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Peta V, Sandler Y, Deckmyn O, Duroselle O, Vinnitskaya E, Khomeriki S, Noskova K, Poynard T. Diagnostic performance of FibroTest-ActiTest, transient elastography, and the fibrosis-4 index in patients with autoimmune hepatitis using histological reference. World J Hepatol 2025; 17:104534. [PMID: 40177191 PMCID: PMC11959656 DOI: 10.4254/wjh.v17.i3.104534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 02/23/2025] [Accepted: 03/06/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Noninvasive tests are crucial for the management and follow-up of patients with autoimmune hepatitis, but their validation is limited because of insufficient data. AIM To investigate the diagnostic performance of three fibrosis noninvasive tests [FibroTest, vibration-controlled transient elastography (VCTE), and the fibrosis-4 index (FIB-4) and two activity biomarkers (alanine aminotransferase (ALT) and ActiTest]. METHODS This study enrolled 103 patients for whom liver biopsy, hepatic elastography results, and laboratory markers were available. Diagnostic performance was assessed with receiver operating characteristic (ROC) curves, the Obuchowski measure (OM), and the Bayesian latent class model. RESULTS FibroTest and VCTE outperformed FIB-4 in cases of significant fibrosis (≥ F2), with areas under the ROC curve of 0.83 [95% confidence interval (CI): 0.73-0.90], 0.86 (95%CI: 0.77-0.92), and 0.71 (95%CI: 0.60-0.80), respectively. The mean (standard error) OM values were 0.92 (0.01), 0.93 (0.01), and 0.88 (0.02) for FibroTest, VCTE, and FIB-4, respectively; FibroTest and VCTE performed comparably, and both were superior to FIB-4 (P = 0.03 and P = 0.005). The areas under the ROC curve values for activity biomarkers were 0.86 (95%CI: 0.76-0.92) for ActiTest and 0.84 (95%CI: 0.73-0.90) for ALT (P = 0.06). The OM values for ActiTest and ALT were 0.92 (0.02) and 0.90 (0.02), respectively (P = 0.005). CONCLUSION FibroTest and VCTE outperformed FIB-4 according to the OM. FibroTest-ActiTest facilitated the evaluation of both fibrosis and activity.
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Affiliation(s)
| | - Yuliya Sandler
- Department of Hepatology, Center for Diagnostics and Treatment of Liver Diseases, Moscow Clinical Scientific and Practical Center, Moscow 111123, Russia
| | | | | | - Elena Vinnitskaya
- Department of Hepatology, Center for Diagnostics and Treatment of Liver Diseases, Moscow Clinical Scientific and Practical Center, Moscow 111123, Russia
| | - Sergey Khomeriki
- Laboratory of Pathomorphology, Moscow Clinical Scientific and Practical Center, Moscow 111123, Russia
| | - Karina Noskova
- Clinical Diagnostic Laboratory, Moscow Clinical Scientific and Practical Center, Moscow 111123, Russia
| | - Thierry Poynard
- BioPredictive, Paris 75007, France
- Sorbonne Université, INSERM Centre de Recherche Saint-Antoine, Paris 75012, France.
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Sharip A, Kunz J. Mechanosignaling via Integrins: Pivotal Players in Liver Fibrosis Progression and Therapy. Cells 2025; 14:266. [PMID: 39996739 PMCID: PMC11854242 DOI: 10.3390/cells14040266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/05/2025] [Accepted: 02/05/2025] [Indexed: 02/26/2025] Open
Abstract
Liver fibrosis, a consequence of chronic liver injury, represents a major global health burden and is the leading cause of liver failure, morbidity, and mortality. The pathological hallmark of this condition is excessive extracellular matrix deposition, driven primarily by integrin-mediated mechanotransduction. Integrins, transmembrane heterodimeric proteins that serve as primary ECM receptors, orchestrate complex mechanosignaling networks that regulate the activation, differentiation, and proliferation of hepatic stellate cells and other ECM-secreting myofibroblasts. These mechanical signals create self-reinforcing feedback loops that perpetuate the fibrotic response. Recent advances have provided insight into the roles of specific integrin subtypes in liver fibrosis and revealed their regulation of key downstream effectors-including transforming growth factor beta, focal adhesion kinase, RhoA/Rho-associated, coiled-coil containing protein kinase, and the mechanosensitive Hippo pathway. Understanding these mechanotransduction networks has opened new therapeutic possibilities through pharmacological manipulation of integrin-dependent signaling.
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Affiliation(s)
- Aigul Sharip
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana 020000, Kazakhstan;
- Laboratory of Bioinformatics and Systems Biology, National Laboratory Astana, Astana 020000, Kazakhstan
| | - Jeannette Kunz
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana 020000, Kazakhstan;
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Yousefi Z, Nourbakhsh M, Sahebghadam Lotfi A. Pirfenidone Downregulates eIF6, P311, and TGF-β Expression and Improves Liver Fibrosis Induced by Bile Duct Ligation in Wistar Rats: Evidence for Liver Regeneration. DNA Cell Biol 2025; 44:109-124. [PMID: 39681345 DOI: 10.1089/dna.2024.0194] [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] [Indexed: 12/18/2024] Open
Abstract
Liver fibrosis (LF) is a clinical disorder characterized by inflammation and excessive accumulation of extracellular matrix (ECM). This study investigates the effects of the antifibrotic compound pirfenidone (PFD) on improving LF through histological changes and modulation of eukaryotic translation initiation factor 6 (eIF6), P311, and transforming growth factor beta (TGF-β) in rats with bile duct ligation (BDL)-induced LF. Rats received daily doses of PFD (200 and 500 mg/kg) for 4 weeks. The study encompassed biochemical, pathological, and immunohistochemical (IHC) analyses. mRNA levels of eIF6, P311, TGF-β, ECM deposition, hepatic stellate cell (HSC) activation, and inflammatory mediator genes were measured by RT-qPCR. Protein levels of eIF6, P311, and TGF-β were detected by western blotting. Compared with the BDL group, PFD dose-dependently reduced hydroxyproline content, liver index, biochemical parameters, fibrosis score, and fibrosis area. PFD also modulated BDL-induced hepatic inflammation, ECM accumulation, and HSC activation. IHC staining of Ki-67 and hepatocyte paraffin-1 revealed that PFD enhanced liver regeneration. The research confirmed that PFD gradually downregulated elevated eIF6, P311, and TGF-β levels in BDL-induced LF. These findings suggest that PFD could be a potential treatment for LF, as it may help attenuate fibrosis and enhance liver regeneration, possibly through the modulation of these specific markers.
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Affiliation(s)
- Zeynab Yousefi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mitra Nourbakhsh
- Department of Clinical Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Abbas Sahebghadam Lotfi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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4
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Liu Y, Zhao X, Wang X, Zhou Q. Adverse events of hepatic anti-fibrotic agents in phase 3 and above clinical trials: a descriptive analysis of the WHO-VigiAccess database. Front Pharmacol 2025; 16:1534628. [PMID: 39925851 PMCID: PMC11802529 DOI: 10.3389/fphar.2025.1534628] [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: 11/26/2024] [Accepted: 01/06/2025] [Indexed: 02/11/2025] Open
Abstract
Introduction Liver fibrosis is a pathological condition in response to chronic liver injuries. Currently, there is no Food and Drug Administration (FDA) approved pharmacotherapy for liver fibrosis. Advances in understanding hepatic fibrogenesis have led to the development of anti-fibrotic agents, and some of them have shown promise in phase 3 and above clinical trials. However, adverse drug reactions (ADRs) associated with emerging anti-fibrotic agents may hinder their efficacy and clinical applicability. This study assessed ADRs associated with anti-fibrotic agents as reported in the World Health Organization (WHO) VigiAccess database and compared the adverse reaction characteristics of these agents for optimizing therapeutic strategies. Methods A detailed search was conducted on ClinicalTrial.gov to identify phase 3 or 4 clinical trials involving hepatic anti-fibrotic agents. The ADR reports were retrieved from the WHO-VigiAccess database, with data categorized by demographic characteristics, geographic distribution, and System Organ Classes (SOCs). The most frequently reported ADRs were identified through descriptive analysis. Disproportionality analysis, measured by reporting odd ratio (ROR) and proportional reporting ratio (PRR), was performed to evaluate ADRs related to gastrointestinal disorders. Results Five hepatic anti-fibrotic agents (empagliflozin, liraglutide, candesartan, obeticholic acid, and resmetirom) were identified. A total of 130,567 ADR reports were analyzed, with empagliflozin, liraglutide, and candesartan showing significantly higher ADRs. The most frequently reported SOCs included gastrointestinal disorders (29.44%), general disorders (24.12%), and nervous system disorders (14.42%). Liraglutide demonstrated a higher risk of gastrointestinal ADRs (ROR: 4.629, 95% CI: 4.517-4.744; PRR: 3.566, 95% CI: 3.492-3.642) compared to the other agents. Severe ADRs were reported in empagliflozin, such as ketoacidosis and infections, while liraglutide was associated with pancreatitis and candesartan with acute kidney injury. Serious ADR rates varied, with candesartan reporting the highest proportion (7.28%). Conclusion While hepatic anti-fibrotic agents showed promise in addressing liver fibrosis, their ADR profiles underscore the importance of pharmacovigilance and personalized treatment approaches. Future efforts should focus on improving the pharmacovigilance system, expanding population diversity in trials, and conducting ongoing research and extensive post-marketing surveillance.
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Affiliation(s)
- Yuwei Liu
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, Jilin, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Xu Zhao
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, Jilin, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Xinrui Wang
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, Jilin, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Qiang Zhou
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, Jilin, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
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5
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Alvarado-Tapias E, Maya-Miles D, Albillos A, Aller R, Ampuero J, Andrade RJ, Arechederra M, Aspichueta P, Banales JM, Blas-García A, Caparros E, Cardoso Delgado T, Carrillo-Vico A, Claria J, Cubero FJ, Díaz-Ruiz A, Fernández-Barrena MG, Fernández-Iglesias A, Fernández-Veledo S, Francés R, Gallego-Durán R, Gracia-Sancho J, Irimia M, Lens S, Martínez-Chantar ML, Mínguez B, Muñoz-Hernández R, Nogueiras R, Ramos-Molina B, Riveiro-Barciela M, Rodríguez-Perálvarez ML, Romero-Gómez M, Sabio G, Sancho-Bru P, Ventura-Cots M, Vidal S, Gahete MD. Proceedings of the 5th Meeting of Translational Hepatology, organized by the Spanish Association for the Study of the Liver (AEEH). GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:502207. [PMID: 38723772 DOI: 10.1016/j.gastrohep.2024.502207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 05/02/2024] [Indexed: 11/30/2024]
Abstract
This is the summary report of the 5th Translational Hepatology Meeting, endorsed by the Spanish Association for the Study of the Liver (AEEH) and held in Seville, Spain, in October 2023. The meeting aimed to provide an update on the latest advances in the field of basic and translational hepatology, covering different molecular, cellular, and pathophysiological aspects of the most relevant clinical challenges in liver pathologies. This includes the identification of novel biomarkers and diagnostic tools, the understanding of the relevance of immune response and inflammation in liver diseases, the characterization of current medical approaches to reverse liver diseases, the incorporation of novel molecular insights through omics techniques, or the characterization of the impact of toxic and metabolic insults, as well as other organ crosstalk, in liver pathophysiology.
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Affiliation(s)
- Edilmar Alvarado-Tapias
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Department of Gastroenterology, Hospital Santa Creu I Sant Pau, Institut de Recerca Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain.
| | - Douglas Maya-Miles
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), CISC, Universidad de Sevilla, Sevilla, Spain.
| | - Agustin Albillos
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal/Universidad de Alcalá/Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Rocio Aller
- BioCritic, Group for Biomedical Research in Critical Care Medicine, Spain; Department of Medicine, Dermatology and Toxicology, Universidad de Valladolid, Spain; Gastroenterology Unit, Hospital Clínico Universitario de Valladolid, 47003 Valladolid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain; Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Javier Ampuero
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), CISC, Universidad de Sevilla, Sevilla, Spain
| | - Raul J Andrade
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Maria Arechederra
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Patricia Aspichueta
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain; Biobizkaia Health Research Institute, Barakaldo, Spain
| | - Jesus M Banales
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute - Donostia University Hospital - University of the Basque Country (UPV/EHU), Ikerbasque, Donostia-San Sebastian, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - Ana Blas-García
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Departamento de Fisiología, Universitat de València, Av. Blasco Ibáñez, 15, 46010 Valencia, Spain; FISABIO (Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana), Av. de Catalunya, 21, 46020 Valencia, Spain
| | - Esther Caparros
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Grupo de Inmunobiología Hepática e Intestinal, Departamento Medicina Clínica, Universidad Miguel Hernández, San Juan, Spain; Instituto de Investigación Sanitaria ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain
| | - Teresa Cardoso Delgado
- Biobizkaia Health Research Institute, Barakaldo, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Antonio Carrillo-Vico
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), CISC, Universidad de Sevilla, Sevilla, Spain; Departamento de Bioquímica Médica y Biología Molecular e Inmunología, Facultad de Medicina, Universidad de Sevilla, Seville, Spain
| | - Joan Claria
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Biochemistry and Molecular Genetics Service, Hospital Clínic, IDIBAPS, Barcelona, Spain; University of Barcelona, Spain
| | - Francisco Javier Cubero
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain; Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain
| | - Alberto Díaz-Ruiz
- Laboratory of Cellular and Molecular Gerontology, Precision Nutrition and Aging, Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM+CSIC, Madrid, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Madrid, Spain
| | - Maite G Fernández-Barrena
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain; Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Spain
| | - Anabel Fernández-Iglesias
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Liver Vascular Biology Research Group, IDIBAPS, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
| | - Sonia Fernández-Veledo
- Department of Endocrinology and Nutrition and Research Unit, University Hospital of Tarragona Joan XXIII, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Ruben Francés
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Grupo de Inmunobiología Hepática e Intestinal, Departamento Medicina Clínica, Universidad Miguel Hernández, San Juan, Spain; Instituto de Investigación Sanitaria ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain
| | - Rocío Gallego-Durán
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), CISC, Universidad de Sevilla, Sevilla, Spain
| | - Jordi Gracia-Sancho
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Liver Vascular Biology Research Group, IDIBAPS, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
| | - Manuel Irimia
- Universitat Pompeu Fabra (UPF), Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, ICREA, Barcelona, Spain
| | - Sabela Lens
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain; Liver Unit, Hospital Clínic, IDIBAPS, Barcelona, Spain
| | - María Luz Martínez-Chantar
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Bizkaia, Spain
| | - Beatriz Mínguez
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Rocío Muñoz-Hernández
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), CISC, Universidad de Sevilla, Sevilla, Spain; Departamento de fisiología, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain
| | - Rubén Nogueiras
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Madrid, Spain; Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain
| | - Bruno Ramos-Molina
- Obesity, Diabetes and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Mar Riveiro-Barciela
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Manuel L Rodríguez-Perálvarez
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Department of Hepatology and Liver Transplantation, Reina Sofia University Hospital, Cordoba, Spain; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), University of Córdoba, Cordoba, Spain
| | - Manuel Romero-Gómez
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), CISC, Universidad de Sevilla, Sevilla, Spain
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Stress Kinases in Diabetes, Cancer and Biochemistry, Spain; Centro Nacional de Investigaciones Oncologicas (CNIO), Organ Crosstalk in Metabolic Diseases, Madrid, Spain
| | - Pau Sancho-Bru
- CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Meritxell Ventura-Cots
- Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Silvia Vidal
- Group of Inflammatory Diseases, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Manuel D Gahete
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Madrid, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Spain; Molecular Hepatology Group, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Spain; Reina Sofia University Hospital, Cordoba, Spain.
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6
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Abdel-Samiee M, Ibrahim ES, Kohla M, Abdelsameea E, Salama M. Regression of hepatic fibrosis after pharmacological therapy for nonalcoholic steatohepatitis. World J Gastrointest Pharmacol Ther 2024; 15:97381. [PMID: 39534523 PMCID: PMC11551621 DOI: 10.4292/wjgpt.v15.i6.97381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 08/28/2024] [Accepted: 09/23/2024] [Indexed: 10/25/2024] Open
Abstract
The global incidence of nonalcoholic fatty liver disease (NAFLD) is escalating considerably. NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis, which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix, leading to fibrosis. Hepatocyte ballooning is a key catalyst for fibrosis progression, potentially advancing to cirrhosis and its decompensated state. Fibrosis is a critical prognostic factor for outcomes in patients with NAFLD; therefore, those with substantial fibrosis require timely intervention. Although liver biopsy is the most reliable method for fibrosis detection, it is associated with certain risks and limitations, particularly in routine screening. Consequently, various noninvasive diagnostic techniques have been introduced. This review examines the increasing prevalence of NAFLD, evaluates the noninvasive diagnostic techniques for fibrosis, and assesses their efficacy in staging the disease. In addition, it critically appraises current and emerging antifibrotic therapies, focusing on their mechanisms, efficacy, and potential in reversing fibrosis. This review underscores the urgent need for effective therapeutic strategies, given the dire consequences of advanced fibrosis.
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Affiliation(s)
- Mohamed Abdel-Samiee
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Essam Salah Ibrahim
- Department of Medicine, RCSI Medical University of Bahrain, Adliya 15503, Bahrain
| | - Mohamed Kohla
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Eman Abdelsameea
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Mohsen Salama
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
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7
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Rodriguez-Sanabria JS, Rosas-Campos R, Vázquez-Esqueda Á, Palacios-Marín I, Jiménez-Chillaron J, Escutia-Gutiérrez R, Jave-Suarez LF, Galicia-Moreno M, Monroy-Ramirez HC, Cerda-Reyes E, Almeida-López M, Martinez-Lopez E, Herrera LA, Armendáriz-Borunda J, Sandoval-Rodriguez A. H3K9me3 demethylation by JMJD2B is regulated by pirfenidone resulting in improved NASH. Sci Rep 2024; 14:24714. [PMID: 39433954 PMCID: PMC11494037 DOI: 10.1038/s41598-024-75458-2] [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: 04/15/2024] [Accepted: 10/04/2024] [Indexed: 10/23/2024] Open
Abstract
NASH is characterized by hepatic lipid accumulation and inflammation; and JMJD2B-a histone demethylase-upregulation has been linked to its progression. Pirfenidone (PFD) is an antifibrotic agent with anti-inflammatory and antioxidant effects recognized to decrease NASH symptoms. Herein, our aim was to investigate PFD-induced epigenetics mechanisms involving JMJD2B and histone modifications in experimental NASH. Male C57BL/6J mice were fed with normo-diet, or high fat/carbohydrate diet (HF) for 16 weeks. A HF-subgroup was treated with PFD 300 mg/kg/d from week 8th to the end of protocol. Insulin tolerance test and liver and fat histological and biochemical analyses were carried out. Hepatic transcriptome was examined. Liver proteins were studied by western blot (WB) and Chromatin immunoprecipitation. In vitro, lipotoxicity was induced in HepG2 cells and proteins were evaluated using WB. Molecular docking was used to explore binding of PFD to JMJD2B. Mice treated with PFD reduced weight gain, epididymal fat and inflammatory nodules, and steatosis in liver tissue, as well as, improved biochemical test. PFD modified the expression of Jmjd2b, Pparg, Fasn and Srebp1, and restored JMJD2B protein and H3K9me3 repressive mark, both in animal and cell models. PFD increased hepatic enrichment of H3K9me2 and H3K9me3 at the promoter region of Fasn and Srebp1, and Pparg. In HepG2 cells, PFD reduced lipid vacuole accumulation. In silico, PFD interacted with JMJD2B catalytic site. PFD is an epigenetic regulator modifying JMJD2B activity, resulting in reduced NASH traits.
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Affiliation(s)
- J Samael Rodriguez-Sanabria
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
- Departamento Academic Department in Basic Sciences, Universidad Autónoma de Guadalajara, 45129, Zapopan, Mexico
| | - Rebeca Rosas-Campos
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
| | - Ángel Vázquez-Esqueda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
| | - Ivonne Palacios-Marín
- Institut de Recerca Sant Joan de Déu, Endocrinology, c/ Santa Rosa 39-57, 4ª planta, 08950, Esplugues, Barcelona, Spain
- Department of Biochemistry and Physiology, Institut de Biomedicina de la Universitat de Barcelona (IBUB), School of Pharmacy and Food Sciences, Universitat de Barcelona, 08028, Barcelona, Spain
| | - Josep Jiménez-Chillaron
- Institut de Recerca Sant Joan de Déu, Endocrinology, c/ Santa Rosa 39-57, 4ª planta, 08950, Esplugues, Barcelona, Spain
- Department Of Physiological Sciences, School of Medicine, Universitat de Barcelona, 08907, L'Hospitalet-Barcelona, Spain
| | - Rebeca Escutia-Gutiérrez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
| | - Luis Felipe Jave-Suarez
- División de Inmunología, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, 44340, Guadalajara, Mexico
| | - Marina Galicia-Moreno
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
| | - Hugo Christian Monroy-Ramirez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
| | - Eira Cerda-Reyes
- Investigation Department, Hospital Central Militar, 11200, Mexico City, Mexico
| | - Mónica Almeida-López
- Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
| | - Erika Martinez-Lopez
- Department of Molecular Biology and Genomics, Institute of Translational Nutrigenetics and Nutrigenomics, CUCS, University of Guadalajara, 44340, Guadalajara, Mexico
| | - Luis Alonso Herrera
- Tecnologico de Monterrey, EMCS, 45201, Zapopan, Mexico
- Cancer Research Unit, Institute of Biomedical Research, UNAM-National Institute of Cancerology, 04510, Mexico City, Mexico
| | - Juan Armendáriz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico.
- Tecnologico de Monterrey, EMCS, 45201, Zapopan, Mexico.
| | - Ana Sandoval-Rodriguez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico.
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8
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Bali AD, Rosenzveig A, Frishman WH, Aronow WS. Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: Causation or Association. Cardiol Rev 2024; 32:453-462. [PMID: 36825899 DOI: 10.1097/crd.0000000000000537] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a disease process that is gaining increasing recognition. The global prevalence of NAFLD is increasing in parallel with growing rates of risk factors for NAFLD such as hypertension, obesity, diabetes, and metabolic syndrome. NAFLD has been referred to as a risk factor for cardiovascular disease (CVD). As CVD is the leading cause of morbidity and mortality worldwide, there are constant efforts to describe and alleviate its risk factors. Although there is conflicting data supporting NAFLD as a causative or associative factor for CVD, NAFLD has been shown to be associated with structural, electrical, and atherosclerotic disease processes of the heart. Shared risk factors and pathophysiologic mechanisms between NAFLD and CVD warrant further explication. Pathologic mechanisms such as endothelial dysfunction, oxidative stress, insulin resistance, genetic underpinnings, and gut microbiota dysregulation have been described in both CVD and NAFLD. The mainstay of treatment for NAFLD is lifestyle intervention including physical exercise and hypocaloric intake in addition to bariatric surgery. Investigations into various therapeutic targets to alleviate hepatic steatosis and fibrosis by way of maintaining the balance between lipid synthesis and breakdown. A major obstacle preventing the success of many pharmacologic approaches has been the effects of these medications on CVD risk. The future of pharmacologic treatment of NAFLD is promising as effective medications with limited CVD harm are being investigated.
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Affiliation(s)
- Atul D Bali
- From the Department of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY
| | | | - William H Frishman
- From the Department of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY
| | - Wilbert S Aronow
- From the Department of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY
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9
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Torre A, Martínez‐Sánchez FD, Narvaez‐Chávez SM, Herrera‐Islas MA, Aguilar‐Salinas CA, Córdova‐Gallardo J. Pirfenidone use in fibrotic diseases: What do we know so far? Immun Inflamm Dis 2024; 12:e1335. [PMID: 38967367 PMCID: PMC11225083 DOI: 10.1002/iid3.1335] [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: 02/04/2024] [Revised: 05/27/2024] [Accepted: 06/19/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND Pirfenidone has demonstrated significant anti-inflammatory and antifibrotic effects in both animal models and some clinical trials. Its potential for antifibrotic activity positions it as a promising candidate for the treatment of various fibrotic diseases. Pirfenidone exerts several pleiotropic and anti-inflammatory effects through different molecular pathways, attenuating multiple inflammatory processes, including the secretion of pro-inflammatory cytokines, apoptosis, and fibroblast activation. OBJECTIVE To present the current evidence of pirfenidone's effects on several fibrotic diseases, with a focus on its potential as a therapeutic option for managing chronic fibrotic conditions. FINDINGS Pirfenidone has been extensively studied for idiopathic pulmonary fibrosis, showing a favorable impact and forming part of the current treatment regimen for this disease. Additionally, pirfenidone appears to have beneficial effects on similar fibrotic diseases such as interstitial lung disease, myocardial fibrosis, glomerulopathies, aberrant skin scarring, chronic liver disease, and other fibrotic disorders. CONCLUSION Given the increasing incidence of chronic fibrotic conditions, pirfenidone emerges as a potential therapeutic option for these patients. However, further clinical trials are necessary to confirm its therapeutic efficacy in various fibrotic diseases. This review aims to highlight the current evidence of pirfenidone's effects in multiple fibrotic conditions.
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Affiliation(s)
- Aldo Torre
- Metabolic UnitInstituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubiran”Mexico CityMexico
| | - Froylan David Martínez‐Sánchez
- Facultad de MedicinaUniversidad Nacional Autonoma de MexicoMexico CityMexico
- Department of Internal MedicineHospital General “Dr. Manuel Gea González”Mexico CityMexico
| | | | | | | | - Jacqueline Córdova‐Gallardo
- Facultad de MedicinaUniversidad Nacional Autonoma de MexicoMexico CityMexico
- Department of HepatologyHospital General “Dr. Manuel Gea González”Mexico CityMexico
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10
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Fuster-Martínez I, Calatayud S. The current landscape of antifibrotic therapy across different organs: A systematic approach. Pharmacol Res 2024; 205:107245. [PMID: 38821150 DOI: 10.1016/j.phrs.2024.107245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 05/28/2024] [Accepted: 05/28/2024] [Indexed: 06/02/2024]
Abstract
Fibrosis is a common pathological process that can affect virtually all the organs, but there are hardly any effective therapeutic options. This has led to an intense search for antifibrotic therapies over the last decades, with a great number of clinical assays currently underway. We have systematically reviewed all current and recently finished clinical trials involved in the development of new antifibrotic drugs, and the preclinical studies analyzing the relevance of each of these pharmacological strategies in fibrotic processes affecting tissues beyond those being clinically studied. We analyze and discuss this information with the aim of determining the most promising options and the feasibility of extending their therapeutic value as antifibrotic agents to other fibrotic conditions.
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Affiliation(s)
- Isabel Fuster-Martínez
- Departamento de Farmacología, Universitat de València, Valencia 46010, Spain; FISABIO (Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana), Valencia 46020, Spain.
| | - Sara Calatayud
- Departamento de Farmacología, Universitat de València, Valencia 46010, Spain; CIBERehd (Centro de Investigación Biomédica en Red - Enfermedades Hepáticas y Digestivas), Spain.
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11
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Miranda-Roblero HO, Saavedra-Salazar LF, Galicia-Moreno M, Arceo-Orozco S, Caloca-Camarena F, Sandoval-Rodriguez A, García-Bañuelos J, Frias-Gonzalez C, Almeida-López M, Martínez-López E, Armendariz-Borunda J, Monroy-Ramirez HC. Pirfenidone Reverts Global DNA Hypomethylation, Promoting DNMT1/UHRF/PCNA Coupling Complex in Experimental Hepatocarcinoma. Cells 2024; 13:1013. [PMID: 38920644 PMCID: PMC11201610 DOI: 10.3390/cells13121013] [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: 03/27/2024] [Revised: 06/03/2024] [Accepted: 06/04/2024] [Indexed: 06/27/2024] Open
Abstract
Hepatocellular carcinoma (HCC) development is associated with altered modifications in DNA methylation, changing transcriptional regulation. Emerging evidence indicates that DNA methyltransferase 1 (DNMT1) plays a key role in the carcinogenesis process. This study aimed to investigate how pirfenidone (PFD) modifies this pathway and the effect generated by the association between c-Myc expression and DNMT1 activation. Rats F344 were used for HCC development using 50 mg/kg of diethylnitrosamine (DEN) and 25 mg/kg of 2-Acetylaminofluorene (2-AAF). The HCC/PFD group received simultaneous doses of 300 mg/kg of PFD. All treatments lasted 12 weeks. On the other hand, HepG2 cells were used to evaluate the effects of PFD in restoring DNA methylation in the presence of the inhibitor 5-Aza. Histopathological, biochemical, immunohistochemical, and western blot analysis were carried out and our findings showed that PFD treatment reduced the amount and size of tumors along with decreased Glipican-3, β-catenin, and c-Myc expression in nuclear fractions. Also, this treatment improved lipid metabolism by modulating PPARγ and SREBP1 signaling. Interestingly, PFD augmented DNMT1 and DNMT3a protein expression, which restores global methylation, both in our in vivo and in vitro models. In conclusion, our results suggest that PFD could slow down HCC development by controlling DNA methylation.
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MESH Headings
- Animals
- DNA (Cytosine-5-)-Methyltransferase 1/metabolism
- DNA (Cytosine-5-)-Methyltransferase 1/genetics
- DNA Methylation/drug effects
- DNA Methylation/genetics
- Pyridones/pharmacology
- Rats
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Humans
- Hep G2 Cells
- Proliferating Cell Nuclear Antigen/metabolism
- Male
- Rats, Inbred F344
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Liver Neoplasms/genetics
- Gene Expression Regulation, Neoplastic/drug effects
- Diethylnitrosamine
- Liver Neoplasms, Experimental/drug therapy
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/genetics
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Affiliation(s)
- Hipolito Otoniel Miranda-Roblero
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, CUCS, University of Guadalajara, Guadalajara 44340, Mexico; (H.O.M.-R.); (L.F.S.-S.)
- Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico; (M.G.-M.); (S.A.-O.); (F.C.-C.); (A.S.-R.); (J.G.-B.)
| | - Liliana Faridi Saavedra-Salazar
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, CUCS, University of Guadalajara, Guadalajara 44340, Mexico; (H.O.M.-R.); (L.F.S.-S.)
- Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico; (M.G.-M.); (S.A.-O.); (F.C.-C.); (A.S.-R.); (J.G.-B.)
| | - Marina Galicia-Moreno
- Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico; (M.G.-M.); (S.A.-O.); (F.C.-C.); (A.S.-R.); (J.G.-B.)
| | - Scarlet Arceo-Orozco
- Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico; (M.G.-M.); (S.A.-O.); (F.C.-C.); (A.S.-R.); (J.G.-B.)
| | - Fernando Caloca-Camarena
- Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico; (M.G.-M.); (S.A.-O.); (F.C.-C.); (A.S.-R.); (J.G.-B.)
| | - Ana Sandoval-Rodriguez
- Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico; (M.G.-M.); (S.A.-O.); (F.C.-C.); (A.S.-R.); (J.G.-B.)
| | - Jesús García-Bañuelos
- Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico; (M.G.-M.); (S.A.-O.); (F.C.-C.); (A.S.-R.); (J.G.-B.)
| | - Claudia Frias-Gonzalez
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, CUCS, University of Guadalajara, Guadalajara 44340, Mexico; (H.O.M.-R.); (L.F.S.-S.)
- Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico; (M.G.-M.); (S.A.-O.); (F.C.-C.); (A.S.-R.); (J.G.-B.)
| | - Mónica Almeida-López
- University Center of Health Sciences, University of Guadalajara, Guadalajara 44340, Mexico
| | - Erika Martínez-López
- Institute of Translational Nutrigenetics and Nutrigenomics, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico
| | - Juan Armendariz-Borunda
- Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico; (M.G.-M.); (S.A.-O.); (F.C.-C.); (A.S.-R.); (J.G.-B.)
- Tecnologico de Monterrey, School of Medicine and Health Sciences, Zapopan 45138, Mexico
| | - Hugo Christian Monroy-Ramirez
- Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico; (M.G.-M.); (S.A.-O.); (F.C.-C.); (A.S.-R.); (J.G.-B.)
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12
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Gato S, García-Fernández V, Gil-Gómez A, Rojas Á, Montero-Vallejo R, Muñoz-Hernández R, Romero-Gómez M. Navigating the Link Between Non-alcoholic Fatty Liver Disease/Non-alcoholic Steatohepatitis and Cardiometabolic Syndrome. Eur Cardiol 2024; 19:e03. [PMID: 38807856 PMCID: PMC11131154 DOI: 10.15420/ecr.2023.26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 12/27/2023] [Indexed: 05/30/2024] Open
Abstract
The global prevalence of non-alcoholic fatty liver disease (NAFLD) is nearly 25% and is increasing rapidly. The spectrum of liver damage in NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis, characterised by the presence of lobular inflammation and hepatocyte ballooning degeneration, with or without fibrosis, which can further develop into cirrhosis and hepatocellular carcinoma. Not only is NAFLD a progressive liver disease, but numerous pieces of evidence also point to extrahepatic consequences. Accumulating evidence suggests that patients with NAFLD are also at increased risk of cardiovascular disease (CVD); in fact, CVDs are the most common cause of mortality in patients with NAFLD. Obesity, type 2 diabetes and higher levels of LDL are common risk factors in both NAFLD and CVD; however, how NAFLD affects the development and progression of CVD remains elusive. In this review, we comprehensively summarise current data on the key extrahepatic manifestations of NAFLD, emphasising the possible link between NAFLD and CVD, including the role of proprotein convertase substilisin/kenin type 9, extracellular vesicles, microbiota, and genetic factors.
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Affiliation(s)
- Sheila Gato
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
| | - Vanessa García-Fernández
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
| | - Antonio Gil-Gómez
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
| | - Ángela Rojas
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
| | - Rocío Montero-Vallejo
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
| | - Rocío Muñoz-Hernández
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
- Departamento de Fisiología, Facultad de Biología, Universidad de SevillaSeville, Spain
| | - Manuel Romero-Gómez
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
- Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen del RocíoSeville, Spain
- Departamento de Medicina, Facultad de Medicina, Universidad de SevillaSeville, Spain
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13
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Poo JL, Aguilar JR, Bernal-Reyes R, Alonso-Campero R, Gasca F, Hernández L, Pineyro-Garza E, Gomez-Silva M, Gamino ME, la Parra MGD, Peña P, Hernández N, Tapia G, Muñoz-Espinosa LE. Prolonged release pirfenidone pharmacokinetics is modified in cirrhosis GENESIS study. Biomed Pharmacother 2023; 168:115712. [PMID: 37871556 DOI: 10.1016/j.biopha.2023.115712] [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: 08/18/2023] [Revised: 10/05/2023] [Accepted: 10/11/2023] [Indexed: 10/25/2023] Open
Abstract
BACKGROUND In both clinical and experimental trials, pirfenidone (PFD) showed anti-inflammatory and antifibrogenic effects. Considering the wide variation in hepatic functional reserve in patients with cirrhosis, we decided to learn more about the pharmacokinetics of a new formulation of prolonged release PFD in this population (PR-PFD), focusing on assessing changes on AUC0-∞, AUC0-t, and Cmax. METHODS In this study, 24 subjects with cirrhosis were included: eight subjects with mild liver impairment (Child-Pugh A) and eight with moderate liver impairment (Child-Pugh B), and a third group of eight age-matched subjects without fibrosis. All participants were under fasting conditions before receiving orally two 600-mg tablets of a prolonged-release formulation of pirfenidone (PR-PFD) and remained in the clinical unit for 36 h after PR-PFD administration. Serial blood samples were collected after dosing (0.5-36 h). A validated high-performance liquid chromatography-mass spectrometry method was used to determine PFD plasma concentrations. RESULTS The exposure to PR-PFD was 3.6- and 4.4-fold greater in subjects with Child-Pugh A and Child-Pugh B than in subjects without cirrhosis, and Cmax was 1.6- and 1.8-fold greater in subjects with Child-Pugh B and Child-Pugh-A than in patients without cirrhosis, without significant differences between the two cirrhotic groups. PFD was well tolerated. CONCLUSION The pharmacokinetic parameters of PR-PFD are significantly modified in patients with cirrhosis compared with those in controls, indicating that liver impairment should be considered in clinical practice.
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Affiliation(s)
- Jorge L Poo
- Grupo Mexicano para el Estudio de las Enfermedades Hepáticas, Mexico.
| | - Juan R Aguilar
- Grupo Mexicano para el Estudio de las Enfermedades Hepáticas, Mexico
| | | | | | - Frida Gasca
- Grupo Mexicano para el Estudio de las Enfermedades Hepáticas, Mexico
| | - Larissa Hernández
- Grupo Mexicano para el Estudio de las Enfermedades Hepáticas, Mexico
| | | | | | | | | | - Pedro Peña
- Grupo Medipharma, Ciudad de Mexico,, Mexico
| | | | - Graciela Tapia
- Departmento de Genética y Bioestadística, Universidad Nacional Autónoma de Mexico, Mexico
| | - Linda E Muñoz-Espinosa
- Grupo Mexicano para el Estudio de las Enfermedades Hepáticas, Mexico; Hospital Universitario, Universidad Autónoma de Nuevo León, Monterrey, Mexico
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14
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Mohammed OS, Attia HG, Mohamed BMSA, Elbaset MA, Fayed HM. Current investigations for liver fibrosis treatment: between repurposing the FDA-approved drugs and the other emerging approaches. JOURNAL OF PHARMACY & PHARMACEUTICAL SCIENCES : A PUBLICATION OF THE CANADIAN SOCIETY FOR PHARMACEUTICAL SCIENCES, SOCIETE CANADIENNE DES SCIENCES PHARMACEUTIQUES 2023; 26:11808. [PMID: 38022905 PMCID: PMC10662312 DOI: 10.3389/jpps.2023.11808] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023]
Abstract
Long-term liver injuries lead to hepatic fibrosis, often progressing into cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. There is currently no effective therapy available for liver fibrosis. Thus, continuous investigations for anti-fibrotic therapy are ongoing. The main theme of anti-fibrotic investigation during recent years is the rationale-based selection of treatment molecules according to the current understanding of the pathology of the disease. The research efforts are mainly toward repurposing current FDA-approved drugs targeting etiological molecular factors involved in developing liver fibrosis. In parallel, investigations also focus on experimental small molecules with evidence to hinder or reverse the fibrosis. Natural compounds, immunological, and genetic approaches have shown significant encouraging effects. This review summarizes the efficacy and safety of current under-investigation antifibrosis medications targeting various molecular targets, as well as the properties of antifibrosis medications, mainly in phase II and III clinical trials.
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Affiliation(s)
- Omima S. Mohammed
- Department of Microbiology, College of Medicine, Najran University, Najran, Saudi Arabia
| | - Hany G. Attia
- Department of Pharmacognosy, College of Pharmacy, Najran University, Najran, Saudi Arabia
| | - Bassim M. S. A. Mohamed
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Marawan A. Elbaset
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Hany M. Fayed
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
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15
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Yang S, Zhang R, Deng W, Chang S, Li Y, Li S. Pirfenidone ameliorates liver steatosis by targeting the STAT3-SCD1 axis. Inflamm Res 2023; 72:1773-1787. [PMID: 37659014 DOI: 10.1007/s00011-023-01776-2] [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: 05/20/2023] [Revised: 07/14/2023] [Accepted: 07/31/2023] [Indexed: 09/05/2023] Open
Abstract
OBJECTIVE Previous studies reported that pirfenidone (PFD) is associated with liver disease. However, the effects of pirfenidone on energy metabolism and hepatic lipid accumulation are still poorly understood. METHODS In this study, C57BL/6J mice were randomly divided into two groups, and fed a normal chow diet (NCD) or a high-fat diet (HFD) for 16 weeks. At the end of the eighth week, half of the mice fed on both diets were treated with PFD. Biochemical and lipid metabolism-related indices were analyzed. Furthermore, Hepa 1-6 cells and mouse primary hepatocytes (MPHs) were incubated with PFD with or without free fatty acid (FFA) treatment. Then, stattic (a p-STAT3 inhibitor) or Ad-shSTAT3 was used to further elucidate the effects of Signal Transducer and Activator of Transcription 3 (STAT3) signaling on PFD regulation of hepatic steatosis. RESULTS PFD ameliorated obesity and hepatic lipid deposition in HFD mice by decreasing stearoyl-CoA desaturase 1 (SCD1) expression and upregulating p-STAT3 in the liver. In Hepa 1-6 cells and MPHs, PFD also down-regulated the expression of SCD1. STAT3 inhibition treatment eliminated the benefits of PFD on both SCD1 and hepatic steatosis. CONCLUSION In summary, our data reveal that PFD may play an important role in mitigating hepatic steatosis in a STAT3-SCD1-dependent manner.
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Affiliation(s)
- Shan Yang
- Department of Endocrinology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Renzi Zhang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenzhen Deng
- Department of Endocrinology, Qianjiang Central Hospital of Chongqing, Chongqing, 409000, China
| | - Shichuan Chang
- Oncology Department, Chongqing University Three Gorges Hospital, Chongqing, 404000, China
| | - Yang Li
- Department of Endocrinology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Sheng Li
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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16
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Musale V, Wasserman DH, Kang L. Extracellular matrix remodelling in obesity and metabolic disorders. LIFE METABOLISM 2023; 2:load021. [PMID: 37383542 PMCID: PMC10299575 DOI: 10.1093/lifemeta/load021] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 05/07/2023] [Accepted: 05/17/2023] [Indexed: 06/30/2023]
Abstract
Obesity causes extracellular matrix (ECM) remodelling which can develop into serious pathology and fibrosis, having metabolic effects in insulin-sensitive tissues. The ECM components may be increased in response to overnutrition. This review will focus on specific obesity-associated molecular and pathophysiological mechanisms of ECM remodelling and the impact of specific interactions on tissue metabolism. In obesity, complex network of signalling molecules such as cytokines and growth factors have been implicated in fibrosis. Increased ECM deposition contributes to the pathogenesis of insulin resistance at least in part through activation of cell surface integrin receptors and CD44 signalling cascades. These cell surface receptors transmit signals to the cell adhesome which orchestrates an intracellular response that adapts to the extracellular environment. Matrix proteins, glycoproteins, and polysaccharides interact through ligand-specific cell surface receptors that interact with the cytosolic adhesion proteins to elicit specific actions. Cell adhesion proteins may have catalytic activity or serve as scaffolds. The vast number of cell surface receptors and the complexity of the cell adhesome have made study of their roles challenging in health and disease. Further complicating the role of ECM-cell receptor interactions is the variation between cell types. This review will focus on recent insights gained from studies of two highly conserved, ubiquitously axes and how they contribute to insulin resistance and metabolic dysfunction in obesity. These are the collagen-integrin receptor-IPP (ILK-PINCH-Parvin) axis and the hyaluronan-CD44 interaction. We speculate that targeting ECM components or their receptor-mediated cell signalling may provide novel insights into the treatment of obesity-associated cardiometabolic complications.
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Affiliation(s)
- Vishal Musale
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, United Kingdom
| | - David H Wasserman
- Department of Molecular Physiology and Biophysics, Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN 37235, United States
| | - Li Kang
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, United Kingdom
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17
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Lee HJ, Tomasini-Johansson BR, Gupta N, Kwon GS. Fibronectin-targeted FUD and PEGylated FUD peptides for fibrotic diseases. J Control Release 2023; 360:69-81. [PMID: 37315694 PMCID: PMC10527082 DOI: 10.1016/j.jconrel.2023.06.008] [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: 02/25/2023] [Revised: 06/03/2023] [Accepted: 06/06/2023] [Indexed: 06/16/2023]
Abstract
Tissue fibrosis is characterized by excessive deposition of extracellular matrix (ECM) molecules. Fibronectin (FN) is a glycoprotein found in the blood and tissues, a key player in the assembly of ECM through interaction with cellular and extracellular components. Functional Upstream Domain (FUD), a peptide derived from an adhesin protein of bacteria, has a high binding affinity for the N-terminal 70-kDa domain of FN that plays a crucial role in FN polymerization. In this regard, FUD peptide has been characterized as a potent inhibitor of FN matrix assembly, reducing excessive ECM accumulation. Furthermore, PEGylated FUD was developed to prevent rapid elimination of FUD and enhance its systemic exposure in vivo. Herein, we summarize the development of FUD peptide as a potential anti-fibrotic agent and its application in experimental fibrotic diseases. In addition, we discuss how modification of the FUD peptide via PEGylation impacts pharmacokinetic profiles of the FUD peptide and can potentially contribute to anti-fibrosis therapy.
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Affiliation(s)
- Hye Jin Lee
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin - Madison, 777 Highland Avenue, Madison, WI 53705, USA
| | - Bianca R Tomasini-Johansson
- Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin - Madison, 1111 Highland Avenue, WIMRII, Madison, WI 53705, USA
| | - Nikesh Gupta
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin - Madison, 777 Highland Avenue, Madison, WI 53705, USA
| | - Glen S Kwon
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin - Madison, 777 Highland Avenue, Madison, WI 53705, USA; Carbone Cancer Center, University of Wisconsin - Madison, 600 Highland Avenue, Madison, WI 53705, USA.
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18
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Martinez-Alvarado Y, Amezcua-Galvez E, Davila-Rodriguez J, Sandoval-Rodriguez A, Galicia-Moreno M, Almeida-López M, Lucano-Landeros S, Santos A, Monroy-Ramirez HC, Armendariz-Borunda J. Pirfenidone Protects from UVB-Induced Photodamage in Hairless Mice. Molecules 2023; 28:molecules28072929. [PMID: 37049691 PMCID: PMC10096127 DOI: 10.3390/molecules28072929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/01/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
Background: Ultraviolet radiation (UV) is the main environmental factor that causes histological degenerative changes of the skin giving rise to a chronic process called photodamage. Non-melanoma skin cancer induced by UVB radiation is a result of a cascade of molecular events caused by DNA damage in epidermis cells, including persistent inflammation, oxidative stress, and suppression of T cell-mediated immunity. Retinoids such as tretinoin have been widely used in skin to treat photoaging and photodamage, though its secondary adverse effects have been recognized. Pirfenidone (PFD) has emerged as an antifibrogenic, anti-inflammatory and antioxidant agent, and in this work its efficacy was evaluated in a model of UVB-induced photodamage. Methods: Epidermal, dermal, and inflammatory changes were measured by histomorphometric parameters. In addition, gene, and protein expression of key molecules in these processes were evaluated. Results: Our results revealed an anti-photodamage effect of topical PFD with absence of inflammatory skin lesions determined by dermoscopy. In addition, PFD reduced elastosis, improved organization, arrangement, and deposition of dermal collagens, downregulated several pro-inflammatory markers such as NF-kB, IL-1, IL-6 and TNFα, and decreased keratinocyte damage. Conclusion: Topical pirfenidone represents a promising agent for the treatment of cell photodamage in humans. Clinical trials need to be carried out to explore this premise.
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19
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Wiering L, Subramanian P, Hammerich L. Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease. Cell Mol Gastroenterol Hepatol 2023; 15:1277-1292. [PMID: 36828280 PMCID: PMC10148161 DOI: 10.1016/j.jcmgh.2023.02.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 02/15/2023] [Accepted: 02/15/2023] [Indexed: 02/26/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a fast growing, chronic liver disease affecting ∼25% of the global population. Nonalcoholic fatty liver disease severity ranges from the less severe simple hepatic steatosis to the more advanced nonalcoholic steatohepatitis (NASH). The presence of NASH predisposes individuals to liver fibrosis, which can further progress to cirrhosis and hepatocellular carcinoma. This makes hepatic fibrosis an important indicator of clinical outcomes in patients with NASH. Hepatic stellate cell activation dictates fibrosis development during NASH. Here, we discuss recent advances in the analysis of the profibrogenic pathways and mediators of hepatic stellate cell activation and inactivation, which ultimately determine the course of disease in nonalcoholic fatty liver disease/NASH.
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Affiliation(s)
- Leke Wiering
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Berlin, Germany
| | - Pallavi Subramanian
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Linda Hammerich
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
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20
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AbouSamra MM, Elgohary R, Mansy SS. Innovated pirfenidone loaded lecithin nanocapsules for targeting liver fibrosis: Formulation, characterization and in vivo study. Int J Pharm 2023; 631:122539. [PMID: 36572266 DOI: 10.1016/j.ijpharm.2022.122539] [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: 08/29/2022] [Revised: 12/18/2022] [Accepted: 12/20/2022] [Indexed: 12/25/2022]
Abstract
Increasing interest in developing antifibrotic therapies became a paramount priority due to the globally raised incidence of deaths secondary to hepatic cirrhosis. This work deals with the development of innovative antifibrotic pirfenidone -loaded lecithin core nanocapsules. This with the intention to target the liver and to increase the drug bioavailability, reducing drug liver toxicity, and studying the associated hepatic microenvironment changes. PFD-loaded lecithin nanocapsules (PFD-LENCs) were prepared using the natural lipoid S45 for its dual benefits of being both a lipid and an amphiphilic surfactant. The selected formulation exhibited in vitro sustained drug release up to 24 h compared to free PFD, which is consistent with the studied pharmacokinetic profile. The studied cytotoxicity of PFD as well as PFD-LENCs exhibited negligible cytotoxicity in normal oral epithelial cells. For exploring the capability of the PFD-LENCs in reaching the liver; in vivo tracing using CLSM, in vivo biodistribution to the vital organs were conducted and electron microscopic examination for depicting nanoparticles in liver tissue was performed. Results revealed the capability of the prepared fluorescent LENC2 in reaching the liver, PFD-LENCs detection in the Disse space of the liver and the significant accumulation of PFD-LENCs in liver tissue compared to the other tested organs. The assessment of the necro-inflammatory, antioxidant and the anti-fibrotic effect of PFD-LENCs (50 & 100 mg/kg) exhibited a significant decrease of liver enzymes, TNF-α, TGF-β, Col-1, α-SMA, and TIMP-1, and a significant increase of catalase enzyme and MMP2 compared to free PFD. EM studies, revealed often detection of dendritic cells in PFD-LENCs (100 mg/kg) treated mice and abnormal collagen structure which can represent an adjunct contribution to the antifibrotic mechanism of PFD-LENCs. In conclusion, the development of this innovative PFD loaded lecithin nanocapsules achieved a targeting ability to the liver, controlled drug release, thereby increase the PFD therapeutic value in downregulating hepatic fibrosis in adjunct with the reduction of liver toxicity.
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Affiliation(s)
- Mona M AbouSamra
- Pharmaceutical Technology Department, National Research Centre, Egypt.
| | - Rania Elgohary
- Narcotics, Ergogenics and Poisons Department, National Research Centre, Egypt
| | - Soheir S Mansy
- Electron Microscopy Research Department, Theodor Bilharz Research Institute, Cairo, Egypt
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21
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Ezhilarasan D, Najimi M. Intercellular communication among liver cells in the perisinusoidal space of the injured liver: Pathophysiology and therapeutic directions. J Cell Physiol 2023; 238:70-81. [PMID: 36409708 DOI: 10.1002/jcp.30915] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/25/2022] [Accepted: 11/03/2022] [Indexed: 11/22/2022]
Abstract
Hepatic stellate cells (HSCs) in the perisinusoidal space are surrounded by hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and other resident immune cells. In the normal liver, HSCs communicate with these cells to maintain normal liver functions. However, after chronic liver injury, injured hepatocytes release several proinflammatory mediators, reactive oxygen species, and damage-associated molecular patterns into the perisinusoidal space. Consequently, such alteration activates quiescent HSCs to acquire a myofibroblast-like phenotype and express high amounts of transforming growth factor-β1, angiopoietins, vascular endothelial growth factors, interleukins 6 and 8, fibril forming collagens, laminin, and E-cadherin. These phenotypic and functional transdifferentiation lead to hepatic fibrosis with a typical abnormal extracellular matrix synthesis and disorganization of the perisinusoidal space of the injured liver. Those changes provide a favorable environment that regulates tumor cell proliferation, migration, adhesion, and survival in the perisinusoidal space. Such tumor cells by releasing transforming growth factor-β1 and other cytokines, will, in turn, activate and deeply interact with HSCs via a bidirectional loop. Furthermore, hepatocellular carcinoma-derived mediators convert HSCs and macrophages into protumorigenic cell populations. Thus, the perisinusoidal space serves as a critical hub for activating HSCs and their interactions with other cell types, which cause a variety of liver diseases such as hepatic inflammation, fibrosis, cirrhosis, and their complications, such as portal hypertension and hepatocellular carcinoma. Therefore, targeting the crosstalk between activated HSCs and tumor cells/immune cells in the tumor microenvironment may also support a promising therapeutic strategy.
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Affiliation(s)
- Devaraj Ezhilarasan
- Department of Pharmacology, Molecular Medicine and Toxicology Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu, India
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
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22
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Gutiérrez-Cuevas J, Lucano-Landeros S, López-Cifuentes D, Santos A, Armendariz-Borunda J. Epidemiologic, Genetic, Pathogenic, Metabolic, Epigenetic Aspects Involved in NASH-HCC: Current Therapeutic Strategies. Cancers (Basel) 2022; 15:23. [PMID: 36612019 PMCID: PMC9818030 DOI: 10.3390/cancers15010023] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed.
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Affiliation(s)
- Jorge Gutiérrez-Cuevas
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Silvia Lucano-Landeros
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Daniel López-Cifuentes
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Arturo Santos
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
| | - Juan Armendariz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
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23
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da Rosa LC, Scales HE, Makhija S, Sutherland K, Benson RA, Brewer JM, Garside P. Revealing stromal and lymphoid sources of Col3a1-expression during inflammation using a novel reporter mouse. DISCOVERY IMMUNOLOGY 2022; 1:kyac008. [PMID: 38566907 PMCID: PMC10917174 DOI: 10.1093/discim/kyac008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 10/04/2022] [Accepted: 11/07/2022] [Indexed: 04/04/2024]
Abstract
One of the earliest signs of dysregulation of the homeostatic process of fibrosis, associated with pathology in chronic conditions such as rheumatoid arthritis, is the overexpression of collagen type III (COL-3). Critically, there is still relatively little known regarding the identity of the cell types expressing the gene encoding COL-3 (Col3a1). Identifying and characterizing Col3a1-expressing cells during the development of fibrosis could reveal new targets for the diagnosis and treatment of fibrosis-related pathologies. As such, a reporter mouse expressing concomitantly Col3a1 and mKate-2, a fluorescent protein, was generated. Using models of footpad inflammation, we demonstrated its effectiveness as a tool to measure the expression of COL-3 during the repair process and provided an initial characterization of some of the stromal and immune cells responsible for Col3a1 expression.
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Affiliation(s)
- Larissa C da Rosa
- School of Infection and Immunity, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
| | - Hannah E Scales
- School of Infection and Immunity, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
| | - Sangeet Makhija
- School of Infection and Immunity, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
| | - Katie Sutherland
- School of Infection and Immunity, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
| | - Robert A Benson
- School of Infection and Immunity, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
| | - James M Brewer
- School of Infection and Immunity, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
| | - Paul Garside
- School of Infection and Immunity, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
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24
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Garbuzenko DV. Current strategies for targeted therapy of liver fibrosis. BULLETIN OF SIBERIAN MEDICINE 2022; 21:154-165. [DOI: 10.20538/1682-0363-2022-3-154-165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Liver fibrosis (LF) is an unfavorable event in the natural course of chronic liver diseases (CLD), therefore, early implementation and widespread use of antifibrotic therapy methods is a pressing issue in hepatology. The aim of the review was to describe current approaches to targeted therapy of LF.PubMed database, Google Scholar search engine, Cochrane Database of Systematic Reviews, eLIBRARY.RU scientific electronic library, as well as reference lists of articles were used to search for scientific articles. The publications that corresponded to the aim of the study were selected for the period from 1998 to 2021 by the terms “liver fibrosis”, “pathogenesis”, and “treatment”. Inclusion criteria were restricted to targeted therapy of LF.Despite the growing evidence for reversibility of LF, there are currently no effective or clinically approved regimens for its specific therapy. However, taking into account the relevance of the issue, scientific research in this area is necessary. Multiple drugs with a good safety profile have been studied, which, though intended for other purposes, can have a positive effect on LF. In addition, a number of innovative approaches that differ from pharmacotherapy inspire optimism about finding a solution to this problem. It is obvious that studies focused on well-characterized groups of patients with confirmed histologic, elastography, clinical, and radiological parameters are required. This is a challenging task, since the key point will be stratification of risk based on ethnicity, etiology, and clinical status, and very large samples will be required for a reliable assessment. Nevertheless, the solution will increase efficiency of treatment for patients with CLD, improve their prognosis and quality of life, and significantly reduce the need for liver transplantation, a demand for which remains extremely high worldwide.
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25
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Wang Z, Ye M, Zhang XJ, Zhang P, Cai J, Li H, She ZG. Impact of NAFLD and its pharmacotherapy on lipid profile and CVD. Atherosclerosis 2022; 355:30-44. [PMID: 35872444 DOI: 10.1016/j.atherosclerosis.2022.07.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 06/16/2022] [Accepted: 07/13/2022] [Indexed: 11/21/2022]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Increasing evidence suggests that, in addition to traditional metabolic risk factors such as obesity, hypercholesterolemia, hypertension, diabetes mellitus, and insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD) is an emerging driver of ASCVD via multiple mechanisms, mainly by disrupting lipid metabolism. The lack of pharmaceutical treatment has spurred substantial investment in the research and development of NAFLD drugs. However, many reagents with promising therapeutic potential for NAFLD also have considerable impacts on the circulating lipid profile. In this review, we first summarize the mechanisms linking lipid dysregulation in NAFLD to the progression of ASCVD. Importantly, we highlight the potential risks of/benefits to ASCVD conferred by NAFLD pharmaceutical treatments and discuss potential strategies and next-generation drugs for treating NAFLD without the unwanted side effects.
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Affiliation(s)
- Zhenya Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China
| | - Mao Ye
- Department of Cardiology, Huanggang Central Hospital, HuBei Province, China; Huanggang Institute of Translational Medicine, Huanggang, China
| | - Xiao-Jing Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China; School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Peng Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China; School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Jingjing Cai
- Institute of Model Animal, Wuhan University, Wuhan, China; Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China; Huanggang Institute of Translational Medicine, Huanggang, China.
| | - Zhi-Gang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China.
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26
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Matthaiou EI, Sharifi H, O'Donnell C, Chiu W, Owyang C, Chatterjee P, Turk I, Johnston L, Brondstetter T, Morris K, Cheng GS, Hsu JL. The safety and tolerability of pirfenidone for bronchiolitis obliterans syndrome after hematopoietic cell transplant (STOP-BOS) trial. Bone Marrow Transplant 2022; 57:1319-1326. [PMID: 35641662 PMCID: PMC9357121 DOI: 10.1038/s41409-022-01716-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 05/09/2022] [Accepted: 05/13/2022] [Indexed: 02/03/2023]
Abstract
Bronchiolitis obliterans syndrome (BOS) is the most morbid form of chronic graft-versus-host disease (cGVHD) after hematopoietic cell transplantation (HCT). Progressive airway fibrosis leads to a 5-year survival of 40%. Treatment options for BOS are limited. A single arm, 52-week, Phase I study of pirfenidone was conducted. The primary outcome was tolerability defined as maintaining the recommended dose of pirfenidone (2403 mg/day) without a dose reduction totaling more than 21 days, due to adverse events (AEs) or severe AEs (SAEs). Secondary outcomes included pulmonary function tests (PFTs) and patient reported outcomes (PROs). Among 22 participants treated for 1 year, 13 (59%) tolerated the recommended dose, with an average daily tolerated dose of 2325.6 mg/day. Twenty-two SAEs were observed, with 90.9% related to infections, none were attributed to pirfenidone. There was an increase in the average percent predicted forced expiratory volume in 1 s (FEV1%) of 7 percentage points annually and improvements in PROs related to symptoms of cGVHD. In this Phase I study, treatment with pirfenidone was safe. The stabilization in PFTs and improvements in PROs suggest the potential of pirfenidone for BOS treatment and support the value of a randomized controlled trial to evaluate the efficacy of pirfenidone in BOS after HCT. The study is registered in ClinicalTrials.gov (NCT03315741).
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Affiliation(s)
- Efthymia Iliana Matthaiou
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Husham Sharifi
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Christian O'Donnell
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Wayland Chiu
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Clark Owyang
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY, USA
| | - Paulami Chatterjee
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Ihsan Turk
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Laura Johnston
- Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, USA
| | - Theresa Brondstetter
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, USA
| | - Karen Morris
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Guang-Shing Cheng
- Clinical Research Division, Section of Pulmonary and Critical Care, Fred Hutchinson Cancer Research Center, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA, USA
| | - Joe L Hsu
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA.
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Cai X, Liu X, Xie W, Ma A, Tan Y, Shang J, Zhang J, Chen C, Yu Y, Qu Y, Zhang L, Luo Y, Yin P, Cheng J, Lu L. Hydronidone for the Treatment of Liver Fibrosis Related to Chronic Hepatitis B: A Phase 2 Randomized Controlled Trial. Clin Gastroenterol Hepatol 2022:S1542-3565(22)00650-4. [PMID: 35842120 DOI: 10.1016/j.cgh.2022.05.056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/26/2022] [Accepted: 05/31/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hepatitis B virus infection frequently leads to liver fibrosis and is the leading cause of hepatocellular carcinoma and cirrhosis in Asia Pacific. Pirfenidone is approved by the United States Food and Drug Administration for treatment of idiopathic pulmonary fibrosis, and hydronidone is a novel structural modification of pirfenidone with the aim of reducing hepatoxicity. We aimed to investigate the safety and efficacy of hydronidone in patients with chronic hepatitis B (CHB)-associated liver fibrosis. METHODS This was a 52-week multicenter, randomized, double-blind, placebo-controlled, phase II study at 8 centers in China. Patients with CHB with biopsied documented liver fibrosis were eligible and were randomly assigned into receiving daily placebo or hydronidone orally (180 mg/day, 270 mg/day, or 360 mg/day). All enrolled subjects also received entecavir 0.5 mg/day. A second liver biopsy was performed at week 52. The primary endpoint was defined as fibrosis improvement (reduction of at least 1 Ishak score at week 52 of treatment). RESULTS From June 25, 2015, to September 5, 2019, 168 patients with CHB and liver fibrosis met the inclusion/exclusion criteria and were subsequently randomized, 43 in the placebo group and 125 in the hydronidone groups (42 in the 180-mg group, 42 in the 270-mg group, and 41 in the 360-mg group). The fibrosis improvement endpoint was achieved by 11 patients (25.6%) in the placebo group and 17 patients (40.5%) in the 180-mg group (P = .12), 23 patients (54.8%) in the 270-mg group (P = .006), and 18 patients (43.90%) in the 360-mg group (P = .08). The improvement rate was 58 of 125 (46.4%) in the combined hydronidone group (P = .014). The overall safety profile and incidence of serious adverse events were similar among the groups. CONCLUSIONS Hydronidone plus entecavir showed clinically significant histological improvement of liver fibrosis in patients with CHB, and the dose of 270 mg showed the best efficacy of fibrosis regression. Further studies are required to assess the long-term effectiveness of hydronidone in regression of hepatic fibrosis. CLINICALTRIALS gov number, NCT02499562.
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Affiliation(s)
- Xiaobo Cai
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xuehan Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China; Core Facility Center for Medical Sciences, The First Affiliated Hospital of USTC, Hefei, China
| | - Wen Xie
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Anlin Ma
- Department of Infectious Diseases, China-Japan Friendship Hospital, Beijing, China
| | - Youwen Tan
- Department of Infectious Diseases, the Third People's Hospital of Zhenjiang, Jiangsu Province, China
| | - Jia Shang
- Department of Infectious Diseases, Henan Provincial People's Hospital, Henan Province, China
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Chengwei Chen
- Center for Liver Diseases, 905th Hospital of PLA Navy, Shanghai, China
| | - Yanyan Yu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Ying Qu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ling Zhang
- Continent Pharmaceuticals, Beijing, China
| | - Ying Luo
- Continent Pharmaceuticals, Beijing, China
| | - Ping Yin
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
| | - Jun Cheng
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
| | - Lungen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
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Qiu JL, Zhang GF, Chai YN, Han XY, Zheng HT, Li XF, Duan F, Chen LY. Ligustrazine Attenuates Liver Fibrosis by Targeting miR-145 Mediated Transforming Growth Factor- β/Smad Signaling in an Animal Model of Biliary Atresia. J Pharmacol Exp Ther 2022; 381:257-265. [PMID: 35398813 DOI: 10.1124/jpet.121.001020] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 03/28/2022] [Indexed: 01/03/2025] Open
Abstract
To investigate therapeutic target for ligustrazine during liver fibrosis in an ethanol-induced biliary atresia rat model and transforming growth factor-β (TGF-β) induced hepatic stellate cell activation cell model, and the underlying mechanism, a total of 30 rats were randomly assigned into five groups (n = 6 per group): control, sham, ethanol-induced biliary atresia model, model plus pirfenidone, and model plus ligustrazine groups. The liver changes were assessed using H&E and Masson staining and transmission electron microscopy. Expression of miR-145 and mRNA and protein levels of TGF-β/smads pathway-related proteins were detected. HSC-T6 cells were infected with LV-miR or rLV-miR-145 in the presence or absence of SMAD3 inhibitor SIS3 and treated with 2.5 ng/ml TGF-β1 and then with ligustrazine. Collected cells were subjected to detect the expression of miR-145 and mRNA and protein expression levels of TGF-β/smads pathway-related proteins. Ligustrazine rescued liver fibrogenesis and pathology for ethanol-caused bile duct injury, revealed by decreased α-smooth muscle actin and collagen I expression and liver tissue and cell morphology integrity. Further experiments showed that ligustrazine inhibited intrinsic and phosphorylated Smad2/3 protein expression and modification. Similar results were obtained in cells. In addition, ligustrazine altered miR-145 expression in both animal and cell models. Lentivirus mediated miR-145 overexpression and knockdown recombinant virus showed that miR-145 enhanced the TGF-β/Smad pathway, which led to hepatic stellate cell activation, and ligustrazine blocked this activation. This work validated that ligustrazine-regulated miR-145 mediated TGF-β/Smad signaling to inhibit the progression of liver fibrosis in a biliary atresia rat model and provided a new therapeutic strategy for liver fibrosis. SIGNIFICANCE STATEMENT: With an ethanol-induced biliary atresia rat model, ligustrazine was found to rescue liver fibrogenesis and pathology for ethanol caused bile duct injury, revealed by decreased α-smooth muscle actin and collagen I expression and liver tissue and cell morphology integrity. Furthermore, we found ligustrazine upregulated miR-145 expression and inhibited TGF-β/SMAD signaling pathway both in vivo and in vitro. In addition, overexpression and knockdown of miR-145 confirmed that miR-145 is involved in the ligustrazine inhibition of liver fibrosis through the TGF-β/SMAD signaling pathway.
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Affiliation(s)
- Jian-Li Qiu
- Department of Pediatrics (J.-L.Q., H.-T.Z., X.-F.L.) and Department of Gastroenterology (F.D.), the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China; Department of Pediatric Surgery (G.-F.Z.) and Department of Pharmacy (Y.-N.C.), the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan University of Chinese Medicine, Zhengzhou, China (X.-Y.H.); and Department of Rehabilitation, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (L.-Y.C.)
| | - Guo-Feng Zhang
- Department of Pediatrics (J.-L.Q., H.-T.Z., X.-F.L.) and Department of Gastroenterology (F.D.), the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China; Department of Pediatric Surgery (G.-F.Z.) and Department of Pharmacy (Y.-N.C.), the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan University of Chinese Medicine, Zhengzhou, China (X.-Y.H.); and Department of Rehabilitation, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (L.-Y.C.)
| | - Yu-Na Chai
- Department of Pediatrics (J.-L.Q., H.-T.Z., X.-F.L.) and Department of Gastroenterology (F.D.), the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China; Department of Pediatric Surgery (G.-F.Z.) and Department of Pharmacy (Y.-N.C.), the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan University of Chinese Medicine, Zhengzhou, China (X.-Y.H.); and Department of Rehabilitation, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (L.-Y.C.)
| | - Xiao-Yan Han
- Department of Pediatrics (J.-L.Q., H.-T.Z., X.-F.L.) and Department of Gastroenterology (F.D.), the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China; Department of Pediatric Surgery (G.-F.Z.) and Department of Pharmacy (Y.-N.C.), the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan University of Chinese Medicine, Zhengzhou, China (X.-Y.H.); and Department of Rehabilitation, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (L.-Y.C.)
| | - Hai-Tao Zheng
- Department of Pediatrics (J.-L.Q., H.-T.Z., X.-F.L.) and Department of Gastroenterology (F.D.), the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China; Department of Pediatric Surgery (G.-F.Z.) and Department of Pharmacy (Y.-N.C.), the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan University of Chinese Medicine, Zhengzhou, China (X.-Y.H.); and Department of Rehabilitation, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (L.-Y.C.)
| | - Xiang-Feng Li
- Department of Pediatrics (J.-L.Q., H.-T.Z., X.-F.L.) and Department of Gastroenterology (F.D.), the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China; Department of Pediatric Surgery (G.-F.Z.) and Department of Pharmacy (Y.-N.C.), the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan University of Chinese Medicine, Zhengzhou, China (X.-Y.H.); and Department of Rehabilitation, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (L.-Y.C.)
| | - Fei Duan
- Department of Pediatrics (J.-L.Q., H.-T.Z., X.-F.L.) and Department of Gastroenterology (F.D.), the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China; Department of Pediatric Surgery (G.-F.Z.) and Department of Pharmacy (Y.-N.C.), the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan University of Chinese Medicine, Zhengzhou, China (X.-Y.H.); and Department of Rehabilitation, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (L.-Y.C.)
| | - Ling-Yan Chen
- Department of Pediatrics (J.-L.Q., H.-T.Z., X.-F.L.) and Department of Gastroenterology (F.D.), the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China; Department of Pediatric Surgery (G.-F.Z.) and Department of Pharmacy (Y.-N.C.), the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan University of Chinese Medicine, Zhengzhou, China (X.-Y.H.); and Department of Rehabilitation, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (L.-Y.C.)
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Prikhodko VA, Bezborodkina NN, Okovityi SV. Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates. Biomedicines 2022; 10:274. [PMID: 35203484 PMCID: PMC8869100 DOI: 10.3390/biomedicines10020274] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic burden of NAFLD, the lack of approved pharmacotherapy regimens remains an unsolved issue. In this paper, we aimed to provide an update on the rapidly changing therapeutic landscape and highlight the major novel approaches to the treatment of this disease. In addition to describing the biomolecules and pathways identified as upcoming pharmacological targets for NAFLD, we reviewed the current status of drug discovery and development pipeline with a special focus on recent evidence from clinical trials.
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Affiliation(s)
- Veronika A. Prikhodko
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
| | - Natalia N. Bezborodkina
- Zoological Institute, Russian Academy of Sciences, 1 Universitetskaya emb., 199034 St. Petersburg, Russia;
| | - Sergey V. Okovityi
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
- Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, Saint Petersburg State University, 7/9 Universitetskaya emb., 199034 St. Petersburg, Russia
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Vilaseca M, Gracia-Sancho J. Drugs to Modify Liver Fibrosis Progression and Regression. PORTAL HYPERTENSION VII 2022:201-218. [DOI: 10.1007/978-3-031-08552-9_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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31
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Qu W, Ma T, Cai J, Zhang X, Zhang P, She Z, Wan F, Li H. Liver Fibrosis and MAFLD: From Molecular Aspects to Novel Pharmacological Strategies. Front Med (Lausanne) 2021; 8:761538. [PMID: 34746195 PMCID: PMC8568774 DOI: 10.3389/fmed.2021.761538] [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: 08/20/2021] [Accepted: 09/27/2021] [Indexed: 12/11/2022] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a new disease definition, and this nomenclature MAFLD was proposed to renovate its former name, non-alcoholic fatty liver disease (NAFLD). MAFLD/NAFLD have shared and predominate causes from nutrition overload to persistent liver damage and eventually lead to the development of liver fibrosis and cirrhosis. Unfortunately, there is an absence of effective treatments to reverse MAFLD/NAFLD-associated fibrosis. Due to the significant burden of MAFLD/NAFLD and its complications, there are active investigations on the development of novel targets and pharmacotherapeutics for treating this disease. In this review, we cover recent discoveries in new targets and molecules for antifibrotic treatment, which target pathways intertwined with the fibrogenesis process, including lipid metabolism, inflammation, cell apoptosis, oxidative stress, and extracellular matrix formation. Although marked advances have been made in the development of antifibrotic therapeutics, none of the treatments have achieved the endpoints evaluated by liver biopsy or without significant side effects in a large-scale trial. In addition to the discovery of new druggable targets and pharmacotherapeutics, personalized medication, and combinatorial therapies targeting multiple profibrotic pathways could be promising in achieving successful antifibrotic interventions in patients with MAFLD/NAFLD.
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Affiliation(s)
- Weiyi Qu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Tengfei Ma
- Institute of Model Animal, Wuhan University, Wuhan, China
- Department of Neurology, Huanggang Central Hospital, Huanggang, China
- Huanggang Institute of Translational Medicine, Huanggang Central Hospital, Huanggang, China
| | - Jingjing Cai
- Institute of Model Animal, Wuhan University, Wuhan, China
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiaojing Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Peng Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Zhigang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Feng Wan
- Department of Neurology, Huanggang Central Hospital, Huanggang, China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
- Huanggang Institute of Translational Medicine, Huanggang Central Hospital, Huanggang, China
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32
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Tan Z, Sun H, Xue T, Gan C, Liu H, Xie Y, Yao Y, Ye T. Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy. Front Cell Dev Biol 2021; 9:730176. [PMID: 34621747 PMCID: PMC8490799 DOI: 10.3389/fcell.2021.730176] [Citation(s) in RCA: 123] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 08/31/2021] [Indexed: 02/05/2023] Open
Abstract
Liver fibrosis is an abnormal wound repair response caused by a variety of chronic liver injuries, which is characterized by over-deposition of diffuse extracellular matrix (ECM) and anomalous hyperplasia of connective tissue, and it may further develop into liver cirrhosis, liver failure or liver cancer. To date, chronic liver diseases accompanied with liver fibrosis have caused significant morbidity and mortality in the world with increasing tendency. Although early liver fibrosis has been reported to be reversible, the detailed mechanism of reversing liver fibrosis is still unclear and there is lack of an effective treatment for liver fibrosis. Thus, it is still a top priority for the research and development of anti-fibrosis drugs. In recent years, many strategies have emerged as crucial means to inhibit the occurrence and development of liver fibrosis including anti-inflammation and liver protection, inhibition of hepatic stellate cells (HSCs) activation and proliferation, reduction of ECM overproduction and acceleration of ECM degradation. Moreover, gene therapy has been proved to be a promising anti-fibrosis method. Here, we provide an overview of the relevant targets and drugs under development. We aim to classify and summarize their potential roles in treatment of liver fibrosis, and discuss the challenges and development of anti-fibrosis drugs.
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Affiliation(s)
- Zui Tan
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hongbao Sun
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Taixiong Xue
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Cailing Gan
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hongyao Liu
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yuting Xie
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yuqin Yao
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Tinghong Ye
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Local Delivery of Pirfenidone by PLA Implants Modifies Foreign Body Reaction and Prevents Fibrosis. Biomedicines 2021; 9:biomedicines9080853. [PMID: 34440057 PMCID: PMC8389617 DOI: 10.3390/biomedicines9080853] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/19/2021] [Accepted: 07/19/2021] [Indexed: 01/04/2023] Open
Abstract
Peri-implant fibrosis (PIF) increases the postsurgical risks after implantation and limits the efficacy of the implantable drug delivery systems (IDDS). Pirfenidone (PF) is an oral anti-fibrotic drug with a short (<3 h) circulation half-life and strong adverse side effects. In the current study, disk-shaped IDDS prototype combining polylactic acid (PLA) and PF, PLA@PF, with prolonged (~3 days) PF release (in vitro) was prepared. The effects of the PLA@PF implants on PIF were examined in the rabbit ear skin pocket model on postoperative days (POD) 30 and 60. Matching blank PLA implants (PLA0) and PLA0 with an equivalent single-dose PF injection performed on POD0 (PLA0+injPF) served as control. On POD30, the intergroup differences were observed in α-SMA, iNOS and arginase-1 expressions in PLA@PF and PLA0+injPF groups vs. PLA0. On POD60, PIF was significantly reduced in PLA@PF group. The peri-implant tissue thickness decreased (532 ± 98 μm vs. >1100 μm in control groups) approaching the intact derma thickness value (302 ± 15 μm). In PLA@PF group, the implant biodegradation developed faster, while arginase-1 expression was suppressed in comparison with other groups. This study proves the feasibility of the local control of fibrotic response on implants via modulation of foreign body reaction with slowly biodegradable PF-loaded IDDS.
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Neshat SY, Quiroz VM, Wang Y, Tamayo S, Doloff JC. Liver Disease: Induction, Progression, Immunological Mechanisms, and Therapeutic Interventions. Int J Mol Sci 2021; 22:ijms22136777. [PMID: 34202537 PMCID: PMC8267746 DOI: 10.3390/ijms22136777] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 02/06/2023] Open
Abstract
The liver is an organ with impressive regenerative potential and has been shown to heal sizable portions after their removal. However, certain diseases can overstimulate its potential to self-heal and cause excessive cellular matrix and collagen buildup. Decompensation of liver fibrosis leads to cirrhosis, a buildup of fibrotic ECM that impedes the liver’s ability to efficiently exchange fluid. This review summarizes the complex immunological activities in different liver diseases, and how failure to maintain liver homeostasis leads to progressive fibrotic tissue development. We also discuss a variety of pathologies that lead to liver cirrhosis, such as alcoholic liver disease and chronic hepatitis B virus (HBV). Mesenchymal stem cells are widely studied for their potential in tissue replacement and engineering. Herein, we discuss the potential of MSCs to regulate immune response and alter the disease state. Substantial efforts have been performed in preclinical animal testing, showing promising results following inhibition of host immunity. Finally, we outline the current state of clinical trials with mesenchymal stem cells and other cellular and non-cellular therapies as they relate to the detection and treatment of liver cirrhosis.
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Affiliation(s)
- Sarah Y. Neshat
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (S.Y.N.); (V.M.Q.); (Y.W.); (S.T.)
| | - Victor M. Quiroz
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (S.Y.N.); (V.M.Q.); (Y.W.); (S.T.)
| | - Yuanjia Wang
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (S.Y.N.); (V.M.Q.); (Y.W.); (S.T.)
| | - Sebastian Tamayo
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (S.Y.N.); (V.M.Q.); (Y.W.); (S.T.)
| | - Joshua C. Doloff
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (S.Y.N.); (V.M.Q.); (Y.W.); (S.T.)
- Department of Materials Science and Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
- Sidney Kimmel Comprehensive Cancer Center, Oncology-Cancer Immunology Sidney Kimmel Comprehensive Cancer Center and the Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
- Correspondence:
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35
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Wei Q, Kong N, Liu X, Tian R, Jiao M, Li Y, Guan H, Wang K, Yang P. Pirfenidone attenuates synovial fibrosis and postpones the progression of osteoarthritis by anti-fibrotic and anti-inflammatory properties in vivo and in vitro. J Transl Med 2021; 19:157. [PMID: 33874948 PMCID: PMC8054406 DOI: 10.1186/s12967-021-02823-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/09/2021] [Indexed: 12/11/2022] Open
Abstract
Background Osteoarthritis (OA) is a disease of the entire joint involving synovial fibrosis and inflammation. Pathological changes to the synovium can accelerate the progression of OA. Pirfenidone (PFD) is a potent anti-fibrotic drug with additional anti-inflammatory properties. However, the influence of PFD on OA is unknown. Methods Proliferation of human fibroblast-like synoviocytes (FLSs) after treatment with TGF-β1 or PFD was evaluated using a Cell Counting Kit-8 assay and their migration using a Transwell assay. The expression of fibrosis-related genes (COL1A1, TIMP-1, and ACTA-2) and those related to inflammation (IL-6 and TNF-α) was quantified by real-time quantitative PCR. The protein expression levels of COL1A1, α-SMA (coded by ACTA-2), IL-6 and TNF-α were measured by enzyme-linked immunosorbent assay. A rabbit model of OA was established and then PFD was administered by gavage. The expression of genes related to fibrosis (COL1A1, TIMP-1, and ADAM-12) and inflammation (IL-6 and TNF-α) was measured using RNA extracted from the synovium. Synovial tissue was examined histologically after staining with H&E, Masson’s trichrome, and immunofluorescence. Synovitis scores, the volume fraction of collagen, and mean fluorescence intensity were calculated. Degeneration of articular cartilage was analyzed using a Safranin O-fast green stain and OARSI grading. Results The proliferation of FLSs was greatest when induced with 2.5 ng/ml TGF-β1 although it did not promote their migration. Therefore, 2.5 ng/ml TGF-β1 was used to stimulate the FLSs and evaluate the effects of PFD, which inhibited the migration of FLSs at concentrations as low as 1.0 mg/ml. PFD decreased the expression of COL1A1 while TGF-β1 increased both mRNA and protein expression levels of IL-6 but had no effect on α-SMA or TNF-α expression. PFD decreased mRNA expression levels of COL1A1, IL-6, and TNF-α in vivo. H&E staining and synovitis scores indicated that PFD reduced synovial inflammation, while Masson’s trichrome and immunofluorescence staining suggested that PFD decreased synovial fibrosis. Safranin O-Fast Green staining and the OARSI scores demonstrated that PFD delayed the progression of OA. Conclusions PFD attenuated synovial fibrosis and inflammation, and postponed the progression of osteoarthritis in a modified Hulth model of OA in rabbits, which was related to its anti-fibrotic and anti-inflammatory properties.
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Affiliation(s)
- Qilu Wei
- Bone and Joint Surgery Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Ning Kong
- Bone and Joint Surgery Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Xiaohui Liu
- Bone and Joint Surgery Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Run Tian
- Bone and Joint Surgery Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Ming Jiao
- Bone and Joint Surgery Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Yiyang Li
- Bone and Joint Surgery Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Huanshuai Guan
- Bone and Joint Surgery Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Kunzheng Wang
- Bone and Joint Surgery Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.
| | - Pei Yang
- Bone and Joint Surgery Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.
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Bai Y, Wang W, Wang L, Ma L, Zhai D, Wang F, Shi R, Liu C, Xu Q, Chen G, Lu Z. Obacunone Attenuates Liver Fibrosis with Enhancing Anti-Oxidant Effects of GPx-4 and Inhibition of EMT. Molecules 2021; 26:molecules26020318. [PMID: 33435504 PMCID: PMC7827035 DOI: 10.3390/molecules26020318] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/04/2021] [Accepted: 01/06/2021] [Indexed: 01/13/2023] Open
Abstract
Obacunone, a limonin triterpenoid extracted from Phellodendronchinense Schneid or Dictamnus dasycarpusb Turcz plant, elicits a variety of pharmacological effects such as anti-inflammatory, anti-neoplastic, anti-oxidation, and anti-lung-fibrosis ones. However, the anti-fibrotic effect of obacunone and the detailed underlying mechanism in liver fibrosis remain unclear. Liver fibrosis is a debilitating disease threatening human health. Transforming growth factor (TGF)-β/P-Smad is a major pathway of fibrosis featured with epithelia mesenchymal transformations (EMT) and collagen depositions, accompanying with excessive oxygen-free radicals. Nrf-2 acts as a key anti-oxidative regulator driving the expressions of various antioxidant-related genes. Glutathionperoxidase-4 (GPx-4) is a member of the glutathione peroxidase family that directly inhibits phospholipid oxidation to alleviate oxidative stress. In the present study, we aimed to explore the role of obacunone in mouse liver fibrosis model induced by carbon tetrachloride (CCl4) and in hepatic stellate cells (LX2 cell line) challenging with TGF-β. Obacunone demonstrated potent ameliorative effects on liver fibrosis both in activated LX2 and in mice liver tissues with reduced levels of α-SMA, collagen1, and vimentin. Obacunone also remarkably suppressed the TGF-β/P-Smad signals and EMT process. Meanwhile, obacunone exerted a potent anti-oxidation effect by reducing the levels of reactive oxygen species (ROS) in both models. The antioxidant effect of obacunone was attributed to the activation of GPx-4 and Nrf-2. In addition, the therapeutic effect of obacunone on LX2 cells was significantly removed in vitro plus with GPx-4 antagonist RSL3, in parallel with the re-elevated levels of ROS. Thus, we demonstrate that obacunone is able to attenuate liver fibrosis via enhancing GPx-4 signal and inhibition of the TGF-β/P-Smad pathway and EMT process.
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Affiliation(s)
- Yongquan Bai
- The College of Life Sciences, Northwest University, Xi’an 710127, China; (Y.B.); (L.M.); (F.W.); (R.S.); (C.L.); (Q.X.)
| | - Wenwen Wang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, Air Force Military Medical University, Xi’an 710083, China; (W.W.); (L.W.)
| | - Li Wang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, Air Force Military Medical University, Xi’an 710083, China; (W.W.); (L.W.)
| | - Lirong Ma
- The College of Life Sciences, Northwest University, Xi’an 710127, China; (Y.B.); (L.M.); (F.W.); (R.S.); (C.L.); (Q.X.)
| | - Dongsheng Zhai
- Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi’an 710083, China;
| | - Furong Wang
- The College of Life Sciences, Northwest University, Xi’an 710127, China; (Y.B.); (L.M.); (F.W.); (R.S.); (C.L.); (Q.X.)
| | - Rui Shi
- The College of Life Sciences, Northwest University, Xi’an 710127, China; (Y.B.); (L.M.); (F.W.); (R.S.); (C.L.); (Q.X.)
| | - Chaoyang Liu
- The College of Life Sciences, Northwest University, Xi’an 710127, China; (Y.B.); (L.M.); (F.W.); (R.S.); (C.L.); (Q.X.)
| | - Qing Xu
- The College of Life Sciences, Northwest University, Xi’an 710127, China; (Y.B.); (L.M.); (F.W.); (R.S.); (C.L.); (Q.X.)
| | - Guo Chen
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, Air Force Military Medical University, Xi’an 710083, China; (W.W.); (L.W.)
- Correspondence: (G.C.); (Z.L.); Tel.: +86-186-2904-7181 (G.C.); +86-152-0296-3679 (Z.L.)
| | - Zifan Lu
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, Air Force Military Medical University, Xi’an 710083, China; (W.W.); (L.W.)
- Correspondence: (G.C.); (Z.L.); Tel.: +86-186-2904-7181 (G.C.); +86-152-0296-3679 (Z.L.)
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Sepulveda-Crespo D, Resino S, Martinez I. Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis. Drugs 2021; 81:419-443. [PMID: 33400242 DOI: 10.1007/s40265-020-01458-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Direct-acting antivirals eliminate hepatitis C virus (HCV) in more than 95% of treated individuals and may abolish liver injury, arrest fibrogenesis, and reverse fibrosis and cirrhosis. However, liver regeneration is usually a slow process that is less effective in the late stages of fibrosis. What is more, fibrogenesis may prevail in patients with advanced cirrhosis, where it can progress to liver failure and hepatocellular carcinoma. Therefore, the development of antifibrotic drugs that halt and reverse fibrosis progression is urgently needed. Fibrosis occurs due to the repair process of damaged hepatic tissue, which eventually leads to scarring. The innate immune response against HCV is essential in the initiation and progression of liver fibrosis. HCV-infected hepatocytes and liver macrophages secrete proinflammatory cytokines and chemokines that promote the activation and differentiation of hepatic stellate cells (HSCs) to myofibroblasts that produce extracellular matrix (ECM) components. Prolonged ECM production by myofibroblasts due to chronic inflammation is essential to the development of fibrosis. While no antifibrotic therapy is approved to date, several drugs are being tested in phase 2 and phase 3 trials with promising results. This review discusses current state-of-the-art knowledge on treatments targeting the innate immune system to revert chronic hepatitis C-associated liver fibrosis. Agents that cause liver damage may vary (alcohol, virus infection, etc.), but fibrosis progression shows common patterns among them, including chronic inflammation and immune dysregulation, hepatocyte injury, HSC activation, and excessive ECM deposition. Therefore, mechanisms underlying these processes are promising targets for general antifibrotic therapies.
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Affiliation(s)
- Daniel Sepulveda-Crespo
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
| | - Isidoro Martinez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
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Heyens LJM, Busschots D, Koek GH, Robaeys G, Francque S. Liver Fibrosis in Non-alcoholic Fatty Liver Disease: From Liver Biopsy to Non-invasive Biomarkers in Diagnosis and Treatment. Front Med (Lausanne) 2021; 8:615978. [PMID: 33937277 PMCID: PMC8079659 DOI: 10.3389/fmed.2021.615978] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 03/22/2021] [Indexed: 12/12/2022] Open
Abstract
An increasing percentage of people have or are at risk to develop non-alcoholic fatty liver disease (NAFLD) worldwide. NAFLD comprises different stadia going from isolated steatosis to non-alcoholic steatohepatitis (NASH). NASH is a chronic state of liver inflammation that leads to the transformation of hepatic stellate cells to myofibroblasts. These cells produce extra-cellular matrix that results in liver fibrosis. In a normal situation, fibrogenesis is a wound healing process that preserves tissue integrity. However, sustained and progressive fibrosis can become pathogenic. This process takes many years and is often asymptomatic. Therefore, patients usually present themselves with end-stage liver disease e.g., liver cirrhosis, decompensated liver disease or even hepatocellular carcinoma. Fibrosis has also been identified as the most important predictor of prognosis in patients with NAFLD. Currently, only a minority of patients with liver fibrosis are identified to be at risk and hence referred for treatment. This is not only because the disease is largely asymptomatic, but also due to the fact that currently liver biopsy is still the golden standard for accurate detection of liver fibrosis. However, performing a liver biopsy harbors some risks and requires resources and expertise, hence is not applicable in every clinical setting and is unsuitable for screening. Consequently, different non-invasive diagnostic tools, mainly based on analysis of blood or other specimens or based on imaging have been developed or are in development. In this review, we will first give an overview of the pathogenic mechanisms of the evolution from isolated steatosis to fibrosis. This serves as the basis for the subsequent discussion of the current and future diagnostic biomarkers and anti-fibrotic drugs.
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Affiliation(s)
- Leen J. M. Heyens
- Faculty of Health and Life Sciences, Hasselt University, Hasselt, Belgium
- School of Nutrition and Translational Research in Metabolism, NUTRIM, Maastricht University, Maastricht, Netherlands
- Department of Gastro-Enterology and Hepatology, Ziekenhuis Oost-Limburg, Genk, Belgium
| | - Dana Busschots
- Faculty of Health and Life Sciences, Hasselt University, Hasselt, Belgium
- School of Nutrition and Translational Research in Metabolism, NUTRIM, Maastricht University, Maastricht, Netherlands
| | - Ger H. Koek
- School of Nutrition and Translational Research in Metabolism, NUTRIM, Maastricht University, Maastricht, Netherlands
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Geert Robaeys
- Faculty of Health and Life Sciences, Hasselt University, Hasselt, Belgium
- Department of Gastro-Enterology and Hepatology, Ziekenhuis Oost-Limburg, Genk, Belgium
- Department of Gastroenterology and Hepatology, University Hospital Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- *Correspondence: Sven Francque
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Odagiri N, Matsubara T, Sato-Matsubara M, Fujii H, Enomoto M, Kawada N. Anti-fibrotic treatments for chronic liver diseases: The present and the future. Clin Mol Hepatol 2020; 27:413-424. [PMID: 33317250 PMCID: PMC8273638 DOI: 10.3350/cmh.2020.0187] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 11/07/2020] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis reflects tissue scarring in the liver due to the accumulation of excessive extracellular matrix in response to chronically persistent liver injury. Hepatocyte cell death can trigger capillarization of liver sinusoidal endothelial cells, stimulation of immune cells including macrophages and Kupffer cells, and activation of hepatic stellate cells (HSCs), resulting in progression of liver fibrosis. Liver cirrhosis is the terminal state of liver fibrosis and is associated with severe complications, such as liver failure, portal hypertension, and liver cancer. Nevertheless, effective therapy for cirrhosis has not yet been established, and liver transplantation is the only radical treatment for severe cases. Studies investigating HSC activation and regulation of collagen production in the liver have made breakthroughs in recent decades that have advanced the knowledge regarding liver fibrosis pathophysiology. In this review, we summarize molecular mechanisms of liver fibrosis and discuss the development of novel anti-fibrotic therapies.
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Affiliation(s)
- Naoshi Odagiri
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Misako Sato-Matsubara
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.,Department of Endowed Laboratory of Synthetic Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Hideki Fujii
- Department of Premier Preventive Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
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Galicia-Moreno M, Lucano-Landeros S, Monroy-Ramirez HC, Silva-Gomez J, Gutierrez-Cuevas J, Santos A, Armendariz-Borunda J. Roles of Nrf2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects. Antioxidants (Basel) 2020; 9:980. [PMID: 33066023 PMCID: PMC7601324 DOI: 10.3390/antiox9100980] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 10/10/2020] [Accepted: 10/11/2020] [Indexed: 02/06/2023] Open
Abstract
Liver diseases represent a critical health problem with 2 million deaths worldwide per year, mainly due to cirrhosis and its complications. Oxidative stress plays an important role in the development of liver diseases. In order to maintain an adequate homeostasis, there must be a balance between free radicals and antioxidant mediators. Nuclear factor erythroid 2-related factor (Nrf2) and its negative regulator Kelch-like ECH-associated protein 1 (Keap1) comprise a defense mechanism against oxidative stress damage, and growing evidence considers this signaling pathway as a key pharmacological target for the treatment of liver diseases. In this review, we provide detailed and updated evidence regarding Nrf2 and its involvement in the development of the main liver diseases such as alcoholic liver damage, viral hepatitis, steatosis, steatohepatitis, cholestatic damage, and liver cancer. The molecular and cellular mechanisms of Nrf2 cellular signaling are elaborated, along with key and relevant antioxidant drugs, and mechanisms on how Keap1/Nrf2 modulation can positively affect the therapeutic response are described. Finally, exciting recent findings about epigenetic modifications and their link with regulation of Keap1/Nrf2 signaling are outlined.
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Affiliation(s)
- Marina Galicia-Moreno
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.G.-M.); (S.L.-L.); (H.C.M.-R.); (J.S.-G.); (J.G.-C.)
| | - Silvia Lucano-Landeros
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.G.-M.); (S.L.-L.); (H.C.M.-R.); (J.S.-G.); (J.G.-C.)
| | - Hugo Christian Monroy-Ramirez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.G.-M.); (S.L.-L.); (H.C.M.-R.); (J.S.-G.); (J.G.-C.)
| | - Jorge Silva-Gomez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.G.-M.); (S.L.-L.); (H.C.M.-R.); (J.S.-G.); (J.G.-C.)
| | - Jorge Gutierrez-Cuevas
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.G.-M.); (S.L.-L.); (H.C.M.-R.); (J.S.-G.); (J.G.-C.)
| | - Arturo Santos
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45201, Jalisco, Mexico;
| | - Juan Armendariz-Borunda
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.G.-M.); (S.L.-L.); (H.C.M.-R.); (J.S.-G.); (J.G.-C.)
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45201, Jalisco, Mexico;
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