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Sohail A, Shams F, Nawaz A, Ain QU, Ijaz B. Antifibrotic potential of reserpine (alkaloid) targeting Keap1/Nrf2; oxidative stress pathway in CCl 4-induced liver fibrosis. Chem Biol Interact 2025; 407:111384. [PMID: 39800144 DOI: 10.1016/j.cbi.2025.111384] [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: 07/31/2024] [Revised: 12/24/2024] [Accepted: 01/09/2025] [Indexed: 01/15/2025]
Abstract
The death rate due to liver cancer approaches 2 million annually, the majority is attributed to fibrosis. Currently, there is no efficient, safe, non-toxic, and anti-fibrotic drug available, suggesting room for better drug discovery. The current study aims to evaluate the anti-fibrotic role of reserpine, an alkaloid plant compound against CCl4-induced liver fibrosis. In-silico docking analysis showed the interaction of reserpine with keap1 protein with the binding energy -9.0 kcal/mol. In-vitro, biochemical analysis, anti-oxidative indexes, and inflammatory cytokines analysis were performed in HepG2 cells. The non-toxic nature of the compound (<100 μg/ml) was evaluated through MTT assay in HepG2 and Vero cell lines. The antifibrotic potential of the reserpine compound (dose of 0.5 mg/kg) was assessed in CCl4-administered C57BL/6J mice models. Hematoxylin & Eosin and Masson staining were performed to study the morphological changes of liver tissues. Immune histochemistry (IHC) analysis was performed to evaluate the effect of reserpine on the liver fibrosis marker. The biochemical assay indicated a significant decrease in ALT, AST, and MDA levels and increased catalase enzyme post-6-week reserpine treatment in mice models. Gene expression analysis revealed that the reserpine targets oxidative stress Keap1/Nrf2 pathway and down-regulated Keap1 expression by 5-fold and up-regulated Nrf2 and Nqo1 expression by 6 and 4.5-fold respectively showing its antioxidant response. It suppressed the expression of Cyp2e1 by 2.2-fold, illustrating the compound's ability to block lipid peroxidation. Histological and immunostaining exhibited improved hepatocyte morphology and reduced collagen deposition in liver tissues due to reserpine. Reserpine treatment lowered the fibrotic markers α-SMA and Col-1 by 1.3 and 1.5 folds respectively as compared to the control group and increased the expression of miR-200a and miR-29b by 15.5 and 8.2 folds (p < 0.05) while decreased miR-128-1-5p expression by 5-fold. A comprehensive In-silico, In-vitro, and In-vivo analysis revealed that reserpine has a strong anti-fibrotic effect against the CCl4-induced liver fibrosis in C57BL/6J mice model by targeting the Keap1/Nrf2 pathway.
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Affiliation(s)
- Aamir Sohail
- Centre of Excellence in Molecular Biology, University of the Punjab, Thokar Niaz Baig, Lahore, 53700, Pakistan
| | - Faiza Shams
- Centre of Excellence in Molecular Biology, University of the Punjab, Thokar Niaz Baig, Lahore, 53700, Pakistan
| | - Aleeza Nawaz
- Centre of Excellence in Molecular Biology, University of the Punjab, Thokar Niaz Baig, Lahore, 53700, Pakistan
| | - Qurrat Ul Ain
- Department of Medical Laboratory Technology, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan
| | - Bushra Ijaz
- Centre of Excellence in Molecular Biology, University of the Punjab, Thokar Niaz Baig, Lahore, 53700, Pakistan; Applied and Functional Genomics Lab, Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
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He C, Wang W, Wei G, Wang Y, Wei Y, Wang J, Zhang Z. Sodium alginate combined with oxymatrine ameliorates CCl 4-induced chemical hepatic fibrosis in mice. Int Immunopharmacol 2023; 125:111144. [PMID: 37922569 DOI: 10.1016/j.intimp.2023.111144] [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: 09/17/2023] [Revised: 10/24/2023] [Accepted: 10/26/2023] [Indexed: 11/07/2023]
Abstract
Hepatic fibrosis (HF) is a challenging clinical problem. Both sodium alginate (SA) and oxymatrine (OM) can be used to treat HF; however, the influence of viscosity on the therapeutic efficacy of sodium alginate is currently unknown. This study used a CCl4-induced HF mouse model to screen the specifications and doses of SA and investigate its therapeutic effects on HF in combination with OM. Sodium alginate of different viscosities ameliorated HF in mice, with 232 mPa·s SA delivered at a dose of 100 mg/kg showing remarkable therapeutic effect, characterized by reduced aspartate transaminase/alanine transaminase levels, reduced expression of α-SMA, collagen I, and other related genes, and increased abundance of beneficial intestinal probiotics such as Lactococcus and Blautia. The combination treatment further improved other related indices and increased the abundance of Phascolarctobacterium and Oscillospiraceae. These results suggest that the oral administration of SA may improve HF via the "gut-liver axis" based on the gut microbiota and has potential clinical applications.
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Affiliation(s)
- Chen He
- State Key Laboratory of Oral Drug Delivery Systems of Chinese Materia Medica, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu 210028, China
| | - Wenjing Wang
- State Key Laboratory of Oral Drug Delivery Systems of Chinese Materia Medica, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu 210028, China
| | - Guoli Wei
- Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu 211200, China
| | - Yuqing Wang
- State Key Laboratory of Oral Drug Delivery Systems of Chinese Materia Medica, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu 210028, China
| | - Yingjie Wei
- State Key Laboratory of Oral Drug Delivery Systems of Chinese Materia Medica, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu 210028, China
| | - Jing Wang
- State Key Laboratory of Oral Drug Delivery Systems of Chinese Materia Medica, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu 210028, China.
| | - Zhenhai Zhang
- State Key Laboratory of Oral Drug Delivery Systems of Chinese Materia Medica, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu 210028, China.
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Liang T, Kota J, Williams KE, Saxena R, Gawrieh S, Zhong X, Zimmers TA, Chalasani N. Dynamic Alterations to Hepatic MicroRNA-29a in Response to Long-Term High-Fat Diet and EtOH Feeding. Int J Mol Sci 2023; 24:14564. [PMID: 37834011 PMCID: PMC10572557 DOI: 10.3390/ijms241914564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 09/18/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
MicroRNA-29a (miR-29a) is a well characterized fibro-inflammatory molecule and its aberrant expression is linked to a variety of pathological liver conditions. The long-term effects of a high-fat diet (HFD) in combination with different levels of EtOH consumption on miR-29a expression and liver pathobiology are unknown. Mice at 8 weeks of age were divided into five groups (calorie-matched diet plus water (CMD) as a control group, HFD plus water (HFD) as a liver disease group, HFD plus 2% EtOH (HFD + 2% E), HFD + 10% E, and HFD + 20% E as intervention groups) and fed for 4, 13, 26, or 39 weeks. At each time point, analyses were performed for liver weight/body weight (BW) ratio, AST/ALT ratio, as well as liver histology assessments, which included inflammation, estimated fat deposition, lipid area, and fibrosis. Hepatic miR-29a was measured and correlations with phenotypic traits were determined. Four-week feeding produced no differences between the groups on all collected phenotypic traits or miR-29a expression, while significant effects were observed after 13 weeks, with EtOH concentration-specific induction of miR-29a. A turning point for most of the collected traits was apparent at 26 weeks, and miR-29a was significantly down-regulated with increasing liver injury. Overall, miR-29a up-regulation was associated with a lower liver/BW ratio, fat deposition, inflammation, and fibrosis, suggesting a protective role of miR-29a against liver disease progression. A HFD plus increasing concentrations of EtOH produces progressive adverse effects on the liver, with no evidence of beneficial effects of low-dose EtOH consumption. Moreover, miR-29a up-regulation is associated with less severe liver injury.
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Affiliation(s)
- Tiebing Liang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (K.E.W.); (S.G.); (N.C.)
| | - Janaiah Kota
- Ultragenyx Pharmaceuticals, Novato, CA 94949, USA;
| | - Kent E. Williams
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (K.E.W.); (S.G.); (N.C.)
| | - Romil Saxena
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Samer Gawrieh
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (K.E.W.); (S.G.); (N.C.)
| | - Xiaoling Zhong
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (X.Z.); (T.A.Z.)
| | - Teresa A. Zimmers
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (X.Z.); (T.A.Z.)
- Indiana Center for Musculoskeletal Health, Indianapolis, IN 46202, USA
- Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202, USA
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (K.E.W.); (S.G.); (N.C.)
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Li H, Liu T, Yang Y, Cho WC, Flynn RJ, Harandi MF, Song H, Luo X, Zheng Y. Interplays of liver fibrosis-associated microRNAs: Molecular mechanisms and implications in diagnosis and therapy. Genes Dis 2023; 10:1457-1469. [PMID: 37397560 PMCID: PMC10311052 DOI: 10.1016/j.gendis.2022.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/09/2022] [Accepted: 08/20/2022] [Indexed: 11/22/2022] Open
Abstract
microRNAs (miRNAs) are a class of non-coding functional small RNA composed of 21-23 nucleotides, having multiple associations with liver fibrosis. Fibrosis-associated miRNAs are roughly classified into pro-fibrosis or anti-fibrosis types. The former is capable of activating hepatic stellate cells (HSCs) by modulating pro-fibrotic signaling pathways, mainly including TGF-β/SMAD, WNT/β-catenin, and Hedgehog; the latter is responsible for maintenance of the quiescent phenotype of normal HSCs, phenotypic reversion of activated HSCs (aHSCs), inhibition of HSCs proliferation and suppression of the extracellular matrix-associated gene expression. Moreover, several miRNAs are involved in regulation of liver fibrosis via alternative mechanisms, such as interacting between hepatocytes and other liver cells via exosomes and increasing autophagy of aHSCs. Thus, understanding the role of these miRNAs may provide new avenues for the development of novel interventions against hepatic fibrosis.
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Affiliation(s)
- Hong Li
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China
| | - Tingli Liu
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China
| | - Yongchun Yang
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, Zhejiang 311300, China
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR 999077, China
| | - Robin J. Flynn
- Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool L3 5RF, UK
- Graduate Studies Office, Department of Research, Innovation and Graduate Studies, Waterford Institute of Technology, X91 K0EK, Ireland
| | - Majid Fasihi Harandi
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman 7616914115, Iran
| | - Houhui Song
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, Zhejiang 311300, China
| | - Xuenong Luo
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China
| | - Yadong Zheng
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, Zhejiang 311300, China
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Ariyachet C, Chuaypen N, Kaewsapsak P, Chantaravisoot N, Jindatip D, Potikanond S, Tangkijvanich P. MicroRNA-223 Suppresses Human Hepatic Stellate Cell Activation Partly via Regulating the Actin Cytoskeleton and Alleviates Fibrosis in Organoid Models of Liver Injury. Int J Mol Sci 2022; 23:ijms23169380. [PMID: 36012644 PMCID: PMC9409493 DOI: 10.3390/ijms23169380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/10/2022] [Accepted: 08/18/2022] [Indexed: 11/30/2022] Open
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that negatively regulate target mRNA expression, and altered expression of miRNAs is associated with liver pathological conditions. Recent studies in animal models have shown neutrophil/myeloid-specific microRNA-223 (miR-223) as a key regulator in the development of various liver diseases including fibrosis, where hepatic stellate cells (HSCs) are the key player in pathogenesis. However, the precise roles of miR-223 in human HSCs and its therapeutic potential to control fibrosis remain largely unexplored. Using primary human HSCs, we demonstrated that miR-223 suppressed the fibrogenic program and cellular proliferation while promoting features of quiescent HSCs including lipid re-accumulation and retinol storage. Furthermore, induction of miR-223 in HSCs decreased cellular motility and contraction. Mechanistically, miR-223 negatively regulated expression of smooth muscle α-actin (α-SMA) and thus reduced cytoskeletal activity, which is known to promote amplification of fibrogenic signals. Restoration of α-SMA in miR-223-overexpressing HSCs alleviated the antifibrotic effects of miR-223. Finally, to explore the therapeutic potential of miR-233 in liver fibrosis, we generated co-cultured organoids of HSCs with Huh7 hepatoma cells and challenged them with acetaminophen (APAP) or palmitic acid (PA) to induce hepatotoxicity. We showed that ectopic expression of miR-223 in HSCs attenuated fibrogenesis in the two human organoid models of liver injury, suggesting its potential application in antifibrotic therapy.
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Affiliation(s)
- Chaiyaboot Ariyachet
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Correspondence: or (C.A.); (P.T.)
| | - Nattaya Chuaypen
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Pornchai Kaewsapsak
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Naphat Chantaravisoot
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Depicha Jindatip
- Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Saranyapin Potikanond
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
- Research Center of Pharmaceutical Nanotechnology, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Pisit Tangkijvanich
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Correspondence: or (C.A.); (P.T.)
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Porcuna J, Mínguez-Martínez J, Ricote M. The PPARα and PPARγ Epigenetic Landscape in Cancer and Immune and Metabolic Disorders. Int J Mol Sci 2021; 22:ijms221910573. [PMID: 34638914 PMCID: PMC8508752 DOI: 10.3390/ijms221910573] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/27/2021] [Accepted: 09/28/2021] [Indexed: 02/07/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-modulated nuclear receptors that play pivotal roles in nutrient sensing, metabolism, and lipid-related processes. Correct control of their target genes requires tight regulation of the expression of different PPAR isoforms in each tissue, and the dysregulation of PPAR-dependent transcriptional programs is linked to disorders, such as metabolic and immune diseases or cancer. Several PPAR regulators and PPAR-regulated factors are epigenetic effectors, including non-coding RNAs, epigenetic enzymes, histone modifiers, and DNA methyltransferases. In this review, we examine advances in PPARα and PPARγ-related epigenetic regulation in metabolic disorders, including obesity and diabetes, immune disorders, such as sclerosis and lupus, and a variety of cancers, providing new insights into the possible therapeutic exploitation of PPAR epigenetic modulation.
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Liu H, Wang L, Dai L, Feng F, Xiao Y. CaMK II/Ca2+ dependent endoplasmic reticulum stress mediates apoptosis of hepatic stellate cells stimulated by transforming growth factor beta 1. Int J Biol Macromol 2021; 172:321-329. [PMID: 33454324 DOI: 10.1016/j.ijbiomac.2021.01.071] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 11/27/2022]
Abstract
Previous studies by our group have demonstrated that the calcium imbalance in rat hepatic stellate cells (HSCs) can induce endoplasmic reticulum stress (ERS) and promote cell apoptosis. KN-62, an inhibitor of Calmodulin kinase II (CaMK II), can decrease the expression of CaMK II that plays a major role in regulating the steady state of intracellular Ca2+. Uridine triphosphate (UTP) plays a biological role in increasing indirectly the level of intracellular Ca2+. In the experiment, we demonstrate that KN-62 and UTP can inhibit the proliferation and promote the apoptosis in HSCs, increase the level of intracellular Ca2+ and the expression of ERS protein GRP78, and increase the apoptosis protein Caspase-12 and Bax expression, while decrease the expression of Bcl-2 protein. Our findings indicate that the CaMK II/Ca2+ signaling pathway regulates the ERS apoptosis pathway and induces HSC apoptosis.
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Affiliation(s)
- Haiying Liu
- Department of Epidemiology and Health Statistics, School of Public Health, North China University of Science and Technology, Hebei, China
| | - Luguang Wang
- Department of Epidemiology and Health Statistics, School of Public Health, North China University of Science and Technology, Hebei, China
| | - Linyu Dai
- Department of Epidemiology and Health Statistics, School of Public Health, North China University of Science and Technology, Hebei, China
| | - Fumin Feng
- Department of Epidemiology and Health Statistics, School of Life Sciences, North China University of Science and Technology, Hebei, China
| | - Yonghong Xiao
- Department of Epidemiology and Health Statistics, School of Public Health, North China University of Science and Technology, Hebei, China.
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Ezhilarasan D. MicroRNA interplay between hepatic stellate cell quiescence and activation. Eur J Pharmacol 2020; 885:173507. [PMID: 32858048 DOI: 10.1016/j.ejphar.2020.173507] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/20/2020] [Accepted: 08/23/2020] [Indexed: 02/08/2023]
Abstract
Hepatic stellate cells (HSCs) activation play a significant role in the progression of hepatic fibrosis. During chronic liver diseases, hepatocytes are damaged severely and secrete several pro-inflammatory markers and profibrogenic cytokines via modulation of a variety of signaling pathways that are responsible for the activation of HSCs. The microRNAs (miRNA or miR) have the potential to modulate fibrogenic signaling pathways in HSCs. A variety of miRNAs are identified as profibrogenic and are capable of activating HSCs by modulating fibrosis-associated signaling pathways such as transforming growth factor-β/Smad, Wnt/β-catenin, Hedgehog, Snail and Notch in the injured liver. On the other hand, HSCs also have certain antifibrotic miRNAs and these include miR-16, miR-19b, miR-29, miR-30, miR-101, miR-122, miR-133a, miR-144, miR-146a, miR-150-5p, miR-155, miR-195, miR-200a, miR-214, miR-335, miR-370, miR-454, miR-483, etc. are responsible for maintenance of the quiescent phenotype of normal HSCs, apoptosis induction and phenotypic reversion of activated HSCs, inhibition of HSCs proliferation, suppression of the extracellular matrix-associated gene expressions, etc. Thus, understanding of HSCs specific miRNAs regulation may provide new ideas for the targeted therapy of hepatic fibrosis at molecular level in the near future. Therefore, this review focusses on the modulation of miRNAs profile during the HSCs activation in the fibrotic liver.
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Affiliation(s)
- Devaraj Ezhilarasan
- Department of Pharmacology, Biomedical Research Unit and Laboratory Animal Centre, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), No.162, PH Road, Chennai, Tamil Nadu, 600 077, India.
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Iacob DG, Rosca A, Ruta SM. Circulating microRNAs as non-invasive biomarkers for hepatitis B virus liver fibrosis. World J Gastroenterol 2020; 26:1113-1127. [PMID: 32231417 PMCID: PMC7093315 DOI: 10.3748/wjg.v26.i11.1113] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 03/04/2020] [Accepted: 03/09/2020] [Indexed: 02/06/2023] Open
Abstract
Viruses can alter the expression of host microRNAs (MiRNA s) and modulate the immune response during a persistent infection. The dysregulation of host MiRNA s by hepatitis B virus (HBV) contributes to the proinflammatory and profibrotic changes within the liver. Multiple studies have documented the differential regulation of intracellular and circulating MiRNA s during different stages of HBV infection. Circulating MiRNA s found in plasma and/or extracellular vesicles can integrate data on viral-host interactions and on the associated liver injury. Hence, the detection of circulating MiRNA s in chronic HBV hepatitis could offer a promising alternative to liver biopsy, as their expression is associated with HBV replication, the progression of liver fibrosis, and the outcome of antiviral treatment. The current review explores the available data on miRNA involvement in HBV pathogenesis with an emphasis on their potential use as biomarkers for liver fibrosis.
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Affiliation(s)
- Diana Gabriela Iacob
- Infectious Diseases Department, "Carol Davila" University of Medicine and Pharmacy, Bucharest 050474, Romania
- Bucharest Emergency University Hospital, Bucharest 050098, Romania
| | - Adelina Rosca
- Virology Department, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania
- Viral Emerging Diseases Department, Ștefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Simona Maria Ruta
- Virology Department, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania
- Viral Emerging Diseases Department, Ștefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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Ulukan B, Sila Ozkaya Y, Zeybel M. Advances in the epigenetics of fibroblast biology and fibrotic diseases. Curr Opin Pharmacol 2019; 49:102-109. [DOI: 10.1016/j.coph.2019.10.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 10/10/2019] [Indexed: 02/09/2023]
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Sosa EA, Moriyama Y, Ding Y, Tejeda-Muñoz N, Colozza G, De Robertis EM. Transcriptome analysis of regeneration during Xenopus laevis experimental twinning. THE INTERNATIONAL JOURNAL OF DEVELOPMENTAL BIOLOGY 2019; 63:301-309. [PMID: 31250914 DOI: 10.1387/ijdb.190006ed] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Animal embryos have the remarkable property of self-organization. Over 125 years ago, Hans Driesch separated the two blastomeres of sea urchin embryos and obtained twins, in what was the foundation of experimental embryology. Since then, embryonic twinning has been obtained experimentally in many animals. In a recent study, we developed bisection methods that generate identical twins reliably from Xenopus blastula embryos. In the present study, we have investigated the transcriptome of regenerating half-embryos after sagittal and dorsal-ventral (D-V) bisections. Individual embryos were operated at midblastula (stage 8) with an eyelash hair and cultured until early gastrula (stage 10.5) or late gastrula (stage 12) and the transcriptome of both halves were analyzed by RNA-seq. Since many genes are activated by wound healing in Xenopus embryos, we resorted to stringent sequence analyses and identified genes up-regulated in identical twins but not in either dorsal or ventral fragments. At early gastrula, cell division-related transcripts such as histones were elevated, whereas at late gastrula, pluripotency genes (such as sox2) and germ layer determination genes (such as eomesodermin, ripply2 and activin receptor ACVRI) were identified. Among the down-regulated transcripts, sizzled, a regulator of Chordin stability, was prominent. These findings are consistent with a model in which cell division is required to heal damage, while maintaining pluripotency to allow formation of the organizer with a displacement of 90 0 from its original site. The extensive transcriptomic data presented here provides a valuable resource for data mining of gene expression during early vertebrate development.
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Affiliation(s)
- Eric A Sosa
- Howard Hughes Medical Institute, Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
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