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1
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Yang XY, Chen Z, Tan J, Xue YK, Zheng H. KLF4 Inhibits the Activation of Human Hepatic Stellate Cell In Vitro. Curr Med Sci 2024; 44:512-518. [PMID: 38789819 DOI: 10.1007/s11596-024-2860-8] [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: 01/08/2024] [Accepted: 03/08/2024] [Indexed: 05/26/2024]
Abstract
OBJECTIVE Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis. Early-stage liver fibrosis is reversible and intimately associated with the state of HSCs. Kruppel-like factor 4 (KLF4) plays a pivotal role in a wide array of physiological and pathological processes. This study aimed to investigate the effect of KLF4 on the proliferation, apoptosis and phenotype of quiescent HSCs METHODS: We designed a KLF4 lentiviral vector and a KLF4 siRNA lentiviral vector, to upregulate and silence KLF4 expression in human HSC LX-2 cells via transfection. Cell proliferation was assessed using the CCK-8 assay. Flow cytometry was used to detect the cell cycle distribution and apoptosis rate. Western blotting was used to determine the levels of some quiescence and activation markers of HSCs RESULTS: Overexpression of KLF4 significantly increased the levels of E-cadherin and ZO-1, which are quiescent HSC markers, while significantly decreased the levels of N-cadherin and a-SMA, known activated HSC markers. In contrast, cell proliferation and apoptosis rates were elevated in LX-2 cells in which KLF4 expression was silenced CONCLUSION: KLF4 inhibits the proliferation and activation of human LX-2 HSCs. It might be a key regulatory protein in the maintenance of HSC quiescence and may serve as a target for the inhibition of hepatic fibrosis.
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Affiliation(s)
- Xing-Yu Yang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhe Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jun Tan
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yin-Kai Xue
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Hai Zheng
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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2
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Castillo-Castro C, Martagón-Rosado AJ, Ortiz-Lopez R, Garrido-Treviño LF, Villegas-Albo M, Bosques-Padilla FJ. Promising diagnostic biomarkers of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: From clinical proteomics to microbiome. World J Hepatol 2021; 13:1494-1511. [PMID: 34904026 PMCID: PMC8637675 DOI: 10.4254/wjh.v13.i11.1494] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/06/2021] [Accepted: 10/14/2021] [Indexed: 02/06/2023] Open
Abstract
Fatty liver has been present in the lives of patients and physicians for almost two centuries. Vast knowledge has been generated regarding its etiology and consequences, although a long path seeking novel and innovative diagnostic biomarkers for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is still envisioned. On the one hand, proteomics and lipidomics have emerged as potential noninvasive resources for NAFLD diagnosis. In contrast, metabolomics has been able to distinguish between NAFLD and NASH, even detecting degrees of fibrosis. On the other hand, genetic and epigenetic markers have been useful in monitoring disease progression, eventually functioning as target therapies. Other markers involved in immune dysregulation, oxidative stress, and inflammation are involved in the instauration and evolution of the disease. Finally, the fascinating gut microbiome is significantly involved in NAFLD and NASH. This review presents state-of-the-art biomarkers related to NAFLD and NASH and new promises that could eventually be positioned as diagnostic resources for this disease. As is evident, despite great advances in studying these biomarkers, there is still a long path before they translate into clinical benefits.
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Affiliation(s)
| | - Alexandro José Martagón-Rosado
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Mexico
- Unidad de Investigación de Enfermedades Metabólicas, Instituto Nacional de Ciencias Médicas y Nutrición, Ciudad de México 14080, Mexico
| | - Rocio Ortiz-Lopez
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Mexico
| | | | - Melissa Villegas-Albo
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Mexico
| | - Francisco Javier Bosques-Padilla
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Mexico
- Centro Regional para el Estudio de las Enfermedades Digestivas, Servicio de Gastroenterología, Facultad de Medicina y Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey 64460, Mexico
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3
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Ji D, Zhao Q, Qin Y, Tong H, Wang Q, Yu M, Mao C, Lu T, Qiu J, Jiang C. Germacrone improves liver fibrosis by regulating the PI3K/AKT/mTOR signalling pathway. Cell Biol Int 2021; 45:1866-1875. [PMID: 33835632 DOI: 10.1002/cbin.11607] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 03/22/2021] [Accepted: 04/01/2021] [Indexed: 01/26/2023]
Abstract
Liver fibrosis is a primary threat to public health, owing to limited therapeutic options. Germacrone (GM) has been shown to exert various curative effects against human diseases, including liver injury. The aim of this study was to investigate the pharmacological effects of GM in the pathophysiology of hepatic fibrosis and determine its potential mechanisms of action. A liver fibrosis rat model was established via carbon tetrachloride (CCl4 ) treatment, and LX-2 cells were stimulated with TGF-β1. The effects of GM on liver fibrosis and its relationship with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway were investigated. In the CCl4 fibrosis-induced rat model, GM improved histological damage, inhibited the activity of hepatic α-smooth muscle actin and improved serum alanine aminotransferase and aspartate aminotransferase levels in a dose-dependent manner. GM potently inhibited hepatic stellate cells (HSCs) growth and epithelial-mesenchymal transition (EMT) progression, as reflected by the altered expression of proliferative (Ki-67, PCNA and cleaved caspase-3) and EMT-related (E-cadherin and vimentin) proteins. In TGF-β1-stimulated LX-2 cells, GM significantly inhibited the survival and activation of HSCs and induced cell apoptosis. GM also suppressed the migration ability and reversed the EMT process in HSCs. Following GM treatment, the phosphorylation of the PI3K, AKT and mTOR proteins was reduced in the liver of CCl4 -treated rats and TGF-β1-stimulated LX-2 cells, indicating that GM may attenuate hepatic fibrosis via the PI3K/AKT/mTOR signalling pathway. These outcomes highlight the anti-fibrotic effects of GM and suggest that it is a potential therapeutic agent for the treatment of liver fibrosis.
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Affiliation(s)
- De Ji
- Department of Chinese Medicinal Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.,Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qi Zhao
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Department of Chinese Medicinal Resources, Biomedical Collaborative Innovation Center of Zhejiang, Wenzhou, China
| | - Yuwen Qin
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Department of Chinese Medicinal Resources, Biomedical Collaborative Innovation Center of Zhejiang, Wenzhou, China
| | - Huangjin Tong
- Department of Chinese Medicinal Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacy, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Qiaohan Wang
- Department of Chinese Medicinal Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mengting Yu
- Department of Chinese Medicinal Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chunqin Mao
- Department of Chinese Medicinal Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Tulin Lu
- Department of Chinese Medicinal Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jinchun Qiu
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Chengxi Jiang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Department of Chinese Medicinal Resources, Biomedical Collaborative Innovation Center of Zhejiang, Wenzhou, China
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4
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Devi P, Khan A, Chattopadhyay P, Mehta P, Sahni S, Sharma S, Pandey R. Co-infections as Modulators of Disease Outcome: Minor Players or Major Players? Front Microbiol 2021; 12:664386. [PMID: 34295314 PMCID: PMC8290219 DOI: 10.3389/fmicb.2021.664386] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022] Open
Abstract
Human host and pathogen interaction is dynamic in nature and often modulated by co-pathogens with a functional role in delineating the physiological outcome of infection. Co-infection may present either as a pre-existing pathogen which is accentuated by the introduction of a new pathogen or may appear in the form of new infection acquired secondarily due to a compromised immune system. Using diverse examples of co-infecting pathogens such as Human Immunodeficiency Virus, Mycobacterium tuberculosis and Hepatitis C Virus, we have highlighted the role of co-infections in modulating disease severity and clinical outcome. This interaction happens at multiple hierarchies, which are inclusive of stress and immunological responses and together modulate the disease severity. Already published literature provides much evidence in favor of the occurrence of co-infections during SARS-CoV-2 infection, which eventually impacts the Coronavirus disease-19 outcome. The availability of biological models like 3D organoids, mice, cell lines and mathematical models provide us with an opportunity to understand the role and mechanism of specific co-infections. Exploration of multi-omics-based interactions across co-infecting pathogens may provide deeper insights into their role in disease modulation.
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Affiliation(s)
- Priti Devi
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Azka Khan
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Partha Chattopadhyay
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Priyanka Mehta
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Shweta Sahni
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Sachin Sharma
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Rajesh Pandey
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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5
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Elucidating Potential Profibrotic Mechanisms of Emerging Biomarkers for Early Prognosis of Hepatic Fibrosis. Int J Mol Sci 2020; 21:ijms21134737. [PMID: 32635162 PMCID: PMC7369895 DOI: 10.3390/ijms21134737] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 06/29/2020] [Accepted: 07/01/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatic fibrosis has been associated with a series of pathophysiological processes causing excessive accumulation of extracellular matrix proteins. Several cellular processes and molecular mechanisms have been implicated in the diseased liver that augments fibrogenesis, fibrogenic cytokines and associated liver complications. Liver biopsy remains an essential diagnostic tool for histological evaluation of hepatic fibrosis to establish a prognosis. In addition to being invasive, this methodology presents with several limitations including poor cost-effectiveness, prolonged hospitalizations, and risks of peritoneal bleeding, while the clinical use of this method does not reveal underlying pathogenic mechanisms. Several alternate noninvasive diagnostic strategies have been developed, to determine the extent of hepatic fibrosis, including the use of direct and indirect biomarkers. Immediate diagnosis of hepatic fibrosis by noninvasive means would be more palatable than a biopsy and could assist clinicians in taking early interventions timely, avoiding fatal complications, and improving prognosis. Therefore, we sought to review some common biomarkers of liver fibrosis along with some emerging candidates, including the oxidative stress-mediated biomarkers, epigenetic and genetic markers, exosomes, and miRNAs that needs further evaluation and would have better sensitivity and specificity. We also aim to elucidate the potential role of cardiotonic steroids (CTS) and evaluate the pro-inflammatory and profibrotic effects of CTS in exacerbating hepatic fibrosis. By understanding the underlying pathogenic processes, the efficacy of these biomarkers could allow for early diagnosis and treatment of hepatic fibrosis in chronic liver diseases, once validated.
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6
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Li J, Guo C, Wu J. Astaxanthin in Liver Health and Disease: A Potential Therapeutic Agent. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:2275-2285. [PMID: 32606597 PMCID: PMC7293384 DOI: 10.2147/dddt.s230749] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 05/18/2020] [Indexed: 12/12/2022]
Abstract
Astaxanthin is a carotenoid derived from oxygen-containing non-vitamin A sources and is mainly obtained from marine organisms. Studies have demonstrated that astaxanthin is a natural antioxidant product and it is widely used in the fields of medicine, health-care products and cosmetics. Studies have shown that astaxanthin has important preventive and therapeutic effects on liver fibrosis, non-alcoholic fatty liver, liver cancer, drug and ischemia-induced liver injury, and its mechanism is related to antioxidant and anti-inflammatory activities, and the regulation of multiple signaling pathways. In this review, we discuss the latest data on astaxanthin in the prevention and treatment of liver diseases. An understanding of the structure, source and mechanism of action of astaxanthin in the body would not only provide a theoretical basis for its clinical application but could also have important significance in screening and improving related compounds for the treatment of liver diseases.
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Affiliation(s)
- Jingjing Li
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai 200060, People's Republic of China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Jianye Wu
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai 200060, People's Republic of China
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7
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Song LY, Ma YT, Fang WJ, He Y, Wu JL, Zuo SR, Deng ZZ, Wang SF, Liu SK. Inhibitory effects of oxymatrine on hepatic stellate cells activation through TGF-β/miR-195/Smad signaling pathway. Altern Ther Health Med 2019; 19:138. [PMID: 31221141 PMCID: PMC6585021 DOI: 10.1186/s12906-019-2560-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 06/11/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Oxymatrine (OM), a quinolizidine alkaloid extracted from a herb Sophorae Flavescentis Radix, has been used to treat liver fibrotic diseases. However, the mechanism of its anti-fibrosis effects is still unclear. TGF-β/Smad signaling and miR-195 have been proved to paly an important role in hepatic stellate cells (HSCs) activation and liver fibrosis. In this study, we investigated whether OM could inhibit HSCs activation through TGF-β1/miR-195/Smads signaling or not. METHODS First, the effects of OM on HSC-T6 in different concentrations and time points were tested by MTT assay. We choose three appropriate concentrations of OM as treatment concentrations in following experiment. By Quantitative Real-time PCR and Western Blot, then we investigated the effect of OM on miR-195, Smad7 and α-SMA's expressions to prove the correlation between OM and the TGF-β1/miR-195/Smads signaling. Last, miR-195 mimic and INF-γ were used to investigate the relation between miR-195 and OM in HSC activation. RESULTS Our results showed that the proliferation of HSC was significantly inhibited when OM concentration was higher than 200 μg/mL after 24 h, 100 μg/mL after 48 h and 10 μg/mL after 72 h. The IC50 of OM after 24, 48 and 72 h were 539, 454, 387 μg/mL respectively. OM could down-regulate miR-195 and α-SMA (P < 0.01), while up-regulate Smad7 (P < 0.05). In HSC-T6 cells transfected with miR-195 mimic and pretreated with OM, miR-195 and α-SMA were up-regulated (P < 0.05), and Smad7 was down-regulated (P < 0.05) . CONCLUSIONS Given these results, OM could inhibit TGF-β1 induced activation of HSC-T6 proliferation in a dose-dependent and time-dependent manner to some extent. We proved that OM inhibited HSC activation through down-regulating the expression of miR-195 and up-regulating Smad7.
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8
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Li L, Zhang L, Zhao X, Cao J, Li J, Chu G. Downregulation of miR-152 contributes to the progression of liver fibrosis via targeting Gli3 in vivo and in vitro. Exp Ther Med 2019; 18:425-434. [PMID: 31258681 PMCID: PMC6566101 DOI: 10.3892/etm.2019.7595] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 01/24/2019] [Indexed: 12/13/2022] Open
Abstract
The Gli family is known to be required for the activation of hedgehog signalling, which participates in the pathogenesis of liver fibrosis. The aim of the present study was to identify the association between microRNA (miR)-152 and GLI family zinc finger 3 (Gli3) and their roles in liver fibrosis. In a carbon tetrachloride (CCl4)-treated rat model, fibrogenesis-associated indexes, including hydroxyproline content, collagen deposition, and α-smooth muscle actin (α-SMA) and albumin expression, were examined in in vivo and in vitro models. The expression of miR-152 and Gli3 in cells and tissues was determined by reverse transcription quantitative polymerase chain reaction and western blot analysis. The interaction of Gli3 and miR-152 was evaluated by bioinformatical analysis and a dual-luciferase reporter assay. The results demonstrated that miR-152 was significantly downregulated in serum samples from clinical patients, liver tissues from CCl4-treated rats and activated LX2 cells. Furthermore, at the cellular level, the mRNA and protein expression levels of α-SMA and albumin were increased and decreased, respectively, in LX2 cells. Nevertheless, following transfection with an miR-152 mimic, the expression levels of α-SMA and albumin were reversed, and Gli3 expression was notably decreased in LX2 cells. Additionally, the target interaction between miR-152 and Gli3 was demonstrated. Finally, an miR-152 mimic was introduced into the rat model and additionally demonstrated that the changes in α-SMA, albumin and Gli3 expression levels were similar to the expression pattern in LX2 cells following miR-152 mimic transfection. These data provided insight into the potential function of miR-152 as an anti-fibrotic therapy through the modulation of Gli3.
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Affiliation(s)
- Li Li
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
| | - Lei Zhang
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
| | - Xiongqi Zhao
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
| | - Jun Cao
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
| | - Jingfeng Li
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
| | - Guang Chu
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
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9
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Xing X, Chen S, Li L, Cao Y, Chen L, Wang X, Zhu Z. The Active Components of Fuzheng Huayu Formula and Their Potential Mechanism of Action in Inhibiting the Hepatic Stellate Cells Viability - A Network Pharmacology and Transcriptomics Approach. Front Pharmacol 2018; 9:525. [PMID: 29881350 PMCID: PMC5976863 DOI: 10.3389/fphar.2018.00525] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 05/01/2018] [Indexed: 12/12/2022] Open
Abstract
Purpose: This study aimed to identify the active components of Fuzheng Huayu (FZHY) formula and the mechanism by which they inhibit the viability of hepatic stellate cells (HSCs) by a combination of network pharmacology and transcriptomics. Methods: The active components of FZHY formula were screened out by text mining. Similarity match and molecular docking were used to predict the target proteins of these compounds. We then searched the STRING database to analyze the key enriched processes, pathways and related diseases of these target proteins. The relevant networks were constructed by Cytoscape. A network analysis method was established by integrating data from above network pharmacology with known transcriptomics analysis of quiescent HSCs-activated HSCs to identify the most possible targets of the active components in FZHY formula. A cell-based assay (LX-2 and T6 cells) and surface plasmon resonance (SPR) analysis were used to validate the most possible active component-target protein interactions (CTPIs). Results: 40 active ingredients in FZHY formula and their 79 potential target proteins were identified by network pharmacology approach. Further network analysis reduced the 79 potential target proteins to 31, which were considered more likely to be the target proteins of the active components in FZHY formula. In addition, further enrichment analysis of 31 target proteins indicated that the HIF-1, PI3K-Akt, FoxO, and chemokine signaling pathways may be the primary pathways regulated by FZHY formula in inhibiting the HSCs viability for the treatment of liver fibrosis. Of the 31 target proteins, peroxisome proliferator activator receptor gamma (PPARG) was selected for validation by experiments at the cellular and molecular level. The results demonstrated that schisandrin B, salvianolic acid A and kaempferol could directly bind to PPARG, decreasing the viability of HSCs (T6 cells and LX-2 cells) and exerting anti-fibrosis effects. Conclusion: The active ingredients of FZHY formula were successfully identified and the mechanisms by which they inhibit HSC viability determined, using network pharmacology and transcriptomics. This work is expected to benefit the clinical application of this formula.
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Affiliation(s)
- Xinrui Xing
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Si Chen
- School of Pharmacy, Second Military Medical University, Shanghai, China.,Postdoctoral Research Workstation, 210th Hospital of the Chinese People's Liberation Army, Dalian, China
| | - Ling Li
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Yan Cao
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Langdong Chen
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Xiaobo Wang
- Postdoctoral Research Workstation, 210th Hospital of the Chinese People's Liberation Army, Dalian, China
| | - Zhenyu Zhu
- School of Pharmacy, Second Military Medical University, Shanghai, China
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10
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Zheng J, Yu F, Dong P, Wu L, Zhang Y, Hu Y, Zheng L. Long non-coding RNA PVT1 activates hepatic stellate cells through competitively binding microRNA-152. Oncotarget 2018; 7:62886-62897. [PMID: 27588491 PMCID: PMC5325334 DOI: 10.18632/oncotarget.11709] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 08/25/2016] [Indexed: 12/18/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) process is considered as a key event in the activation of hepatic stellate cells (HSCs). Hedgehog (Hh) pathway is known to be required for EMT process. Long non-coding RNAs (lncRNAs) have been reported to be involved in a wide range of biological processes. Plasmacytoma variant translocation 1 (PVT1), a novel lncRNA, is often up-regulated in various human cancers. However, the role of PVT1 in liver fibrosis remains undefined. In this study, PVT1 was increased in fibrotic liver tissues and activated HSCs. Depletion of PVT1 attenuated collagen deposits in vivo. In vitro, PVT1 down-regulation inhibited HSC activation including the reduction of HSC proliferation, α-SMA and type I collagen. Further studies showed that PVT1 knockdown suppressed HSC activation was through inhibiting EMT process and Hh pathway. Patched1 (PTCH1), a negative regulator factor of Hh pathway, was enhanced by PVT1 knockdown. PTCH1 demethylation caused by miR-152 was responsible for the effects of PVT1 knockdown on PTCH1 expression. Notably, miR-152 inhibitor reversed the effects of PVT1 knockdown on HSC activation. Luciferase reporter assays and pull-down assays showed a direct interaction between miR-152 and PVT1. Collectively, we demonstrate that PVT1 epigenetically down-regulates PTCH1 expression via competitively binding miR-152, contributing to EMT process in liver fibrosis.
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Affiliation(s)
- Jianjian Zheng
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China.,Key Laboratory of Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
| | - Fujun Yu
- Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
| | - Peihong Dong
- Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
| | - Limei Wu
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Yuan Zhang
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Yanwei Hu
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Lei Zheng
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
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11
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MicroRNA-195 Activates Hepatic Stellate Cells In Vitro by Targeting Smad7. BIOMED RESEARCH INTERNATIONAL 2017; 2017:1945631. [PMID: 28929107 PMCID: PMC5591989 DOI: 10.1155/2017/1945631] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2017] [Revised: 07/03/2017] [Accepted: 07/26/2017] [Indexed: 12/16/2022]
Abstract
Background and Aim Aberrant activation of the TGF-β1/Smad pathway contributes to the activation of hepatic stellate cells (HSCs). MicroRNA-195 has been shown to regulate the activation of HSCs. The aim of this study was to investigate the role of miRNA-195 in HSCs activation. Methods A liver fibrotic rat model induced by diethylnitrosamine was established. Dual luciferase reporter assays were performed to verify that Smad7 was the target of miRNA-195. The expression levels of miR-195, Smad7, and α-SMA in HSC-T6 transfected, respectively, with miR-195 mimic, inhibitor, or control were measured by qRT-PCR. The protein expression of Smad7 was detected by Western blot analysis. Results Enhanced miR-195 and decreased Smad7 were observed in diethylnitrosamine-induced liver fibrotic rats (P < 0.05). Dual luciferase reporter assays showed that the miR-195 mimic significantly suppressed the luciferase activity of a reporter plasmid carrying the binding site of miR-195 on the 3′UTR of Smad7 (P < 0.05). The miR-195 mimics activated HSCs, further elevated miR-195 and α-SMA (P < 0.01), and reduced the Smad7 level (P < 0.05). The miR-195 inhibitors blocked the activation of HSCs, reduced the expression of miR-195 and α-SMA (P < 0.01), and upregulated the expression of Smad7 (P < 0.05). Conclusion Collectively, we demonstrated that miRNA-195 activated HSCs by targeting Smad7.
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Zhao J, Fan YC, Chen LY, Gao S, Li F, Wang K. Alteration of methyl-CpG binding domain family in patients with chronic hepatitis B. Clin Res Hepatol Gastroenterol 2017; 41:272-283. [PMID: 28065745 DOI: 10.1016/j.clinre.2016.11.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 10/25/2016] [Accepted: 11/30/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVE Epigenetics contributes to the outcome of chronic hepatitis B virus (HBV) infection. However, the role of methyl-CpG binding domain (MBD) family in the natural history of chronic hepatitis B (CHB) has not been demonstrated. It is aimed to investigate the dynamic expression of MBD family and assess the potential association of MBD family in the progression of CHB. METHODS Quantitative real-time polymerase chain reaction (RT-PCR) was used to determine the mRNA levels of MBD family in peripheral blood mononuclear cells (PBMCs) from 223 patients with CHB as training cohort, 146 patients with CHB as validation cohort [immune-tolerant (IT), immune clearance (IC), non/low-replicative (LR) and HBeAg negative hepatitis (ENH)], and 14 healthy controls (HCs). RESULTS The mRNA levels of MeCP2, MBD1, MBD2 and MBD4 were upregulated in patients with CHB compared with HCs. MBD1 mRNA was highest expressed in IT phase than other phases. The optimal cut-off value for MBD1 mRNA in discriminating IT phase from CHB was 0.0305 in both training and validation cohorts. Both MBD2 and MBD4 mRNA were highest expressed in IC phase than other phases. Moreover, the optimal cut-off values for MBD2 and MBD4 mRNA in discriminating IC phase from CHB were 0.0069 and 0.00099. Furthermore, MBD2 plus MBD4 performed better than MBD2 alone for discriminating IC phase from CHB in training (area under the curve of receiver operating characteristics [AUC] 0.736 vs. 0.671, P=0.0225) and validation cohorts (AUC 0.754 vs. 0.665, P=0.004). MeCP2 mRNA was highest expressed in patients with S3+S4. MeCP2 mRNA has higher AUC than APRI score for predicting S3+S4 and S4 in fibrosis. CONCLUSIONS MBD family is involved in the pathogenesis of CHB and is correlated with disease progression, suggesting the value in evaluating disease severity.
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Affiliation(s)
- Jing Zhao
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China; Institute of Hepatology, Shandong University, Jinan 250012, China
| | - Long-Yan Chen
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China; Institute of Hepatology, Shandong University, Jinan 250012, China
| | - Shuai Gao
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China; Institute of Hepatology, Shandong University, Jinan 250012, China
| | - Feng Li
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China; Institute of Hepatology, Shandong University, Jinan 250012, China.
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Review on intrauterine programming: Consequences in rodent models of mild diabetes and mild fat overfeeding are not mild. Placenta 2017; 52:21-32. [PMID: 28454694 DOI: 10.1016/j.placenta.2017.02.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 02/06/2017] [Accepted: 02/09/2017] [Indexed: 02/08/2023]
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Choi JH, Jin SW, Choi CY, Kim HG, Lee GH, Kim YA, Chung YC, Jeong HG. Capsaicin Inhibits Dimethylnitrosamine-Induced Hepatic Fibrosis by Inhibiting the TGF-β1/Smad Pathway via Peroxisome Proliferator-Activated Receptor Gamma Activation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:317-326. [PMID: 27991776 DOI: 10.1021/acs.jafc.6b04805] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Capsaicin (CPS) exerts many pharmacological effects, but any possible influence on liver fibrosis remains unclear. Therefore, we evaluated the inhibitory effects of CPS on dimethylnitrosamine (DMN) and TGF-β1-induced liver fibrosis in rats and hepatic stellate cells (HSCs). CPS inhibited DMN-induced hepatotoxicity, NF-κB activation, and collagen accumulation. CPS also suppressed the DMN-induced increases in α-SMA, collagen type I, MMP-2, and TNF-α. In addition, CPS inhibited DMN-induced TGF-β1 expression (from 2.3 ± 0.1 to 1.0 ± 0.1) and Smad2/3 phosphorylation (from 1.5 ± 0.1 to 1.1 ± 0.1 and from 1.6 ± 0.1 to 1.1 ± 0.1, respectively) by activating Smad7 expression (from 0.1 ± 0.0 to 0.9 ± 0.1) via PPAR-γ induction (from 0.2 ± 0.0 to 0.8 ± 0.0) (p < 0.05). Furthermore, in HSCs, CPS inhibited the TGF-β1-induced increases in α-SMA and collagen type I expression, via PPAR-γ activation. These results indicate that CPS can ameliorate hepatic fibrosis by inhibiting the TGF-β1/Smad pathway via PPAR-γ activation.
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Affiliation(s)
- Jae Ho Choi
- College of Pharmacy, Chungnam National University , Daejeon, Republic of Korea
| | - Sun Woo Jin
- College of Pharmacy, Chungnam National University , Daejeon, Republic of Korea
| | - Chul Yung Choi
- Jeollanamdo Institute of Natural Resources Research , Jeollanamdo, Republic of Korea
| | - Hyung Gyun Kim
- College of Pharmacy, Chungnam National University , Daejeon, Republic of Korea
| | - Gi Ho Lee
- College of Pharmacy, Chungnam National University , Daejeon, Republic of Korea
| | - Yong An Kim
- College of Pharmacy, Chungnam National University , Daejeon, Republic of Korea
| | - Young Chul Chung
- Department of Food Science, International University of Korea , Jinju, Republic of Korea
| | - Hye Gwang Jeong
- College of Pharmacy, Chungnam National University , Daejeon, Republic of Korea
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Histone deacetylase 9 plays a role in the antifibrogenic effect of astaxanthin in hepatic stellate cells. J Nutr Biochem 2016; 40:172-177. [PMID: 27915160 DOI: 10.1016/j.jnutbio.2016.11.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Revised: 10/12/2016] [Accepted: 11/07/2016] [Indexed: 01/04/2023]
Abstract
Activation of hepatic stellate cells (HSCs) is critical for liver fibrosis development. Previously, we showed that astaxanthin (ASTX), a xanthophyll carotenoid, has antifibrogenic effects in LX-2 cells, a human HSC cell line. We sought to determine the effect of ASTX on HSC activation, and to identify molecular mediators that are critically involved in the processes. ASTX prevented the activation of mouse primary HSCs, as evidenced by attenuated induction of procollagen type I α1. In human primary HSCs, ASTX also inhibited transforming growth factor β1 (TGFβ1)-induced fibrogenic gene expression. Among 11 classical histone deacetylases (HDACs), difference in HDAC9 mRNA levels between quiescent and activated HSCs was most evident while ASTX significantly decreased the expression of HDAC9 and its transcriptional regulator myocyte enhancer factor 2 (MEF2). ASTX decreased HDAC9 protein as well. In the activated HSCs, ASTX significantly reduced mRNA of HDAC9 and MEF2. Human primary biliary cirrhosis livers showed significantly higher HDAC9 mRNA and protein levels than normal livers, and other liver pathologies also exhibited induced HDAC9 expression. HDAC9 knockdown in LX-2 cells decreased TGFβ1-induced fibrogenic gene expression. In conclusion, ASTX inhibits HSC activation and facilitates HSC inactivation, which is attributable to its inhibitory action on HDAC9 expression.
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16
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Protective effects of curcumin against liver fibrosis through modulating DNA methylation. Chin J Nat Med 2016; 14:255-264. [PMID: 27114312 DOI: 10.1016/s1875-5364(16)30025-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Indexed: 02/06/2023]
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Ramos-Lopez O, Martinez-Lopez E, Roman S, Fierro NA, Panduro A. Genetic, metabolic and environmental factors involved in the development of liver cirrhosis in Mexico. World J Gastroenterol 2015; 21:11552-11566. [PMID: 26556986 PMCID: PMC4631960 DOI: 10.3748/wjg.v21.i41.11552] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/29/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis (LC) is a chronic illness caused by inflammatory responses and progressive fibrosis. Globally, the most common causes of chronic liver disease include persistent alcohol abuse, followed by viral hepatitis infections and nonalcoholic fatty liver disease. However, regardless of the etiological factors, the susceptibility and degree of liver damage may be influenced by genetic polymorphisms that are associated with distinct ethnic and cultural backgrounds. Consequently, metabolic genes are influenced by variable environmental lifestyle factors, such as diet, physical inactivity, and emotional stress, which are associated with regional differences among populations. This Topic Highlight will focus on the genetic and environmental factors that may influence the metabolism of alcohol and nutrients in the setting of distinct etiologies of liver disease. The interaction between genes and environment in the current-day admixed population, Mestizo and Native Mexican, will be described. Additionally, genes involved in immune regulation, insulin sensitivity, oxidative stress and extracellular matrix deposition may modulate the degree of severity. In conclusion, LC is a complex disease. The onset, progression, and clinical outcome of LC among the Mexican population are influenced by specific genetic and environmental factors. Among these are an admixed genome with a heterogenic distribution of European, Amerindian and African ancestry; a high score of alcohol consumption; viral infections; a hepatopathogenic diet; and a high prevalence of obesity. The variance in risk factors among populations suggests that intervention strategies directed towards the prevention and management of LC should be tailored according to such population-based features.
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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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El-Ashmawy NE, El-Bahrawy HA, Shamloula MM, Ibrahim AO. Antifibrotic effect of AT-1 blocker and statin in rats with hepatic fibrosis. Clin Exp Pharmacol Physiol 2015; 42:979-987. [PMID: 26175230 DOI: 10.1111/1440-1681.12446] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Revised: 06/10/2015] [Accepted: 06/22/2015] [Indexed: 01/30/2023]
Abstract
Hepatic fibrosis is an outcome of chronic liver injury. Angiotensin II (ANG II) may play a role in the pathogenesis of hepatic fibrosis. Certain drugs such as ACE inhibitors, ANG II antagonists, and even statins could interfere with the renin angiotensin system and modulate its deleterious effects. This study was carried out to investigate the possible role of losartan and atorvastatin in liver fibrosis. Liver fibrosis was induced in rats by i.p. injection of 50% CCl4 twice per week for 8 weeks. The rats intoxicated with CCl4 were divided into four groups: fibrosis control; losartan group; atorvastatin group; and co-treated group. A fifth group of normal healthy rats served as a control group. The results showed that losartan and atorvastatin, either alone or in combination, significantly decreased ALT, AST, hyaluronic acid and hydroxyproline levels in their groups compared to those of the fibrosis control group. A significant decrease in TGF-β was found in the losartan and co-treated groups but not in the atorvastatin group. These biochemical data were supported by liver histopathology and α-SMA. The results indicate that the combined treatment with both losartan and atorvastatin produced a greater effect than either drug alone and proved a beneficial role in inhibiting or reversing liver fibrosis.
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Affiliation(s)
- Nahla E El-Ashmawy
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Hoda A El-Bahrawy
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Maha M Shamloula
- Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Amera O Ibrahim
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
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20
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Epigenetic Changes during Hepatic Stellate Cell Activation. PLoS One 2015; 10:e0128745. [PMID: 26065684 PMCID: PMC4466775 DOI: 10.1371/journal.pone.0128745] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 05/01/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIMS Hepatic stellate cells (HSC), which can participate in liver regeneration and fibrogenesis, have recently been identified as liver-resident mesenchymal stem cells. During their activation HSC adopt a myofibroblast-like phenotype accompanied by profound changes in the gene expression profile. DNA methylation changes at single genes have been reported during HSC activation and may participate in the regulation of this process, but comprehensive DNA methylation analyses are still missing. The aim of the present study was to elucidate the role of DNA methylation during in vitro activation of HSC. METHODS AND RESULTS The analysis of DNA methylation changes by antibody-based assays revealed a strong decrease in the global DNA methylation level during culture-induced activation of HSC. To identify genes which may be regulated by DNA methylation, we performed a genome-wide Methyl-MiniSeq EpiQuest sequencing comparing quiescent and early culture-activated HSC. Approximately 400 differentially methylated regions with a methylation change of at least 20% were identified, showing either hypo- or hypermethylation during activation. Further analysis of selected genes for DNA methylation and expression were performed revealing a good correlation between DNA methylation changes and gene expression. Furthermore, global DNA demethylation during HSC activation was investigated by 5-bromo-2-deoxyuridine assay and L-mimosine treatment showing that demethylation was independent of DNA synthesis and thereby excluding a passive DNA demethylation mechanism. CONCLUSIONS In summary, in vitro activation of HSC initiated strong DNA methylation changes, which were associated with gene regulation. These results indicate that epigenetic mechanisms are important for the control of early HSC activation. Furthermore, the data show that global DNA demethylation during activation is based on an active DNA demethylation mechanism.
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21
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Yao HW, Li J. Epigenetic modifications in fibrotic diseases: implications for pathogenesis and pharmacological targets. J Pharmacol Exp Ther 2015; 352:2-13. [PMID: 25362107 DOI: 10.1124/jpet.114.219816] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Organ fibrosis is a complex and chronic disorder that results from a variety of acute injuries and contributes to thirty percent of naturally occurring deaths worldwide. The main feature of organ fibrosis is the excessive accumulation and deposit of extracellular matrix, thereby leading to organ dysfunction, loss of elasticity, and development of a rigid organ. Accumulating evidence shows that epigenetic remodeling, including aberrant DNA methylation and noncoding RNA expression as well as histone post-translational modifications, play important roles in the pathogenesis of fibrosis through the regulation of fibroblast activation, differentiation, and apoptosis, as well as collagen synthesis and profibrotic gene transcription. In this review, we discuss the basic regulation of DNA methylation, noncoding RNA expression, and histone post-translational modification, and their participation in the pathogenesis and development of organ fibrosis. This review also provides the latest insights into the novel biomarkers and therapeutic targets for fibrosis through modulation of epigenetic remodeling.
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Affiliation(s)
- Hong-Wei Yao
- School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China
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Mastroianni CM, Lichtner M, Mascia C, Zuccalà P, Vullo V. Molecular mechanisms of liver fibrosis in HIV/HCV coinfection. Int J Mol Sci 2014; 15:9184-208. [PMID: 24865485 PMCID: PMC4100089 DOI: 10.3390/ijms15069184] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Revised: 05/15/2014] [Accepted: 05/15/2014] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in people coinfected with human immunodeficiency virus (HIV). Several studies have shown that HIV infection promotes accelerated HCV hepatic fibrosis progression, even with HIV replication under full antiretroviral control. The pathogenesis of accelerated hepatic fibrosis among HIV/HCV coinfected individuals is complex and multifactorial. The most relevant mechanisms involved include direct viral effects, immune/cytokine dysregulation, altered levels of matrix metalloproteinases and fibrosis biomarkers, increased oxidative stress and hepatocyte apoptosis, HIV-associated gut depletion of CD4 cells, and microbial translocation. In addition, metabolic alterations, heavy alcohol use, as well drug use, may have a potential role in liver disease progression. Understanding the pathophysiology and regulation of liver fibrosis in HIV/HCV co-infection may lead to the development of therapeutic strategies for the management of all patients with ongoing liver disease. In this review, we therefore discuss the evidence and potential molecular mechanisms involved in the accelerated liver fibrosis seen in patients coinfected with HIV and HCV.
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Affiliation(s)
- Claudio M Mastroianni
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Miriam Lichtner
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Claudia Mascia
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Paola Zuccalà
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Vincenzo Vullo
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
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Wang Y, Borlak J, Tong W. Toxicogenomics – A Drug Development Perspective. GENOMIC BIOMARKERS FOR PHARMACEUTICAL DEVELOPMENT 2014:127-155. [DOI: 10.1016/b978-0-12-397336-8.00006-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Expression and function of methylthioadenosine phosphorylase in chronic liver disease. PLoS One 2013; 8:e80703. [PMID: 24324622 PMCID: PMC3855635 DOI: 10.1371/journal.pone.0080703] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2013] [Accepted: 10/07/2013] [Indexed: 12/21/2022] Open
Abstract
To study expression and function of methylthioadenosine phosphorylase (MTAP), the rate-limiting enzyme in the methionine and adenine salvage pathway, in chronic liver disease.
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Miao CG, Yang YY, He X, Huang C, Huang Y, Zhang L, Lv XW, Jin Y, Li J. Wnt signaling in liver fibrosis: progress, challenges and potential directions. Biochimie 2013; 95:2326-35. [PMID: 24036368 DOI: 10.1016/j.biochi.2013.09.003] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 09/02/2013] [Indexed: 12/25/2022]
Abstract
Liver fibrosis is a common wound-healing response to chronic liver injuries, including alcoholic or drug toxicity, persistent viral infection, and genetic factors. Myofibroblastic transdifferentiation (MTD) is the pivotal event during liver fibrogenesis, and research in the past few years has identified key mediators and molecular mechanisms responsible for MTD of hepatic stellate cells (HSCs). HSCs are undifferentiated cells which play an important role in liver regeneration. Recent evidence demonstrates that HSCs derive from mesoderm and at least in part via septum transversum and mesothelium, and HSCs express markers for different cell types which derive from multipotent mesenchymal progenitors. There is a regulatory commonality between differentiation of adipocytes and that of HSC, and the shift from adipogenic to myogenic or neuronal phenotype characterizes HSC MTD. Central of this shift is a loss of expression of the master adipogenic regulator peroxisome proliferator activated receptor γ (PPARγ). Restored expression of PPARγ and/or other adipogenic transcription genes can reverse myofibroblastic HSCs to differentiated cells. Vertebrate Wnt and Drosophila wingless are homologous genes, and their translated proteins have been shown to participate in the regulation of cell proliferation, cell polarity, cell differentiation, and other biological roles. More recently, Wnt signaling is implicated in human fibrosing diseases, such as pulmonary fibrosis, renal fibrosis, and liver fibrosis. Blocking the canonical Wnt signal pathway with the co-receptor antagonist Dickkopf-1 (DKK1) abrogates these epigenetic repressions and restores the gene PPARγ expression and HSC differentiation. The identified morphogen mediated epigenetic regulation of PPARγ and HSC differentiation also serves as novel therapeutic targets for liver fibrosis and liver regeneration. In conclusion, the Wnt signaling promotes liver fibrosis by enhancing HSC activation and survival, and we herein discuss what we currently know and what we expect will come in this field in the next future.
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Affiliation(s)
- Cheng-gui Miao
- School of Pharmacy, Institute for Liver Diseases of Anhui Medical University, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Mei Shan Road, Hefei 230032, Anhui Province, China; School of Food and Drug, Anhui Science and Technology University, Bengbu 233100, China
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