and Immunology, Beijing Chao-Yang Hospital, Capital Medical University, China
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28
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Are targeted therapies for diabetic cardiomyopathy on the horizon? Clin Sci (Lond) 2017; 131:897-915. [PMID: 28473471 DOI: 10.1042/cs20160491] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 02/02/2017] [Accepted: 02/03/2017] [Indexed: 12/12/2022]
Abstract
Diabetes increases the risk of heart failure approximately 2.5-fold, independent of coronary artery disease and other comorbidities. This process, termed diabetic cardiomyopathy, is characterized by initial impairment of left ventricular (LV) relaxation followed by LV contractile dysfunction. Post-mortem examination reveals that human diastolic dysfunction is closely associated with LV damage, including cardiomyocyte hypertrophy, apoptosis and fibrosis, with impaired coronary microvascular perfusion. The pathophysiological mechanisms underpinning the characteristic features of diabetic cardiomyopathy remain poorly understood, although multiple factors including altered lipid metabolism, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, inflammation, as well as epigenetic changes, are implicated. Despite a recent rise in research interrogating these mechanisms and an increased understanding of the clinical importance of diabetic cardiomyopathy, there remains a lack of specific treatment strategies. How the chronic metabolic disturbances observed in diabetes lead to structural and functional changes remains a pertinent question, and it is hoped that recent advances, particularly in the area of epigenetics, among others, may provide some answers. This review hence explores the temporal onset of the pathological features of diabetic cardiomyopathy, and their relative contribution to the resultant disease phenotype, as well as both current and potential therapeutic options. The emergence of glucose-optimizing agents, namely glucagon-like peptide-1 (GLP-1) agonists and sodium/glucose co-transporter (SGLT)2 inhibitors that confer benefits on cardiovascular outcomes, together with novel experimental approaches, highlight a new and exciting era in diabetes research, which is likely to result in major clinical impact.
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Oksala N, Seppälä I, Rahikainen R, Mäkelä KM, Raitoharju E, Illig T, Klopp N, Kholova I, Laaksonen R, Karhunen P, Hytönen V, Lehtimäki T. Synergistic Expression of Histone Deacetylase 9 and Matrix Metalloproteinase 12 in M4 Macrophages in Advanced Carotid Plaques. Eur J Vasc Endovasc Surg 2017; 53:632-640. [DOI: 10.1016/j.ejvs.2017.02.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 02/09/2017] [Indexed: 01/16/2023]
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30
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Lelièvre SA, Kwok T, Chittiboyina S. Architecture in 3D cell culture: An essential feature for in vitro toxicology. Toxicol In Vitro 2017; 45:287-295. [PMID: 28366709 DOI: 10.1016/j.tiv.2017.03.012] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 03/20/2017] [Accepted: 03/28/2017] [Indexed: 01/06/2023]
Abstract
Three-dimensional cell culture has the potential to revolutionize toxicology studies by allowing human-based reproduction of essential elements of organs. Beyond the study of toxicants on the most susceptible organs such as liver, kidney, skin, lung, gastrointestinal tract, testis, heart and brain, carcinogenesis research will also greatly benefit from 3D cell culture models representing any normal tissue. No tissue function can be suitably reproduced without the appropriate tissue architecture whether mimicking acini, ducts or tubes, sheets of cells or more complex cellular organizations like hepatic cords. In this review, we illustrate the fundamental characteristics of polarity that is an essential architectural feature of organs for which different 3D cell culture models are available for toxicology studies in vitro. The value of tissue polarity for the development of more accurate carcinogenesis studies is also exemplified, and the concept of using extracellular gradients of gaseous or chemical substances produced with microfluidics in 3D cell culture is discussed. Indeed such gradients-on-a-chip might bring unprecedented information to better determine permissible exposure levels. Finally, the impact of tissue architecture, established via cell-matrix interactions, on the cell nucleus is emphasized in light of the importance in toxicology of morphological and epigenetic alterations of this organelle.
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Affiliation(s)
- Sophie A Lelièvre
- Purdue University, Department of Basic Medical Sciences, 625 Harrison Street, West Lafayette, IN 47907, USA; 3D Cell Culture Core (3D3C) Facility, Birck Nanotechnology Center, Purdue University Discovery Park, 1205 West State Street, West Lafayette, IN 47907, USA; Purdue University Center for Cancer Research, 201 S University Street, West Lafayette, IN 47907, USA.
| | - Tim Kwok
- 3D Cell Culture Core (3D3C) Facility, Birck Nanotechnology Center, Purdue University Discovery Park, 1205 West State Street, West Lafayette, IN 47907, USA
| | - Shirisha Chittiboyina
- Purdue University, Department of Basic Medical Sciences, 625 Harrison Street, West Lafayette, IN 47907, USA; 3D Cell Culture Core (3D3C) Facility, Birck Nanotechnology Center, Purdue University Discovery Park, 1205 West State Street, West Lafayette, IN 47907, USA
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31
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Yang Z, Liu Y, Qin L, Wu P, Xia Z, Luo M, Zeng Y, Tsukamoto H, Ju Z, Su D, Kang H, Xiao Z, Zheng S, Duan Z, Hu R, Wang Q, Pandol SJ, Han YP. Cathepsin H-Mediated Degradation of HDAC4 for Matrix Metalloproteinase Expression in Hepatic Stellate Cells: Implications of Epigenetic Suppression of Matrix Metalloproteinases in Fibrosis through Stabilization of Class IIa Histone Deacetylases. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:781-797. [PMID: 28157489 DOI: 10.1016/j.ajpath.2016.12.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 11/30/2016] [Accepted: 12/08/2016] [Indexed: 12/24/2022]
Abstract
In three-dimensional extracellular matrix, mesenchymal cells including hepatic stellate cells (HSCs) gain the ability to express matrix metalloproteinases (MMPs) on injury signals. In contrast, in myofibroblastic HSCs in fibrotic liver, many MMP genes are silenced into an epigenetically nonpermissive state. The mechanism by which the three-dimensional extracellular matrix confers the MMP genes into an epigenetically permissive state has not been well characterized. In continuation of previous work, we show here that the up-regulation of MMP genes is mediated through degradation of class IIa histone deacetylases (HDACs) by certain cysteine cathepsins (Cts). In three-dimensional extracellular matrix culture, CtsH, among other cysteine cathepsins, was up-regulated and localized as puncta in the nuclear and cytoplasmic compartments in a complex with HDAC4 for its degradation. Conversely, along with HSC trans-differentiation, CtsH and CtsL were progressively down-regulated, whereas HDAC4 was concurrently stabilized. The inhibition of cysteine cathepsins by specific proteinase inhibitors or chloroquine, which raises cellular pH, restored HDAC4. Recombinant CtsH could break down HDAC4 in the transfected cells and in vitro at acidic pH. In human cirrhotic liver, activated HSCs express high levels of class IIa HDACs but little CtsH. We propose that cysteine cathepsin-mediated degradation of class IIa HDACs plays a key role in the modulation of MMP expression/suppression and HSC functions in tissue injury and fibrosis.
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Affiliation(s)
- Zemin Yang
- The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China
| | - Yu Liu
- The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China
| | - Lan Qin
- Department of Surgery, University of Southern California, Los Angeles, California
| | - Pengfei Wu
- The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China
| | - Zanxian Xia
- State Key Laboratory of Medical Genetics & School of Life Sciences, Central South University, Changsha, China
| | - Mei Luo
- The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China; Chengdu Public Health Clinical Center, Chengdu, China
| | - Yilan Zeng
- Chengdu Public Health Clinical Center, Chengdu, China
| | - Hidekazu Tsukamoto
- Department of Surgery, University of Southern California, Los Angeles, California
| | - Zongyun Ju
- Chengdu Tongde Pharmaceutical Co. Ltd., Chengdu, China
| | - Danmei Su
- The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China
| | - Han Kang
- The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China
| | - Zhixiong Xiao
- The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China
| | - Sujun Zheng
- Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhongping Duan
- Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Richard Hu
- Olive View-UCLA Medical Center, Los Angeles, California
| | - Qiang Wang
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Stephen J Pandol
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Yuan-Ping Han
- The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
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El Taghdouini A, van Grunsven LA. Epigenetic regulation of hepatic stellate cell activation and liver fibrosis. Expert Rev Gastroenterol Hepatol 2016; 10:1397-1408. [PMID: 27762150 DOI: 10.1080/17474124.2016.1251309] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Chronic liver injury to hepatocytes or cholangiocytes, when left unmanaged, leads to the development of liver fibrosis, a condition characterized by the excessive intrahepatic deposition of extracellular matrix proteins. Activated hepatic stellate cells constitute the predominant source of extracellular matrix in fibrotic livers and their transition from a quiescent state during fibrogenesis is associated with important alterations in their transcriptional and epigenetic landscape. Areas covered: We briefly describe the processes involved in hepatic stellate cell activation and discuss our current understanding of alterations in the epigenetic landscape, i.e DNA methylation, histone modifications and the functional role of non-coding RNAs that accompany this key event in the development of chronic liver disease. Expert commentary: Although great progress has been made, our understanding of the epigenetic regulation of hepatic stellate cell activation is limited and, thus far, insufficient to allow the development of epigenetic drugs that can selectively interrupt liver fibrosis.
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Affiliation(s)
- Adil El Taghdouini
- a Institut de Recherche Expérimentale et Clinique (IREC), Laboratory of Pediatric Hepatology and Cell Therapy , Université Catholique de Louvain , Brussels , Belgium.,b Liver Cell Biology Laboratory , Vrije Universiteit Brussel (VUB) , Brussels , Belgium
| | - Leo A van Grunsven
- b Liver Cell Biology Laboratory , Vrije Universiteit Brussel (VUB) , Brussels , Belgium
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Chaturvedi P, Tyagi SC. Epigenetic silencing of TIMP4 in heart failure. J Cell Mol Med 2016; 20:2089-2101. [PMID: 27396717 PMCID: PMC5082395 DOI: 10.1111/jcmm.12901] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 05/10/2016] [Indexed: 12/19/2022] Open
Abstract
Tissue inhibitor of matrix metalloprotease 4 (TIMP4) is endogenously one of the key modulators of matrix metalloprotease 9 (MMP9) and we have reported earlier that cardiac specific TIMP4 instigates contractility and helps in differentiation of cardiac progenitor cells. Although studies show that the expression of TIMP4 goes down in heart failure but the mechanism is unknown. This study aims to determine the mechanism of silencing of TIMP4 in heart failure progression created by aorta-vena cava (AV) fistula. We hypothesize that there is epigenetic silencing of TIMP4 in heart failure. To validate this hypothesis, we created heart failure model by creating AV fistula in C57BL/6 mice and looked into the promoter methylation (methylation specific PCR, high resolution melting, methylation sensitive restriction enzyme and Na bisulphite treatment followed by sequencing), histone modification (ChIP assay) and microRNAs that regulate TIMP4 (mir122a) and MMP9 (mir29b and mir455-5p). The physiological parameters in terms of cardiac function after AV fistula were assessed by echocardiography. We observed that there are 7 CpG islands in the TIMP4 promoter which get methylated during the progression of heart failure which leads to its epigenetic silencing. In addition, the up-regulated levels of mir122a in part, contribute to regulation of TIMP4. Consequently, MMP9 gets up-regulated and leads to cardiac remodeling. This is a novel report to explain the epigenetic silencing of TIMP4 in heart failure.
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Affiliation(s)
- Pankaj Chaturvedi
- Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY, USA.
| | - Suresh C Tyagi
- Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY, USA
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Epigenetics in fibrosis. Mol Aspects Med 2016; 54:89-102. [PMID: 27720780 DOI: 10.1016/j.mam.2016.10.001] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 09/29/2016] [Accepted: 10/04/2016] [Indexed: 12/16/2022]
Abstract
Fibrosis is a common and important disease. It is a pathological state due to excessive scar formation mediated by an increase in activated fibroblasts that express alpha smooth muscle actin and copious amounts of extracellular matrix molecules. Epigenetics is an area of research that encompasses three main mechanisms: methylation, histone modifications to the tails of histones and also non-coding RNAs including long and short non-coding RNAs. These three mechanisms all seek to regulate gene expression without a change in the underlying DNA sequence. In recent years an explosion of research, aided by deep sequencing technology becoming available, has demonstrated a role for epigenetics in fibrosis, either organ specific like lung fibrosis or more widespread as in systemic sclerosis. While the great majority of epigenetic work in fibrosis is centered on histone codes, more recently the non-coding RNAs have been examined in greater detail. It is known that one modification can affect the other and cross-talk among all three adds a new layer of complexity. This review aims to examine the role of epigenetics in fibrosis, evaluating all three mechanisms, and to suggest possible areas where epigenetics could be targeted therapeutically.
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Guerra S, Mamede AC, Carvalho MJ, Laranjo M, Tralhão JG, Abrantes AM, Maia CJ, Botelho MF. Liver diseases: what is known so far about the therapy with human amniotic membrane? Cell Tissue Bank 2016; 17:653-663. [PMID: 27550013 DOI: 10.1007/s10561-016-9579-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Accepted: 08/13/2016] [Indexed: 01/20/2023]
Abstract
Liver, the largest intern organ of the human body, is responsible for several vital tasks such as digestive and excretory functions, as well as for nutrients storage and metabolic functions, synthesis of new molecules and purification of toxic chemicals. Cirrhosis, fibrosis and hepatocellular carcinoma are the most prevalent liver diseases. Despite all the studies performed so far, treatment options for these diseases are very limited. For this reason, it is urgent to find effective therapies for these pathologies. Several studies have been performed during the last decade about the possible application of human amniotic membrane in hepatic diseases therapy. Promising results about human amniotic membrane or its derived cells, in vitro and in vivo, applications in fibrosis, cirrhosis and hepatocellular carcinoma were already published. Since it is an attractive study area, it is becoming a dynamic scientific subject. However, the action mechanisms of human amniotic membrane and its derived cells in hepatic diseases therapy must be precisely known in order that this promising therapy could be clinically used.
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Affiliation(s)
- Sara Guerra
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba - Celas, 3000-548, Coimbra, Portugal
| | - Ana Catarina Mamede
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba - Celas, 3000-548, Coimbra, Portugal. .,CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal. .,CIMAGO, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. .,CNC.IBILI, University of Coimbra, Coimbra, Portugal.
| | - Maria João Carvalho
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba - Celas, 3000-548, Coimbra, Portugal.,CIMAGO, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,CNC.IBILI, University of Coimbra, Coimbra, Portugal.,Obstetrics Service, Coimbra Hospital and University Centre, Coimbra, Portugal
| | - Mafalda Laranjo
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba - Celas, 3000-548, Coimbra, Portugal.,CIMAGO, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,CNC.IBILI, University of Coimbra, Coimbra, Portugal
| | - José Guilherme Tralhão
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba - Celas, 3000-548, Coimbra, Portugal.,CIMAGO, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Surgical Department A, Coimbra Hospital and University Centre, Coimbra, Portugal
| | - Ana Margarida Abrantes
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba - Celas, 3000-548, Coimbra, Portugal.,CIMAGO, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,CNC.IBILI, University of Coimbra, Coimbra, Portugal
| | - Cláudio Jorge Maia
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Maria Filomena Botelho
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba - Celas, 3000-548, Coimbra, Portugal.,CIMAGO, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,CNC.IBILI, University of Coimbra, Coimbra, Portugal
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Li X, Wu XQ, Xu T, Li XF, Yang Y, Li WX, Huang C, Meng XM, Li J. Role of histone deacetylases(HDACs) in progression and reversal of liver fibrosis. Toxicol Appl Pharmacol 2016; 306:58-68. [PMID: 27396813 DOI: 10.1016/j.taap.2016.07.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 06/19/2016] [Accepted: 07/06/2016] [Indexed: 01/10/2023]
Abstract
Liver fibrosis refers to a reversible wound healing process response to chronic liver injuries. Activation of hepatic stellate cells (HSCs) is closely correlated with the development of liver fibrosis. Histone deacetylases(HDACs) determine the acetylation levels of core histones to modulate expression of genes. To demonstrate the link between HDACs and liver fibrosis, CCl4-induced mouse liver fibrosis model and its spontaneous reversal model were established. Results of the current study demonstrated that deregulation of liver HDACs may involved in the development of liver fibrosis. Among 11 HDACs tested in our study (Class I, II, and IV HDACs), expression of HDAC2 was maximally increased in CCl4-induced fibrotic livers but decreased after spontaneous recovery. Moreover, expression of HDAC2 was elevated in human liver fibrotic tissues. In this regard, the potential role of HDAC2 in liver fibrosis was further evaluated. Our results showed that administration of HSC-T6 cells with transforming growth factor-beta1 (TGF-β1) resulted in an increase of HDAC2 protein expression in dose- and time-dependent manners. Moreover, HDAC2 deficiency inhibited HSC-T6 cell proliferation and activation induced by TGF-β1. More importantly, the present study showed HDAC2 may regulate HSCs activation by suppressing expression of Smad7, which is a negative modulator in HSCs activation and liver fibrosis. Collectively, these observations revealed that HDAC2 may play a pivotal role in HSCs activation and liver fibrosis while deregulation of HDACs may serve as a novel mechanism underlying liver fibrosis.
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Affiliation(s)
- Xing Li
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China
| | - Xiao-Qin Wu
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China
| | - Tao Xu
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China
| | - Xiao-Feng Li
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China
| | - Yang Yang
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China
| | - Wan-Xia Li
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China
| | - Cheng Huang
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China
| | - Xiao-Ming Meng
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China.
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Arteaga M, Shang N, Ding X, Yong S, Cotler SJ, Denning MF, Shimamura T, Breslin P, Lüscher B, Qiu W. Inhibition of SIRT2 suppresses hepatic fibrosis. Am J Physiol Gastrointest Liver Physiol 2016; 310:G1155-68. [PMID: 27125275 PMCID: PMC4935480 DOI: 10.1152/ajpgi.00271.2015] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 04/20/2016] [Indexed: 01/31/2023]
Abstract
Liver fibrosis can progress to cirrhosis and result in serious complications of liver disease. The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs), the underlying mechanisms of which are not fully known. Emerging evidence suggests that the classic histone deacetylases play a role in liver fibrosis, but the role of another subfamily of histone deacetylases, the sirtuins, in the development of hepatic fibrosis remains unknown. In this study, we found that blocking the activity of sirtuin 2 (SIRT2) by using inhibitors or shRNAs significantly suppressed fibrogenic gene expression in HSCs. We further demonstrated that inhibition of SIRT2 results in the degradation of c-MYC, which is important for HSC activation. In addition, we discovered that inhibition of SIRT2 suppresses the phosphorylation of ERK, which is critical for the stabilization of c-MYC. Moreover, we found that Sirt2 deficiency attenuates the hepatic fibrosis induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). Furthermore, we showed that SIRT2, p-ERK, and c-MYC proteins are all overexpressed in human hepatic fibrotic tissues. These data suggest a critical role for the SIRT2/ERK/c-MYC axis in promoting hepatic fibrogenesis. Inhibition of the SIRT2/ERK/c-MYC axis represents a novel strategy to prevent and to potentially treat liver fibrosis and cirrhosis.
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Affiliation(s)
| | | | | | | | | | | | | | - Peter Breslin
- 5Molecular/Cellular Physiology, Oncology Institute, Loyola University Chicago, Maywood, Illinois; and
| | - Bernhard Lüscher
- 6Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany
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Nwosu ZC, Alborzinia H, Wölfl S, Dooley S, Liu Y. Evolving Insights on Metabolism, Autophagy, and Epigenetics in Liver Myofibroblasts. Front Physiol 2016; 7:191. [PMID: 27313533 PMCID: PMC4887492 DOI: 10.3389/fphys.2016.00191] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 05/12/2016] [Indexed: 12/14/2022] Open
Abstract
Liver myofibroblasts (MFB) are crucial mediators of extracellular matrix (ECM) deposition in liver fibrosis. They arise mainly from hepatic stellate cells (HSCs) upon a process termed “activation.” To a lesser extent, and depending on the cause of liver damage, portal fibroblasts, mesothelial cells, and fibrocytes may also contribute to the MFB population. Targeting MFB to reduce liver fibrosis is currently an area of intense research. Unfortunately, a clog in the wheel of antifibrotic therapies is the fact that although MFB are known to mediate scar formation, and participate in liver inflammatory response, many of their molecular portraits are currently unknown. In this review, we discuss recent understanding of MFB in health and diseases, focusing specifically on three evolving research fields: metabolism, autophagy, and epigenetics. We have emphasized on therapeutic prospects where applicable and mentioned techniques for use in MFB studies. Subsequently, we highlighted uncharted territories in MFB research to help direct future efforts aimed at bridging gaps in current knowledge.
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Affiliation(s)
- Zeribe C Nwosu
- Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg Mannheim, Germany
| | - Hamed Alborzinia
- Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg Heidelberg, Germany
| | - Stefan Wölfl
- Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg Heidelberg, Germany
| | - Steven Dooley
- Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg Mannheim, Germany
| | - Yan Liu
- Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg Mannheim, Germany
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Feng M, Wang Q, Jiang Z, Ding J, Wang H, Wang M, Lu L, Guan W. Adoptive transferred hepatic stellate cells attenuated drug-induced liver injury by modulating the rate of regulatory T cells/T helper 17 cells. Clin Immunol 2016; 165:12-8. [DOI: 10.1016/j.clim.2016.02.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2015] [Revised: 02/15/2016] [Accepted: 02/16/2016] [Indexed: 12/26/2022]
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Zhang X, Feng M, Liu X, Bai L, Kong M, Chen Y, Zheng S, Liu S, Wan YJY, Duan Z, Han YP. Persistence of cirrhosis is maintained by intrahepatic regulatory T cells that inhibit fibrosis resolution by regulating the balance of tissue inhibitors of metalloproteinases and matrix metalloproteinases. Transl Res 2016; 169:67-79.e1-2. [PMID: 26613891 DOI: 10.1016/j.trsl.2015.10.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 10/07/2015] [Accepted: 10/29/2015] [Indexed: 12/26/2022]
Abstract
Fibrosis is the result of the abnormal accumulation of the extracellular matrix and ineffective clearance of fibroplasia. CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are immunosuppressive lymphocytes that are highly expressed in the fibrotic tissues and peripheral blood of patients with cirrhosis or hepatocellular carcinoma. The role of Tregs in the progression of liver fibrosis is not well understood. Our experiments reveal that abundant of Tregs was scattered around sites of fibroplasia. Conversely, the depletion of Tregs promoted the resolution of liver fibrosis. As a consequence of Tregs depletion, the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) was altered; mmp9 and timp1 were reduced, whereas mmp2 and mmp14 were enhanced. The mmp9/timp1, mmp13/timp1, and mmp14/timp2 ratios were significantly increased in association with fibrosis resolution. Kupffer cells (KCs) are the main source of MMP. We observed that when KCs were cocultured with Tregs, the Tregs were able to inhibit MMP expression of KCs even at a low ratio; and anti-transforming growth factor-β (TGF-β) significantly reversed the inhibition of Tregs on MMP. Meanwhile, we also found that after Tregs depletion, TGF-β levels decreased in the mice liver, unlike in fibrosis. Furthermore, double depletion of both KCs and Tregs did not cause fiber resolution in mice. Thus, our results demonstrate that the persistence of liver cirrhosis is maintained by increased Tregs in the sites of fibroplasia and the subsequent regulation of the MMP/TIMP balance and that the suppression of KC-mediated MMP expression contributed to the regulatory process.
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Affiliation(s)
- Xiaohui Zhang
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Min Feng
- Department of Liver Transplantation, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Xin Liu
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Li Bai
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Ming Kong
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Yu Chen
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Sujun Zheng
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Shuang Liu
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Yu-Jui Yvonne Wan
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento, Calif
| | - Zhongping Duan
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
| | - Yuan-Ping Han
- The Center for Growth, Metabolism and Aging, The Key Laboratory for Bio-Resource and Eco-Environment, College of Life Science, and The National Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
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Abstract
INTRODUCTION Peyronie disease (PD) is a progressive fibrotic disorder of the penile tunica albuginea that results in fibrotic penile plaques and can lead to penile deformity. Characterized by aberrant fibrosis resulting in part from the persistence of myofibroblasts and altered gene expression, the molecular factors underpinning PD and other related fibrotic diatheses are just being elucidated. A genetic link to PD was first identified three decades ago using pedigree analyses. However, the specific genetic factors that predispose patients to aberrant fibrosis remain unknown, and the relations between these fibrotic conditions and other heritable diseases, including malignancy, are uncharacterized. AIM To review the current landscape linking molecular and genetic factors to aberrant fibrosis in PD and related fibrotic diatheses, including Dupuytren disease. METHODS Review and evaluation of the literature from 1970 to the present for genetic factors associated with PD were performed. MAIN OUTCOME MEASURES Data describing the genetic factors associated with PD were obtained. RESULTS We describe the known structural chromosomal abnormalities and single-nucleotide polymorphisms associated with fibrotic diatheses and discuss the spectrum of differential gene expression data comparing normal tissues with those derived from men with PD or Dupuytren disease. We discuss epigenetic mechanisms that might regulate gene expression and alter predisposition to fibrosis. CONCLUSION Although the current understanding of the genetic factors associated with PD is limited, significant advances have been made during the past three decades. Further research is necessary to provide a more comprehensive understanding of the landscape of genetic factors responsible for the development of PD.
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Yang JJ, Tao H, Deng ZY, Lu C, Li J. Non-coding RNA-mediated epigenetic regulation of liver fibrosis. Metabolism 2015; 64:1386-94. [PMID: 26362725 DOI: 10.1016/j.metabol.2015.08.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 07/06/2015] [Accepted: 08/08/2015] [Indexed: 12/27/2022]
Abstract
Hepatic stellate cells (HSC) activation plays a key role in liver fibrosis. Numerous studies have indicated that non-coding RNAs (ncRNAs) control liver fibrosis and fibroblasts proliferation. Greater knowledge of the role of the ncRNAs-mediated epigenetic mechanism in liver fibrosis could improve understanding of the liver fibrosis pathogenesis. The aim of this review is to describe the present knowledge about the ncRNAs significantly participating in liver fibrosis and HSC activation, and look ahead on new perspectives of ncRNAs-mediated epigenetic mechanism research. Moreover, we will discuss examples of non-coding RNAs that interact with histone modification or DNA methylation to regulate gene expression in liver fibrosis. Diverse classes of ncRNAs, ranging from microRNAs (miRs) to long non-coding RNAs (LncRNAs), have emerged as key regulators of several important aspects of function, including cell proliferation, activation, etc. In addition, recent advances suggest the important role of ncRNAs transcripts in epigenetic gene regulation. Targeting the miRs and LncRNAs can be a promising direction in liver fibrosis treatment. We discuss new perspectives of miRs and LncRNAs in liver fibrosis and HSC activation, mainly including interaction with histone modification or DNA methylation to regulate gene expression. These epigenetic mechanisms form powerful ncRNAs surveillance systems that may represent new targets for liver fibrosis therapeutic intervention.
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Affiliation(s)
- Jing-Jing Yang
- Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China, 230601
| | - Hui Tao
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, China, 230601
| | - Zi-Yu Deng
- Department of Scientific and Educational, The Second Hospital of Anhui Medical University, Hefei, China, 230601.
| | - Chao Lu
- Department of Scientific and Educational, The Second Hospital of Anhui Medical University, Hefei, China, 230601
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei, China, 230032.
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Craig VJ, Zhang L, Hagood JS, Owen CA. Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 2015; 53:585-600. [PMID: 26121236 PMCID: PMC4742954 DOI: 10.1165/rcmb.2015-0020tr] [Citation(s) in RCA: 323] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 06/29/2015] [Indexed: 12/14/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high morbidity and mortality. Current medical therapies are not fully effective at limiting mortality in patients with IPF, and new therapies are urgently needed. Matrix metalloproteinases (MMPs) are proteinases that, together, can degrade all components of the extracellular matrix and numerous nonmatrix proteins. MMPs and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the pathogenesis of IPF based upon the results of clinical studies reporting elevated levels of MMPs (including MMP-1, MMP-7, MMP-8, and MMP-9) in IPF blood and/or lung samples. Surprisingly, studies of gene-targeted mice in murine models of pulmonary fibrosis (PF) have demonstrated that most MMPs promote (rather than inhibit) the development of PF and have identified diverse mechanisms involved. These mechanisms include MMPs: (1) promoting epithelial-to-mesenchymal transition (MMP-3 and MMP-7); (2) increasing lung levels or activity of profibrotic mediators or reducing lung levels of antifibrotic mediators (MMP-3, MMP-7, and MMP-8); (3) promoting abnormal epithelial cell migration and other aberrant repair processes (MMP-3 and MMP-9); (4) inducing the switching of lung macrophage phenotypes from M1 to M2 types (MMP-10 and MMP-28); and (5) promoting fibrocyte migration (MMP-8). Two MMPs, MMP-13 and MMP-19, have antifibrotic activities in murine models of PF, and two MMPs, MMP-1 and MMP-10, have the potential to limit fibrotic responses to injury. Herein, we review what is known about the contributions of MMPs and TIMPs to the pathogenesis of IPF and discuss their potential as therapeutic targets for IPF.
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Affiliation(s)
- Vanessa J. Craig
- Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of California–San Diego, La Jolla, California
| | - Li Zhang
- Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts
| | - James S. Hagood
- Division of Pediatric Respiratory Medicine, University of California–San Diego, La Jolla, California, and
- Rady Children’s Hospital of San Diego, San Diego, California; and
| | - Caroline A. Owen
- Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts
- Lovelace Respiratory Research Institute, Albuquerque, New Mexico
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Decoding liver injury: A regulatory role for histone modifications. Int J Biochem Cell Biol 2015; 67:188-93. [DOI: 10.1016/j.biocel.2015.03.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 03/05/2015] [Accepted: 03/11/2015] [Indexed: 01/05/2023]
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Survey of the Literature for September 2015 Issue of Sexual Medicine Journal. Sex Med 2015. [PMCID: PMC4599550 DOI: 10.1002/sm2.87] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Ponnusamy M, Zhuang MA, Zhou X, Tolbert E, Bayliss G, Zhao TC, Zhuang S. Activation of Sirtuin-1 Promotes Renal Fibroblast Activation and Aggravates Renal Fibrogenesis. J Pharmacol Exp Ther 2015; 354:142-51. [PMID: 26022003 PMCID: PMC4518074 DOI: 10.1124/jpet.115.224386] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 05/27/2015] [Indexed: 01/24/2023] Open
Abstract
Although activation of sirtuin-1 (SIRT1) has been shown to protect the kidney from acute injury, its role in renal fibrosis remains controversial since both inhibition and activation of SIRT1 have been reported to attenuate renal fibrosis. To resolve this conflict, we further examined the effect of SIRT1 activators on the activation of renal interstitial fibroblasts and development of renal fibrosis in vivo and in vitro. In a murine model of renal fibrosis induced by unilateral ureteral obstruction, administration of SRT1720 (N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b][1,3]thiazol-6-yl]phenyl]quinoxaline-2-carboxamide), a potent activator of SIRT1, accelerated deposition of collagen fibrils and increased expression of fibroblast activation markers (α-smooth muscle actin [α-SMA], collagen I, and fibronectin) in the obstructive kidney of mice. In cultured rat renal interstitial fibroblasts (NRK-49F), exposure of cells to SRT1720 or YK-3-237 (B-[2-methoxy-5-[(1E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propen-1-yl]phenyl]-boronic acid), another SIRT1 activator, also resulted in enhanced expression of α-SMA and fibronectin. Mechanistic studies showed that augmentation of renal fibrogenesis by SRT1720 is associated with elevated phosphorylation of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor β (PDGFRβ). SRT1720 treatment also increased the phosphorylation of signal transducer and activator of transcription 3 and protein kinase B in the fibrotic kidney and NRK-49F cells. However, SRT1720 treatment did not affect expression of proliferating cell nuclear protein, a proliferation marker and activation of extracellular signal regulated kinase 1/2 in vitro and in vivo. These results indicate that SIRT1-activating compounds can provoke renal fibrogenesis through a mechanism involved in the activation of EGFR and PDGFR signaling pathways and suggest that long-term use of SIRT1 activators risks the development and progression of chronic kidney disease.
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Affiliation(s)
- Murugavel Ponnusamy
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island (M.P., M.A.Z., X.Z., E.T., G.B., S.Z.); Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.); and Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China (S.Z.)
| | - Michelle A Zhuang
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island (M.P., M.A.Z., X.Z., E.T., G.B., S.Z.); Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.); and Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China (S.Z.)
| | - Xiaoxu Zhou
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island (M.P., M.A.Z., X.Z., E.T., G.B., S.Z.); Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.); and Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China (S.Z.)
| | - Evelyn Tolbert
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island (M.P., M.A.Z., X.Z., E.T., G.B., S.Z.); Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.); and Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China (S.Z.)
| | - George Bayliss
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island (M.P., M.A.Z., X.Z., E.T., G.B., S.Z.); Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.); and Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China (S.Z.)
| | - Ting C Zhao
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island (M.P., M.A.Z., X.Z., E.T., G.B., S.Z.); Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.); and Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China (S.Z.)
| | - Shougang Zhuang
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island (M.P., M.A.Z., X.Z., E.T., G.B., S.Z.); Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.); and Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China (S.Z.)
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Wang YG, Xu L, Wang T, Wei J, Meng WY, Wang N, Shi M. Givinostat inhibition of hepatic stellate cell proliferation and protein acetylation. World J Gastroenterol 2015; 21:8326-8339. [PMID: 26217084 PMCID: PMC4507102 DOI: 10.3748/wjg.v21.i27.8326] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 03/02/2015] [Accepted: 05/21/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the effect of the histone deacetylase inhibitor givinostat on proteins related to regulation of hepatic stellate cell proliferation.
METHODS: The cell counting kit-8 assay and flow cytometry were used to observe changes in proliferation, apoptosis, and cell cycle in hepatic stellate cells treated with givinostat. Western blot was used to observe expression changes in p21, p57, CDK4, CDK6, cyclinD1, caspase-3, and caspase-9 in hepatic stellate cells exposed to givinostat. The scratch assay was used to analyze the effect of givinostat on cell migration. Effects of givinostat on the reactive oxygen species profile, mitochondrial membrane potential, and mitochondrial permeability transition pore opening in JS-1 cells were observed by laser confocal microscopy.
RESULTS: Givinostat significantly inhibited JS-1 cell proliferation and promoted cell apoptosis, leading to cell cycle arrest in G0/G1 phases. Treatment with givinostat downregulated protein expression of CDK4, CDK6, and cyclin D1, whereas expression of p21 and p57 was significantly increased. The givinostat-induced apoptosis of hepatic stellate cells was mainly mediated through p38 and extracellular signal-regulated kinase 1/2. Givinostat treatment increased intracellular reactive oxygen species production, decreased mitochondrial membrane potential, and promoted mitochondrial permeability transition pore opening. Acetylation of superoxide dismutase (acetyl K68) and nuclear factor-κB p65 (acetyl K310) was upregulated, while there was no change in protein expression. Moreover, the notable beneficial effect of givinostat on liver fibrosis was also confirmed in the mouse models.
CONCLUSION: Givinostat has antifibrotic activities via regulating the acetylation of nuclear factor-κB and superoxide dismutase 2, thus inhibiting hepatic stellate cell proliferation and inducing apoptosis.
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Epigenetic modifications by histone deacetylases: Biological implications and therapeutic potential in liver fibrosis. Biochimie 2015; 116:61-9. [PMID: 26116886 DOI: 10.1016/j.biochi.2015.06.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 06/20/2015] [Indexed: 01/19/2023]
Abstract
Liver fibrosis is an important pathological repair process in reaction to liver injury characterized by progressive accumulation of extracellular matrix (ECM) components. Mechanism that orchestrates this fibrotic disorder is the activation of hepatic stellate cell (HSC) that requires extensive alterations in gene expression. Reversible deacetylation of histone proteins is one of the most abundant epigenetic modifications and is crucial in modulating gene expression. Recent evidence has highlighted a pathological imbalance between the acetylation and deacetylation of histone proteins regulated by histone deacetylases (HDACs). In the past several years, the role of HDACs in liver fibrosis initiation and progression, as well as the therapeutic effects of HDAC inhibitors, has been well studied. Here, the innovative aspects of histone deacetylation will be presented, with respect to the roles of HDACs in liver fibrosis, the affected genes and signal pathways involved in HSCs activation, as well as significant data emerging from the field in support of HDAC inhibitors as potential therapeutic targets for the treatment of liver fibrosis.
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Attenuation of choroidal neovascularization by histone deacetylase inhibitor. PLoS One 2015; 10:e0120587. [PMID: 25807249 PMCID: PMC4373846 DOI: 10.1371/journal.pone.0120587] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 01/24/2015] [Indexed: 01/13/2023] Open
Abstract
Choroidal neovascularization (CNV) is a blinding complication of age-related macular degeneration that manifests as the growth of immature choroidal blood vessels through Bruch’s membrane, where they can leak fluid or hemorrhage under the retina. Here, we demonstrate that the histone deacetylase inhibitor (HDACi) trichostatin A (TSA) can down-regulate the pro-angiogenic hypoxia-inducible factor-1α and vascular endothelial growth factor (VEGF), and up-regulate the anti-angiogenic and neuro-protective pigment epithelium derived factor in human retinal pigment epithelial (RPE) cells. Most strikingly, TSA markedly down-regulates the expression of VEGF receptor-2 in human vascular endothelial cells and, thus, can knock down pro-angiogenic cell signaling. Additionally, TSA suppresses CNV-associated wound healing response and RPE epithelial-mesenchymal transdifferentiation. In the laser-induced model of CNV using C57Bl/6 mice, systemic administration of TSA significantly reduces fluorescein leakage and the size of CNV lesions at post—laser days 7 and 14 as well as the immunohistochemical expression of VEGF, VEGFR2, and smooth muscle actin in CNV lesions at post-laser day 7. This report suggests that TSA, and possibly HDACi’s in general, should be further evaluated for their therapeutic potential for the treatment of CNV.
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Ti D, Li M, Fu X, Han W. Causes and consequences of epigenetic regulation in wound healing. Wound Repair Regen 2015; 22:305-12. [PMID: 24844330 DOI: 10.1111/wrr.12160] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Accepted: 02/12/2014] [Indexed: 12/19/2022]
Abstract
Wound healing is a complex and systematic tissue level response to mechanical and chemical injuries that may cause the release of growth factors, cytokines, and chemokines by damaged tissues. For the complex features of these restorative processes, it is a crucial challenge to identify the relevant cell types and biochemical pathways that are involved in wound healing. Epigenetic mechanisms, such as DNA methylation, histone modification, and noncoding regulatory RNA editing, play important roles in many biological processes, including cell proliferation, migration and differentiation, signal pathway activation or inhibition, and cell senescence. Epigenetic regulations can coordinately control a considerable subset of known repair genes and thus serve as master regulators of wound healing. An abundance of evidence has also shown that epigenetic modifications participate in the short- and long-term control of crucial gene expression and cell signal transduction that are involved in the healing process. These data provide a foundation for probable epigenetic-based therapeutic strategies that are aimed at stimulating tissue regeneration. This review describes the epigenetic alterations in different cellular types at injury sites, induced signals, and resulting tissue repair. With the increased interest in the epigenetics of wound and repair processes, this field will soon begin to flourish.
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Affiliation(s)
- Dongdong Ti
- Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, China
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