1
|
Liu Y, Feng LL, Han B, Cai LJ, Liu RY, Tang S, Yang Q. Exploring the molecular mechanisms through which overexpression of TET3 alleviates liver fibrosis in mice via ferroptosis in hepatic stellate cells. Cell Signal 2025; 131:111747. [PMID: 40096933 DOI: 10.1016/j.cellsig.2025.111747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 02/19/2025] [Accepted: 03/13/2025] [Indexed: 03/19/2025]
Abstract
Hepatic stellate cell (HSC) activation is crucial in the onset and progression of liver fibrosis, and inhibiting or eliminating activated HSCs is a key therapeutic strategy. Ferroptosis may help eliminate activated HSCs; however, its role and regulatory pathways in liver fibrosis remain unclear. As a DNA demethylase, TET3 regulates gene expression via DNA demethylation. We previously demonstrated that TET3 overexpression alleviates CCL4-induced liver fibrosis in mice; however, the specific mechanisms, including whether TET3 affects ferroptosis in HSCs, remain unexplored. Thus, we aimed to explore the molecular mechanisms wherein TET3 overexpression improves liver fibrosis in mice via ferroptosis in HSCs. Our in vivo observations showed that overexpression of TET3 ameliorate liver fibrosis in mice, and is associated with increased levels of malondialdehyde (MDA) and Fe2+ in liver tissue, as well as decreased protein expression of SLC7A11, GPX4, and FTH1. Further in vitro studies on HSCs showed that TET3 overexpression inhibits the expression of SLC7A11, GPX4, and FTH1, and reduces intracellular GSH levels, leading to accumulation of MDA and iron ions. This induces ferroptosis in HSC-LX2 cells, while simultaneously decreasing ECM accumulation in HSCs. Furthermore, hMeDIP-SEQ and ChIP-qPCR analyses revealed that TET3 directly interacts with the promoter regions of GPX4 and FTH1 to regulate their transcriptional expression. We propose that overexpression of TET3 modulates the gene methylation status of ferroptosis-related proteins, thereby regulating HSC ferroptosis, reducing activated HSCs, and decreasing ECM deposition in the liver. This may represent one of the molecular mechanisms wherein TET3 overexpression ameliorates liver fibrosis in mice.
Collapse
Affiliation(s)
- Yin Liu
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, 550025 Guiyang, Guizhou, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, 550025 Guiyang, Guizhou, China
| | - Lin-Lin Feng
- Center for Clinical Laboratories, Affiliated Hospital of Guizhou Medical University, 550025 Guiyang, Guizhou, China
| | - Bing Han
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, 550025 Guiyang, Guizhou, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, 550025 Guiyang, Guizhou, China
| | - Li-Jun Cai
- Department of Rehabilitation Medicine, The Affiliated Hospital of Guizhou Medical University, 550025 Guiyang, Guizhou, China
| | - Ran-Yang Liu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China
| | - Shuang Tang
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, 550025 Guiyang, Guizhou, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, 550025 Guiyang, Guizhou, China
| | - Qin Yang
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, 550025 Guiyang, Guizhou, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, 550025 Guiyang, Guizhou, China.
| |
Collapse
|
2
|
Castanho Martins M, Dixon ED, Lupo G, Claudel T, Trauner M, Rombouts K. Role of PNPLA3 in Hepatic Stellate Cells and Hepatic Cellular Crosstalk. Liver Int 2025; 45:e16117. [PMID: 39394864 PMCID: PMC11891384 DOI: 10.1111/liv.16117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/16/2024] [Accepted: 09/17/2024] [Indexed: 10/14/2024]
Abstract
AIMS Since its discovery, the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified. METHODS We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation-induced fibrosis. RESULTS Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo-apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP-1, LXRα and TGFβ activity and signalling. CONCLUSIONS The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations.
Collapse
Affiliation(s)
- Maria Castanho Martins
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive HealthUniversity College London, Royal Free CampusLondonUK
| | - Emmanuel Dauda Dixon
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Giulia Lupo
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive HealthUniversity College London, Royal Free CampusLondonUK
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Krista Rombouts
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive HealthUniversity College London, Royal Free CampusLondonUK
| |
Collapse
|
3
|
Yoon J, Choi WI, Lee WH, Lee GB, Choi BW, Kim P, Heo Y, Kim DG, Kim HA, Bae MA, Kim SS, Lee EY, Oh CM, Lee HJ, Kim HW, Namkung W, Kim H, Ahn JH. Synthesis and Biological Evaluation of Peripheral 5HT 2B Antagonists for Liver Fibrosis. J Med Chem 2025; 68:6493-6506. [PMID: 40048549 DOI: 10.1021/acs.jmedchem.4c03003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
Abstract
Liver fibrosis is characterized by an excessive accumulation of extracellular matrix components, leading to the distortion of liver architecture and function. Recent studies have shown that antagonizing 5-hydroxytryptamine receptor 2B (5HT2B) stimulates the apoptosis of activated hepatic stellate cells and inhibits their proliferation while concurrently regressing hepatocyte proliferation. In this study, we present compound 19c, which demonstrates promising efficacy both in vitro and in vivo. 19c showed robust in vitro activity with an IC50 value of 1.09 nM and limited blood-brain barrier penetration. Furthermore, 19c did not significantly inhibit hERG and cytochrome P450 enzymes. 19c markedly reduced fibrotic deposition, with a decrease in fibrosis stage and area in the CCl4-induced liver fibrosis mouse model. Additionally, treatment with 19c led to downregulation of key fibrosis-related genes, including α-SMA, Timp1, Col1a1, and Col3a1. Taken together, these results suggest that 19c has the potential to be a novel antifibrotic agent.
Collapse
Affiliation(s)
- Jihyeon Yoon
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Won-Il Choi
- Department of Physiology, Jeonbuk National University Medical School, Jeonju 54907, Republic of Korea
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
| | - Won Hee Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
- Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
| | - Gwi Bin Lee
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Byeong Wook Choi
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Pyeongkeun Kim
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Yerim Heo
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Dong Gun Kim
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Hyeon Ah Kim
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Myung Ae Bae
- Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
| | - Seong Soon Kim
- Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
| | - Eun Young Lee
- JD Bioscience Inc., TJS Knowledge Industrial Center, Suite 801, 208 Beon-gil Cheomdangwagi-ro, Buk-gu, Gwangju 61011, Republic of Korea
| | - Chang-Myung Oh
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Hyeok Jae Lee
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Hyun Woo Kim
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
- Center for Quantum Information, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Wan Namkung
- College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - Hail Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
- Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
| | - Jin Hee Ahn
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
- JD Bioscience Inc., TJS Knowledge Industrial Center, Suite 801, 208 Beon-gil Cheomdangwagi-ro, Buk-gu, Gwangju 61011, Republic of Korea
| |
Collapse
|
4
|
Kisseleva T, Ganguly S, Murad R, Wang A, Brenner DA. Regulation of Hepatic Stellate Cell Phenotypes in Metabolic Dysfunction-Associated Steatohepatitis. Gastroenterology 2025:S0016-5085(25)00528-1. [PMID: 40120772 DOI: 10.1053/j.gastro.2025.03.010] [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: 12/16/2024] [Revised: 02/13/2025] [Accepted: 03/05/2025] [Indexed: 03/25/2025]
Abstract
Hepatic stellate cells (HSCs) play a crucial role in the pathogenesis of liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH), a condition characterized by excessive fat accumulation in the hepatocytes, unrelated to alcohol consumption. In a healthy liver, HSCs are quiescent, store vitamin A, and function as pericytes. However, in response to liver injury and inflammation, HSCs become activated. In MASH, HSC activation is driven by metabolic stress, lipotoxicity, and chronic inflammation. Injured hepatocytes, recruited macrophage, capillarized sinusoidal endothelial cells, and permeable intestinal epithelium may each contribute to activating HSCS. This leads to a unique inflammatory environment that promotes fibrosis. MASH HSCs change their metabolism to favor glycolysis, glutaminolysis, and lactate generation. Activated HSCs transform into myofibroblast-like cells, producing excessive extracellular matrix components that result in fibrosis. In addition, HSCs in MASH have inflammatory and intermediate activated phenotypes. This fibrotic process is a key feature of MASH, which can lead to cirrhosis and liver cancer. Understanding the mechanisms of HSC activation and their role in MASH progression is essential for developing targeted therapies to treat and prevent liver fibrosis in affected individuals.
Collapse
Affiliation(s)
- Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, California
| | | | - Rabi Murad
- Sanford Burnham Prebys, La Jolla, California
| | - Allen Wang
- Center for Epigenetics, University of California, San Diego, La Jolla, California
| | - David A Brenner
- Sanford Burnham Prebys, La Jolla, California; Department of Medicine, University of California, La Jolla California.
| |
Collapse
|
5
|
Meyer J, Teixeira AM, Richter S, Larner DP, Syed A, Klöting N, Matz-Soja M, Gaul S, Barnikol-Oettler A, Kiess W, Le Duc D, Penke M, Garten A. Sex differences in diet-induced MASLD - are female mice naturally protected? Front Endocrinol (Lausanne) 2025; 16:1567573. [PMID: 40162312 PMCID: PMC11949793 DOI: 10.3389/fendo.2025.1567573] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 02/25/2025] [Indexed: 04/02/2025] Open
Abstract
Males suffer more often from profibrotic changes in liver than females. The underlying mechanism for this sex difference in the prevalence and manifestation of Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) is not yet completely known. We studied male and female mice that were induced to develop MASLD by consuming a "fast food" diet (FFD) and assessed metabolic phenotype as well as liver histology and compared them with mice fed with a matched control diet (CD). Our aim was to check for sex-specific differences in MASLD development in a mouse model of diet-induced profibrotic changes in the liver. Our results demonstrate a clear difference in body weight, fat distribution and changes in liver tissue for male and female mice fed with FFD. We found that female mice stored lipids mainly in subcutaneous and visceral adipose tissue while males increased ectopic lipid accumulation in the liver which resulted in hepatomegaly and increased transforming growth factor β 1 (Tgfb1) and collagen I (Col1a1) expression concomitant to fibrosis development. This was absent in female mice. Analysis of estrogen receptor -α (Esr1) and -β (Esr2) expression revealed an upregulation of Esr2 in livers of male FFD-fed mice whereas in female liver tissue a higher expression in Esr1 could be observed. This study supports Esr1 and Esr2 as potential targets to reverse negative effects of diet-induced profibrotic changes in the liver.
Collapse
Affiliation(s)
- Jana Meyer
- Center for Pediatric Research, University Hospital for Children and Adolescents, Leipzig University, Leipzig, Germany
| | - Ana Mendes Teixeira
- Center for Pediatric Research, University Hospital for Children and Adolescents, Leipzig University, Leipzig, Germany
| | - Sandy Richter
- Center for Pediatric Research, University Hospital for Children and Adolescents, Leipzig University, Leipzig, Germany
| | - Dean P. Larner
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Asifuddin Syed
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Nora Klöting
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) belonging to Helmholtz Center Munich at the University and University Hospital, Leipzig, Germany
| | - Madlen Matz-Soja
- Division of Hepatology, Clinic and Polyclinic for Oncology, Gastroenterology, Hepatology, and Pneumology, University Hospital Leipzig, Leipzig, Germany
| | - Susanne Gaul
- Center for Pediatric Research, University Hospital for Children and Adolescents, Leipzig University, Leipzig, Germany
- Klinik und Poliklinik für Kardiologie, University Hospital Leipzig, Leipzig University, Leipzig, Germany
| | - Anja Barnikol-Oettler
- Center for Pediatric Research, University Hospital for Children and Adolescents, Leipzig University, Leipzig, Germany
| | - Wieland Kiess
- Center for Pediatric Research, University Hospital for Children and Adolescents, Leipzig University, Leipzig, Germany
| | - Diana Le Duc
- Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany
- Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
| | - Melanie Penke
- Center for Pediatric Research, University Hospital for Children and Adolescents, Leipzig University, Leipzig, Germany
| | - Antje Garten
- Center for Pediatric Research, University Hospital for Children and Adolescents, Leipzig University, Leipzig, Germany
| |
Collapse
|
6
|
Sererols-Viñas L, Garcia-Vicién G, Ruiz-Blázquez P, Lee TF, Lee YA, Gonzalez-Sanchez E, Vaquero J, Moles A, Filliol A, Affò S. Hepatic Stellate Cells Functional Heterogeneity in Liver Cancer. Semin Liver Dis 2025; 45:33-51. [PMID: 40043738 DOI: 10.1055/a-2551-0724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
Abstract
Hepatic stellate cells (HSCs) are the liver's pericytes, and play key roles in liver homeostasis, regeneration, fibrosis, and cancer. Upon injury, HSCs activate and are the main origin of myofibroblasts and cancer-associated fibroblasts (CAFs) in liver fibrosis and cancer. Primary liver cancer has a grim prognosis, ranking as the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) being the predominant type, followed by intrahepatic cholangiocarcinoma (iCCA). Moreover, the liver hosts 35% of all metastatic lesions. The distinct spatial distribution and functional roles of HSCs across these malignancies represent a significant challenge for universal therapeutic strategies, requiring a nuanced and tailored understanding of their contributions. This review examines the heterogeneous roles of HSCs in liver cancer, focusing on their spatial localization, dynamic interactions within the tumor microenvironment (TME), and emerging therapeutic opportunities, including strategies to modulate their activity, and harness their potential as targets for antifibrotic and antitumor interventions.
Collapse
Affiliation(s)
- Laura Sererols-Viñas
- Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- University of Barcelona, Barcelona, Spain
| | - Gemma Garcia-Vicién
- Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Paloma Ruiz-Blázquez
- University of Barcelona, Barcelona, Spain
- Tissue Remodeling Fibrosis and Cancer Group, Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain
- Institute of Biomedical Research of Barcelona (IDIBAPS), Barcelona, Spain
- CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
| | - Ting-Fang Lee
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Youngmin A Lee
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ester Gonzalez-Sanchez
- HepatoBiliary Tumours Lab, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain
- Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
| | - Javier Vaquero
- CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
- HepatoBiliary Tumours Lab, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Anna Moles
- Tissue Remodeling Fibrosis and Cancer Group, Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain
- Institute of Biomedical Research of Barcelona (IDIBAPS), Barcelona, Spain
- CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
| | - Aveline Filliol
- Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Silvia Affò
- Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| |
Collapse
|
7
|
Di X, Li Y, Wei J, Li T, Liao B. Targeting Fibrosis: From Molecular Mechanisms to Advanced Therapies. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410416. [PMID: 39665319 PMCID: PMC11744640 DOI: 10.1002/advs.202410416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/27/2024] [Indexed: 12/13/2024]
Abstract
As the final stage of disease-related tissue injury and repair, fibrosis is characterized by excessive accumulation of the extracellular matrix. Unrestricted accumulation of stromal cells and matrix during fibrosis impairs the structure and function of organs, ultimately leading to organ failure. The major etiology of fibrosis is an injury caused by genetic heterogeneity, trauma, virus infection, alcohol, mechanical stimuli, and drug. Persistent abnormal activation of "quiescent" fibroblasts that interact with or do not interact with the immune system via complicated signaling cascades, in which parenchymal cells are also triggered, is identified as the main mechanism involved in the initiation and progression of fibrosis. Although the mechanisms of fibrosis are still largely unknown, multiple therapeutic strategies targeting identified molecular mechanisms have greatly attenuated fibrotic lesions in clinical trials. In this review, the organ-specific molecular mechanisms of fibrosis is systematically summarized, including cardiac fibrosis, hepatic fibrosis, renal fibrosis, and pulmonary fibrosis. Some important signaling pathways associated with fibrosis are also introduced. Finally, the current antifibrotic strategies based on therapeutic targets and clinical trials are discussed. A comprehensive interpretation of the current mechanisms and therapeutic strategies targeting fibrosis will provide the fundamental theoretical basis not only for fibrosis but also for the development of antifibrotic therapies.
Collapse
Affiliation(s)
- Xingpeng Di
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Ya Li
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Jingwen Wei
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Tianyue Li
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Banghua Liao
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| |
Collapse
|
8
|
Sah J, Singh I. Role of Essential Oils and Antioxidants in the Treatment of Fibrosis. Curr Drug Res Rev 2025; 17:76-89. [PMID: 40183147 DOI: 10.2174/0125899775271616231205111827] [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: 08/14/2023] [Revised: 10/14/2023] [Accepted: 11/06/2023] [Indexed: 04/05/2025]
Abstract
Fibrosis is the leading cause of many lethal diseases. It is characterized by the accumulation of extracellular matrix (ECM) components, which leads to damaged tissue functioning in the influenced organs. Essential oils are concentrated hydrophobic liquid having volatile compounds extracted from plant or plant parts while antioxidants are the compounds that help in scavenging free radicals and prevent reducing the oxidation processes. In this review, challenges that come during the treatment of fibrosis have been covered, mechanism of action of both essential oil and antioxidants is also outlined in this article. This review aimed to provide scientific fundamental and knowledge, ideas for the development and application of essential oils and antioxidants in the treatment of fibrosis.
Collapse
Affiliation(s)
- Jaishree Sah
- Amity Institute of Pharmacy, Amity University, Noida, India
| | - Indu Singh
- Amity Institute of Pharmacy, Amity University, Noida, India
| |
Collapse
|
9
|
Da Silva K, Kumar P, Choonara YE. The paradigm of stem cell secretome in tissue repair and regeneration: Present and future perspectives. Wound Repair Regen 2025; 33:e13251. [PMID: 39780313 PMCID: PMC11711308 DOI: 10.1111/wrr.13251] [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: 08/01/2024] [Revised: 12/04/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025]
Abstract
As the number of patients requiring organ transplants continues to rise exponentially, there is a dire need for therapeutics, with repair and regenerative properties, to assist in alleviating this medical crisis. Over the past decade, there has been a shift from conventional stem cell treatments towards the use of the secretome, the protein and factor secretions from cells. These components may possess novel druggable targets and hold the key to profoundly altering the field of regenerative medicine. Despite the progress in this field, clinical translation of secretome-containing products is limited by several challenges including but not limited to ensuring batch-to-batch consistency, the prevention of further heterogeneity, production of sufficient secretome quantities, product registration, good manufacturing practice protocols and the pharmacokinetic/pharmacodynamic profiles of all the components. Despite this, the secretome may hold the key to unlocking the regenerative blockage scientists have encountered for years. This review critically analyses the secretome derived from different cell sources and used in several tissues for tissue regeneration. Furthermore, it provides an overview of the current delivery strategies and the future perspectives for the secretome as a potential therapeutic. The success and possible shortcomings of the secretome are evaluated.
Collapse
Affiliation(s)
- Kate Da Silva
- Wits Advanced Drug Delivery Platform (WADDP) Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health SciencesUniversity of the WitwatersrandJohannesburgSouth Africa
| | - Pradeep Kumar
- Wits Advanced Drug Delivery Platform (WADDP) Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health SciencesUniversity of the WitwatersrandJohannesburgSouth Africa
| | - Yahya E. Choonara
- Wits Advanced Drug Delivery Platform (WADDP) Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health SciencesUniversity of the WitwatersrandJohannesburgSouth Africa
| |
Collapse
|
10
|
Kim S, Hong HS. Substance P alleviates liver fibrosis by modulating inflammation and mobilizing reparative stem cells. Int Immunopharmacol 2024; 142:113211. [PMID: 39321699 DOI: 10.1016/j.intimp.2024.113211] [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: 05/12/2024] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024]
Abstract
Repetitive hepatic damage resulting from viral hepatitis, toxins, and alcohol abuse induces chronic inflammation and excessive accumulation of the extracellular matrix, leading to the development of liver cirrhosis. Substance P (SP) promotes endogenous wound healing by mobilizing bone marrow stem cells and stimulating anti-inflammatory responses. This study aimed to investigate whether SP exerts a therapeutic effect on liver fibrosis by recruiting endogenous stem cells and modulating immune responses. A non-clinical model of liver cirrhosis was established through repeated injections of thioacetamide and recombinant leptin. After confirming liver fibrosis, SP was administered intravenously for 6 weeks. SP treatment decreased the formation of hepatic micronodules on the external surface of the liver and the infiltration of immune cells. Furthermore, SP treatment notably reduced the deposition of collagen and the activation of hepatic stellate cells, concomitant with decreased levels of transforming growth factor-β1 and matrix metalloproteinase activity. In the context of severe hepatic damage, SP increased the number of circulating stem cells, leading to the restoration of the reparative stem cell pool in the bone marrow. The findings of this study suggest that SP alleviates liver fibrosis by modulating the mobilization of functional stem cells and the immune response.
Collapse
Affiliation(s)
- Suna Kim
- Department of Genetic Engineering, Graduate School of Biotechnology, Kyung Hee University, Deokyoung dae-ro, 1732, Yong In 17104, Republic of Korea; Kyung Hee Institute of Regenerative Medicine (KIRM), Medical Science Research Institute, Kyung Hee University Medical Center, Kyung Hee dae-ro 23, Hoegi-dong, Seoul 02447, Republic of Korea
| | - Hyun Sook Hong
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Kyung Hee dae-ro, 24, Seoul 02461, Republic of Korea; East-West Medical Research Institute, Kyung Hee University, Kyung Hee dae-ro, 24, Hoegi-dong, Seoul 02461, Republic of Korea; Kyung Hee Institute of Regenerative Medicine (KIRM), Medical Science Research Institute, Kyung Hee University Medical Center, Kyung Hee dae-ro 23, Hoegi-dong, Seoul 02447, Republic of Korea.
| |
Collapse
|
11
|
Liu J, Li H, Chen H, Xiao X, Jin Z, Paerhati P, Bao W, Cui C, Zhu J, Yuan Y. An anti-RAGE chimeric antibody alleviates CCl 4-induced liver fibrosis via RAGE/NF-kB pathway in mice. Biomed Pharmacother 2024; 181:117737. [PMID: 39657505 DOI: 10.1016/j.biopha.2024.117737] [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: 08/31/2024] [Revised: 11/23/2024] [Accepted: 12/03/2024] [Indexed: 12/12/2024] Open
Abstract
Liver fibrosis is a progressive condition characterized by excessive deposition of extracellular matrix components, leading to organ dysfunction. Chronic inflammation and activation of hepatic stellate cells (HSCs) are two dominant events in all stages of fibrosis development. The receptor for advanced glycation end products (RAGE) pathway is involved in modulating liver injury and fibrosis, and preventing it, or deletion of Ager gene can protect the liver against fibrosis progression. To investigate functions and mechanism of chimeric anti-RAGE monoclonal antibody against liver fibrosis, murine-derived monoclonal anti-RAGE antibodies were used to construct murine-human chimeric antibodies. The properties of the chimeric antibody were characterized, and the biological functions of antibody A5 or its evolved humanized molecule, huA5, were investigated in cell or animal model. The data showed that blocking the RAGE pathway with huA5 robustly reduced liver injury and fibrosis. Furthermore, huA5 significantly suppressed the activation of HSCs and inhibited expression of fibrosis-associated genes, including COL1A1,TIMP1, and ACTA2. huA5 also interfered with RAGE downstream signal transduction and down-regulate both ERK and NF-κB phosphorylation, inhibited the RAGE/NF-kB pathway, leading to reduced expression of pro-inflammatory cytokines and profibrotic markers. Finally, RAGE silencing significantly decreased the expression of activation-related genes in HSCs, inhibiting HSCs proliferation and migration. These results clearly revealed that the anti-RAGE chimeric antibody exerted antifibrotic efficacy in vitro and attenuated liver fibrosis in vivo. HuA5 can be further developed as a lead molecule of drug to treat patients with liver fibrosis.
Collapse
Affiliation(s)
- Jing Liu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Huiyi Li
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Hui Chen
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Xinyi Xiao
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Zhedong Jin
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Pameila Paerhati
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Wenxin Bao
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Caixia Cui
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Jianwei Zhu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| | - Yunsheng Yuan
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 201100, China.
| |
Collapse
|
12
|
Kao C, Ho CH. Time-course RNA sequencing reveals high similarity in mRNAome between hepatic stellate cells activated by agalactosyl IgG and TGF-β1. Funct Integr Genomics 2024; 24:215. [PMID: 39549087 DOI: 10.1007/s10142-024-01502-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 11/18/2024]
Abstract
Previous studies have demonstrated the clinical relevance of aberrant serum immunoglobulin G (IgG) N-glycomic profiles in liver fibrosis and the pathogenic effects of agalactosyl IgG on activating hepatic stellate cells (HSCs). However, the dynamics of gene expression changes during HSC activation by agalactosyl IgG remain poorly understood. We performed RNA sequencing to analyze the mRNAome of human LX-2 HSCs at multiple time points after treatment with agalactosyl IgG and then compared these results with those obtained after normal IgG and transforming growth factor (TGF)-β1 treatments. Gene expression changes were significantly pronounced on day 5 and subsided by day 11 after HSC activation. A high degree of similarity in gene expression patterns between HSCs treated with agalactosyl IgG and TGF-β1 was observed, of which 1796 and 1785 differentially expressed genes (DEGs) were identified, respectively. Disease ontology analyses revealed that 114 and 105 DEGs in activated HSCs following agalactosyl IgG and TGF-β1 treatments, respectively, were linked to liver cirrhosis, hepatitis, fatty liver disease, hepatitis B, and alcoholic hepatitis, with CCL5 and FAS being the most commonly affected genes. DEGs associated with liver fibrosis or aforementioned liver diseases involved in gene annotation, physiological functions, and signaling pathways regarding secretion of cytokines and chemokines, expression of fibrosis-related growth factors and their receptors, modification of extracellular matrices, and regulation of cell viability in activated HSCs. In conclusion, this study characterized the dynamics of mRNAome and gene networks and identified the liver fibrosis-related DEGs during HSC activation by agalactosyl IgG and TGF-β1.
Collapse
Affiliation(s)
- Chieh Kao
- Department of Medical Laboratory Science, College of Medical Science and Technology, I-Shou University, No.8, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City, 82445, Taiwan
- School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan
| | - Cheng-Hsun Ho
- Department of Medical Laboratory Science, College of Medical Science and Technology, I-Shou University, No.8, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City, 82445, Taiwan.
| |
Collapse
|
13
|
Calvillo-Robledo A, Samson-Soleil, Marichal-Cancino BA, Medina-Pizaño MY, Ibarra-Martínez D, Ventura-Juárez J, Muñoz-Ortega M. Rapid liver self-recovery: A challenge for rat models of tissue damage. Life Sci 2024; 357:122975. [PMID: 39142508 DOI: 10.1016/j.lfs.2024.122975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/11/2024] [Accepted: 08/10/2024] [Indexed: 08/16/2024]
Abstract
Animal models, mainly murine, stay as a fundamental resource in diverse research pursuits, notably contributing to significant strides in discovering novel treatments for therapeutic applications. Preclinical assays must consider the existence of self-recovery mechanisms in the murine species to achieve a well-designed control group. This study focuses on unveiling the innate rapid regenerative capacity of rat liver by utilizing the thioacetamide-induced sub-chronic liver injury model. Employing histopathological, biochemical, and molecular liver function tests, we assessed the recovery of liver tissue functionality. Moreover, animals were housed with voluntary running wheels and locomotory activity was recorded and employed as an indirect index of overall animal recuperation. Remarkably, basal locomotory activity reestablished to normal levels only two weeks post-thioacetamide exposure. Our results raise vital considerations about the importance of temporal synchronicity in comparative assays to validate the real action of treatments, emphasizing the role of the rapid rat liver endogenous self-recovery.
Collapse
Affiliation(s)
- Argelia Calvillo-Robledo
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Samson-Soleil
- Departamento de Morfología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Bruno A Marichal-Cancino
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | | | - David Ibarra-Martínez
- Departamento de Química, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Javier Ventura-Juárez
- Departamento de Morfología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Martin Muñoz-Ortega
- Departamento de Química, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico.
| |
Collapse
|
14
|
McElhinney K, Irnaten M, O’Callaghan J, O’Brien C. p53 and the E3 Ubiquitin Ligase MDM2 in Glaucomatous Lamina Cribrosa Cells. Int J Mol Sci 2024; 25:12173. [PMID: 39596239 PMCID: PMC11595009 DOI: 10.3390/ijms252212173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/09/2024] [Accepted: 11/10/2024] [Indexed: 11/28/2024] Open
Abstract
Lamina cribrosa (LC) cells play an integral role in extracellular matrix remodeling and fibrosis in human glaucoma. LC cells bear similarities to myofibroblasts that adopt an apoptotic-resistant, proliferative phenotype, a process linked to dysregulation of tumor suppressor-gene p53 pathways, including ubiquitin-proteasomal degradation via murine-double-minute-2 (MDM2). Here, we investigate p53 and MDM2 in glaucomatous LC cells. Primary human LC cells were isolated from glaucomatous donor eyes (GLC) and age-matched normal controls (NLC) (n = 3 donors/group). LC cells were cultured under standard conditions ± 48-h treatment with p53-MDM2-interaction inhibitor RG-7112. Markers of p53-MDM2, fibrosis, and apoptosis were analyzed by real-time polymerase chain reaction (qRT-PCR), western blotting, and immunofluorescence. Cellular proliferation and viability were assessed using colorimetric methyl-thiazolyl-tetrazolium salt assays (MTS/MTT). In GLC versus NLC cells, protein expression of p53 was significantly decreased (p < 0.05), MDM2 was significantly increased, and immunofluorescence showed reduced p53 and increased MDM2 expression in GLC nuclei. RG-7112 treatment significantly increased p53 and significantly decreased MDM2 gene and protein expression. GLC cells had significantly increased protein expression of αSMA, significantly decreased caspase-3 protein expression, and significantly increased proliferation after 96 h. RG-7112 treatment significantly decreased COL1A1 and αSMA, significantly increased BAX and caspase-3 gene expression, and significantly decreased proliferation in GLC cells. MTT-assay showed equivocal cellular viability in NLC/GLC cells with/without RG-7112 treatment. Our data suggests that proliferation and the ubiquitin-proteasomal pathway are dysregulated in GLC cells, with MDM2-led p53 protein degradation negatively impacting its protective role.
Collapse
Affiliation(s)
- Kealan McElhinney
- UCD Clinical Research Centre, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
- Department of Ophthalmology, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
| | - Mustapha Irnaten
- UCD Clinical Research Centre, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
| | - Jeffrey O’Callaghan
- Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College, University of Dublin, D02 PN40 Dublin, Ireland
| | - Colm O’Brien
- UCD Clinical Research Centre, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
- Department of Ophthalmology, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
| |
Collapse
|
15
|
Guihu W, Wei D, Hailong Z, Chongyu Z, Jin S, Mengchen Z, Jian Z, Rui Z, Song R, Chen Z, Xi L, Zongfang L, An J. Activation of MEK-ERK-c-MYC signaling pathway promotes splenic M2-like macrophage polarization to inhibit PHcH-liver cirrhosis. Front Immunol 2024; 15:1417521. [PMID: 39620221 PMCID: PMC11605246 DOI: 10.3389/fimmu.2024.1417521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 10/21/2024] [Indexed: 01/04/2025] Open
Abstract
INTRODUCTION Portal hypertension combined with hypersplenism (PHcH) is the main cause of hypocytosis and esophagogastric variceal hemorrhage in patients with liver cirrhosis. Activated macrophages that destroy excess blood cells are the main cause of hypersplenism, but the activating pathway is not very clear. This study aims to investigate the activation types of splenic macrophages and their activation mechanisms, to provide experimental evidence for the biological treatment of splenomegaly, and to find a strategy to improve liver fibrosis and inflammation by intervening in splenic immune cells. This study revealed the occurrence of M2-like polarization of macrophages and upregulation of c-Myc gene expression in the PH spleen. METHODS RNAseq, protein chip, western blot, and chip-seq were performed on macrophages and the in vitro MEK inhibitor rafametinib was used. Carbon tetrachloride and thioacetamide induced mouse cirrhosis models were separately constructed. RESULTS c-Myc gene knockout in splenic macrophages reduced M2-like polarization and exacerbated liver fibrosis inflammation. c-Myc activated the MAPK signaling pathway and upregulated the expression of IL-4 and M2-like related genes in PH hypersplenism through the MEK-ERK-c-Myc axis. In addition, the c-Myc gene exerted anti-inflammatory effects by upregulating IL-4-mediated signal transduction to promote M2-like differentiation and anti-inflammatory cytokine secretion. CONCLUSIONS Activation of MEK-ERK-c-MYC signaling pathway promotes splenic M2-like macrophage polarization to inhibit PHcH-liver cirrhosis. Therefore, the induction of macrophage depolarization might represent a new therapeutic approach in the cure of PH hypersplenism, making c-Myc a potential candidate for macrophage polarization therapy.
Collapse
Affiliation(s)
- Wang Guihu
- National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Dong Wei
- National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Zhang Hailong
- National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Zhang Chongyu
- National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Sun Jin
- National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Zhu Mengchen
- National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Zhang Jian
- National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Zhou Rui
- National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Ren Song
- National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Zhang Chen
- National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Liu Xi
- National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Li Zongfang
- National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Jiang An
- National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary pancreas surgery and liver transplantation, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| |
Collapse
|
16
|
Erdenebileg S, Kim M, Nam Y, Cha KH, Le TT, Jung SH, Nho CW. Artemisia argyi ethanol extract ameliorates nonalcoholic steatohepatitis-induced liver fibrosis by modulating gut microbiota and hepatic signaling. JOURNAL OF ETHNOPHARMACOLOGY 2024; 333:118415. [PMID: 38848971 DOI: 10.1016/j.jep.2024.118415] [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: 03/27/2024] [Revised: 05/27/2024] [Accepted: 05/31/2024] [Indexed: 06/09/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Artemisia argyi (AA), a herbal medicine traditionally used in Asian countries, to treat inflammatory conditions such as eczema, dermatitis, arthritis, allergic asthma and colitis. However, the mechanism of action of this plant with regard to hepatitis and other liver-related diseases is still unclear. AIM This study aimed to investigate the effects of AA ethanol extract on NASH-related fibrosis and gut microbiota in a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced mouse model. METHODS Male C57BL/6J mice were fed CDAHFD, with or without AA ethanol extract treatment. Biochemical markers, lipid profiles, hepatic mRNA expression levels of key genes, and the fibrosis area were assessed. In vitro, TGF-β-stimulated human hepatic stellate LX-2 cells and mouse primary hepatic stellate cells (mHSCs) were used to elucidate the effects of AA ethanol extract on fibrosis and steatosis. 16S rRNA sequencing, QIIME2, and PICRUST2 were employed to analyze gut microbial diversity, composition, and functional pathways. RESULTS Treatment with the AA ethanol extract improved plasma and liver lipid profiles, modulated hepatic mRNA expression levels of antioxidant, lipolytic, and fibrosis-related genes, and significantly reduced CDAHFD-induced hepatic fibrosis. Gut microbiota analysis revealed a marked decrease in Acetivibrio ethanolgignens abundance upon treatment with the AA ethanol extract, and its functional pathways were significantly correlated with NASH/fibrosis markers. The AA ethanol extract and its active components (jaceosidin, eupatilin, and chlorogenic acid) inhibited fibrosis-related markers in LX-2 and mHSC. CONCLUSION The AA ethanol extract exerted therapeutic effects on CDAHFD-induced liver disease by modulating NASH/fibrosis-related factors and gut microbiota composition. Notably, AA treatment reduced the abundance of the potentially profibrotic bacterium (A. ethanolgignens). These findings suggest that AA is a promising candidate for treating NASH-induced fibrosis.
Collapse
Affiliation(s)
- Saruul Erdenebileg
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute of Natural Products, Gangneung, Gangwon-do, 25451, South Korea; Natural Product Applied Science, KIST School, University of Science and Technology (UST), Gangneung, Gangwon-do, 25451, South Korea
| | - Myungsuk Kim
- Natural Product Applied Science, KIST School, University of Science and Technology (UST), Gangneung, Gangwon-do, 25451, South Korea; Natural Product Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute of Natural Products, Gangneung, Gangwon-do, 25451, South Korea; Department of Convergence Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, 26426, South Korea
| | - Yunseong Nam
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute of Natural Products, Gangneung, Gangwon-do, 25451, South Korea; Natural Product Applied Science, KIST School, University of Science and Technology (UST), Gangneung, Gangwon-do, 25451, South Korea
| | - Kwang Hyun Cha
- Natural Product Applied Science, KIST School, University of Science and Technology (UST), Gangneung, Gangwon-do, 25451, South Korea; Department of Convergence Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, 26426, South Korea; Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute of Natural Products, Gangneung, Gangwon-do, 25451, South Korea
| | - Tam Thi Le
- Natural Product Applied Science, KIST School, University of Science and Technology (UST), Gangneung, Gangwon-do, 25451, South Korea; Natural Product Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute of Natural Products, Gangneung, Gangwon-do, 25451, South Korea
| | - Sang Hoon Jung
- Natural Product Applied Science, KIST School, University of Science and Technology (UST), Gangneung, Gangwon-do, 25451, South Korea; Natural Product Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute of Natural Products, Gangneung, Gangwon-do, 25451, South Korea
| | - Chu Won Nho
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute of Natural Products, Gangneung, Gangwon-do, 25451, South Korea; Natural Product Applied Science, KIST School, University of Science and Technology (UST), Gangneung, Gangwon-do, 25451, South Korea.
| |
Collapse
|
17
|
Selc M, Macova R, Babelova A. Novel Strategies Enhancing Bioavailability and Therapeutical Potential of Silibinin for Treatment of Liver Disorders. Drug Des Devel Ther 2024; 18:4629-4659. [PMID: 39444787 PMCID: PMC11498047 DOI: 10.2147/dddt.s483140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 10/02/2024] [Indexed: 10/25/2024] Open
Abstract
Silibinin, a bioactive component found in milk thistle extract (Silybum marianum), is known to have significant therapeutic potential in the treatment of various liver diseases. It is considered a key element of silymarin, which is traditionally used to support liver function. The main mechanisms of action of silibinin are attributed to its antioxidant properties protecting liver cells from damage caused by free radicals. Experimental studies conducted in vitro and in vivo have confirmed its ability to inhibit inflammatory and fibrotic processes, as well as promote the regeneration of damaged liver tissue. Therefore, silibinin represents a promising tool for the treatment of liver diseases. Since the silibinin molecule is insoluble in water and has poor bioavailability in vivo, new perspectives on solving this problem are being sought. The two most promising approaches are the water-soluble derivative silibinin-C-2',3-dihydrogen succinate, disodium salt, and the silibinin-phosphatidylcholine complex. Both drugs are currently under evaluation in liver disease clinical trials. Nevertheless, the mechanism underlying silibinin biological activity is still elusive and its more detailed understanding would undoubtedly increase its potential in the development of effective therapeutic strategies against liver diseases. This review is focused on the therapeutic potential of silibinin and its derivates, approaches to increase the bioavailability and the benefits in the treatment of liver diseases that have been achieved so far. The review discusses the relevant in vitro and in vivo studies that investigated the protective effects of silibinin in various forms of liver damage.
Collapse
Affiliation(s)
- Michal Selc
- Centre for Advanced Material Application, Slovak Academy of Sciences, Bratislava, Slovakia
- Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Radka Macova
- Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
- Department of Genetics, Faculty of Natural Sciences, Comenius University Bratislava, Bratislava, Slovakia
| | - Andrea Babelova
- Centre for Advanced Material Application, Slovak Academy of Sciences, Bratislava, Slovakia
- Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| |
Collapse
|
18
|
Diwan R, Gaytan SL, Bhatt HN, Pena-Zacarias J, Nurunnabi M. Liver fibrosis pathologies and potentials of RNA based therapeutics modalities. Drug Deliv Transl Res 2024; 14:2743-2770. [PMID: 38446352 DOI: 10.1007/s13346-024-01551-8] [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] [Accepted: 02/14/2024] [Indexed: 03/07/2024]
Abstract
Liver fibrosis (LF) occurs when the liver tissue responds to injury or inflammation by producing excessive amounts of scar tissue, known as the extracellular matrix. This buildup stiffens the liver tissue, hinders blood flow, and ultimately impairs liver function. Various factors can trigger this process, including bloodborne pathogens, genetic predisposition, alcohol abuse, non-steroidal anti-inflammatory drugs, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease. While some existing small-molecule therapies offer limited benefits, there is a pressing need for more effective treatments that can truly cure LF. RNA therapeutics have emerged as a promising approach, as they can potentially downregulate cytokine levels in cells responsible for liver fibrosis. Researchers are actively exploring various RNA-based therapeutics, such as mRNA, siRNA, miRNA, lncRNA, and oligonucleotides, to assess their efficacy in animal models. Furthermore, targeted drug delivery systems hold immense potential in this field. By utilizing lipid nanoparticles, exosomes, nanocomplexes, micelles, and polymeric nanoparticles, researchers aim to deliver therapeutic agents directly to specific biomarkers or cytokines within the fibrotic liver, increasing their effectiveness and reducing side effects. In conclusion, this review highlights the complex nature of liver fibrosis, its underlying causes, and the promising potential of RNA-based therapeutics and targeted delivery systems. Continued research in these areas could lead to the development of more effective and personalized treatment options for LF patients.
Collapse
Affiliation(s)
- Rimpy Diwan
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA
| | - Samantha Lynn Gaytan
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Interdisciplinary Health Sciences, College of Health Sciences, The University of Texas El Paso, El Paso, Texas, 79968, USA
| | - Himanshu Narendrakumar Bhatt
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA
| | - Jacqueline Pena-Zacarias
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biological Sciences, College of Science, The University of Texas El Paso, El Paso, Texas, 79968, USA
| | - Md Nurunnabi
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA.
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA.
- Department of Interdisciplinary Health Sciences, College of Health Sciences, The University of Texas El Paso, El Paso, Texas, 79968, USA.
- Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX, 79968, USA.
| |
Collapse
|
19
|
Ye Q, Taleb SJ, Zhao J, Zhao Y. Emerging role of BMPs/BMPR2 signaling pathway in treatment for pulmonary fibrosis. Biomed Pharmacother 2024; 178:117178. [PMID: 39142248 PMCID: PMC11364484 DOI: 10.1016/j.biopha.2024.117178] [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: 05/06/2024] [Revised: 07/18/2024] [Accepted: 07/22/2024] [Indexed: 08/16/2024] Open
Abstract
Pulmonary fibrosis is a fatal and chronic lung disease that is characterized by accumulation of thickened scar in the lungs and impairment of gas exchange. The cases with unknown etiology are referred as idiopathic pulmonary fibrosis (IPF). There are currently no effective therapeutics to cure the disease; thus, the investigation of the pathogenesis of IPF is of great importance. Recent studies on bone morphogenic proteins (BMPs) and their receptors have indicated that reduction of BMP signaling in lungs may play a significant role in the development of lung fibrosis. BMPs are members of TGF-β superfamily, and they have been shown to play an anti-fibrotic role in combating TGF-β-mediated pathways. The impact of BMP receptors, in particular BMPR2, on pulmonary fibrosis is growing attraction to researchers. Previous studies on BMPR2 have often focused on pulmonary arterial hypertension (PAH). Given the strong clinical association between PAH and lung fibrosis, understanding BMPs/BMPR2-mediated signaling pathway is important for development of therapeutic strategies to treat IPF. In this review, we comprehensively review recent studies regarding the biological functions of BMPs and their receptors in lungs, especially focusing on their roles in the pathogenesis of pulmonary fibrosis and fibrosis resolution.
Collapse
Affiliation(s)
- Qinmao Ye
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, United States
| | - Sarah J Taleb
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, United States
| | - Jing Zhao
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, United States; Department of internal Medicine, the Ohio State University, Columbus, OH, United States
| | - Yutong Zhao
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, United States; Department of internal Medicine, the Ohio State University, Columbus, OH, United States.
| |
Collapse
|
20
|
Habib S. Team players in the pathogenesis of metabolic dysfunctions-associated steatotic liver disease: The basis of development of pharmacotherapy. World J Gastrointest Pathophysiol 2024; 15:93606. [PMID: 39220834 PMCID: PMC11362842 DOI: 10.4291/wjgp.v15.i4.93606] [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: 03/01/2024] [Revised: 05/14/2024] [Accepted: 07/23/2024] [Indexed: 08/22/2024] Open
Abstract
Nutrient metabolism is regulated by several factors. Social determinants of health with or without genetics are the primary regulator of metabolism, and an unhealthy lifestyle affects all modulators and mediators, leading to the adaptation and finally to the exhaustion of cellular functions. Hepatic steatosis is defined by presence of fat in more than 5% of hepatocytes. In hepatocytes, fat is stored as triglycerides in lipid droplet. Hepatic steatosis results from a combination of multiple intracellular processes. In a healthy individual nutrient metabolism is regulated at several steps. It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component. Several hormones, peptides, and genes have been described that participate in nutrient metabolism. Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP. As of now several publications have revealed very intricate regulation of nutrient metabolism, where most of the regulatory factors are tied to each other bidirectionally, making it difficult to comprehend chronological sequence of events. Insulin hormone is the primary regulator of all nutrients' metabolism both in prandial and fasting states. Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes; metabolic, inflammation and repair, and cell growth and regeneration. Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands, adiponectin, leptin, and adiponutrin. Insulin hormone has direct effect on these final modulators. Whereas blood glucose level, serum lipids, incretin hormones, bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle. The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) that help us understand the disease natural course, risk stratification, role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine. PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states; MASLD, cardiovascular disease and cancer. More than 1000 publications including original research and review papers were reviewed.
Collapse
Affiliation(s)
- Shahid Habib
- Department of Hepatology, Liver Institute PLLC, Tucson, AZ 85712, United States
| |
Collapse
|
21
|
Akkız H, Gieseler RK, Canbay A. Liver Fibrosis: From Basic Science towards Clinical Progress, Focusing on the Central Role of Hepatic Stellate Cells. Int J Mol Sci 2024; 25:7873. [PMID: 39063116 PMCID: PMC11277292 DOI: 10.3390/ijms25147873] [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: 05/23/2024] [Revised: 06/28/2024] [Accepted: 06/29/2024] [Indexed: 07/28/2024] Open
Abstract
The burden of chronic liver disease is globally increasing at an alarming rate. Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such as cirrhosis, liver cancer, and mortality. LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; and produce proinflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. In addition, the accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. The main source of myofibroblasts is resident HSCs. Activated HSCs migrate to the site of active fibrogenesis to initiate the formation of a fibrous scar. Single-cell technologies revealed that quiescent HSCs are highly homogenous, while activated HSCs/myofibroblasts are much more heterogeneous. The complex process of inflammation results from the response of various hepatic cells to hepatocellular death and inflammatory signals related to intrahepatic injury pathways or extrahepatic mediators. Inflammatory processes modulate fibrogenesis by activating HSCs and, in turn, drive immune mechanisms via cytokines and chemokines. Increasing evidence also suggests that cellular stress responses contribute to fibrogenesis. Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. However, despite numerous clinical studies on plausible drug candidates, an approved antifibrotic therapy still remains elusive. This state-of-the-art review presents cellular and molecular mechanisms involved in hepatic fibrogenesis and its resolution, as well as comprehensively discusses the drivers linking liver injury to chronic liver inflammation and LF.
Collapse
Affiliation(s)
- Hikmet Akkız
- Department of Gastroenterology and Hepatology, University of Bahçeşehir, Beşiktaş, Istanbul 34353, Turkey
| | - Robert K. Gieseler
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
| | - Ali Canbay
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
| |
Collapse
|
22
|
Liu XY, Zhang W, Ma BF, Sun MM, Shang QH. Advances in Research on the Effectiveness and Mechanism of Active Ingredients from Traditional Chinese Medicine in Regulating Hepatic Stellate Cells Autophagy Against Hepatic Fibrosis. Drug Des Devel Ther 2024; 18:2715-2727. [PMID: 38974122 PMCID: PMC11227309 DOI: 10.2147/dddt.s467480] [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: 03/06/2024] [Accepted: 06/10/2024] [Indexed: 07/09/2024] Open
Abstract
Hepatic fibrosis (HF) is a pathological process of structural and functional impairment of the liver and is a key component in the progression of chronic liver disease. There are no specific anti-hepatic fibrosis (anti-HF) drugs, and HF can only be improved or prevented by alleviating the cause. Autophagy of hepatic stellate cells (HSCs) is closely related to the development of HF. In recent years, traditional Chinese medicine (TCM) has achieved good therapeutic effects in the prevention and treatment of HF. Several active ingredients from TCM (AITCM) can regulate autophagy in HSCs to exert anti-HF effects through different pathways, but relevant reviews are lacking. This paper reviewed the research progress of AITCM regulating HSCs autophagy against HF, and also discussed the relationship between HSCs autophagy and HF, pointing out the problems and limitations of the current study, in order to provide references for the development of anti-HF drugs targeting HSCs autophagy in TCM. By reviewing the literature in PubMed, Web of Science, Embase, CNKI and other databases, we found that the relationship between autophagy of HSCs and HF is currently controversial. HSCs autophagy may promote HF by consuming lipid droplets (LDs) to provide energy for their activation. However, in contrast, inducing autophagy in HSCs can exert the anti-HF effect by stimulating their apoptosis or senescence, reducing type I collagen accumulation, inhibiting the extracellular vesicles release, degrading pro-fibrotic factors and other mechanisms. Some AITCM inhibit HSCs autophagy to resist HF, with the most promising direction being to target LDs. While, others induce HSCs autophagy to resist HF, with the most promising direction being to target HSCs apoptosis. Future research needs to focus on cell targeting research, autophagy targeting research and in vivo verification research, and to explore the reasons for the contradictory effects of HSCs autophagy on HF.
Collapse
Affiliation(s)
- Xin-Yu Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250000, People’s Republic of China
| | - Wei Zhang
- Department of Liver Disease, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, Shandong, 250000, People’s Republic of China
| | - Bao-Feng Ma
- The third department of encephalopathy, Jinan Integrated Traditional Chinese and Western Medicine Hospital, Jinan, Shandong, 271100, People’s Republic of China
| | - Mi-Mi Sun
- Diagnosis and Treatment Center for Liver Diseases, Tai’an 88 Hospital, Tai’an, Shandong, 271000, People’s Republic of China
| | - Qing-Hua Shang
- Department of Liver Disease, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, Shandong, 250000, People’s Republic of China
| |
Collapse
|
23
|
Maroto-García J, Moreno Álvarez A, Sanz de Pedro MP, Buño-Soto A, González Á. Serum biomarkers for liver fibrosis assessment. ADVANCES IN LABORATORY MEDICINE 2024; 5:115-130. [PMID: 38939201 PMCID: PMC11206202 DOI: 10.1515/almed-2023-0081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 10/12/2023] [Indexed: 06/29/2024]
Abstract
Liver fibrosis is the result of chronic liver injury of different etiologies produced by an imbalance between the synthesis and degeneration of the extracellular matrix and dysregulation of physiological mechanisms. Liver has a high regenerative capacity in the early stage of chronic diseases so a prompt liver fibrosis detection is important. Consequently, an easy and economic tool that could identify patients with liver fibrosis at the initial stages is needed. To achieve this, many non-invasive serum direct, such as hyaluronic acid or metalloproteases, and indirect biomarkers have been proposed to evaluate liver fibrosis. Also, there have been developed formulas that combine these biomarkers, some of them also introduce clinical and/or demographic parameters, like FIB-4, non-alcoholic fatty liver disease fibrosis score (NFS), enhance liver fibrosis (ELF) or Hepamet fibrosis score (HFS). In this manuscript we critically reviewed different serum biomarkers and formulas for their utility in the diagnosis and progression of liver fibrosis.
Collapse
Affiliation(s)
| | - Ana Moreno Álvarez
- Biochemistry Department, Clínica Universidad de Navarra, Pamplona, Spain
| | | | - Antonio Buño-Soto
- Laboratory Medicine Department, Hospital Universitario La Paz, Madrid, Spain
- Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain
| | - Álvaro González
- Biochemistry Department, Clínica Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| |
Collapse
|
24
|
Maroto-García J, Moreno-Álvarez A, Sanz de Pedro MP, Buño-Soto A, González Á. Biomarcadores séricos para la evaluación de la fibrosis hepática. ADVANCES IN LABORATORY MEDICINE 2024; 5:131-147. [PMID: 38939202 PMCID: PMC11206201 DOI: 10.1515/almed-2023-0172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 10/12/2023] [Indexed: 06/29/2024]
Abstract
La fibrosis hepática se desarrolla como respuesta a la presencia de daño hepático crónico de diferentes etiologías, provocando un desequilibrio entre la síntesis y degeneración de la matriz extracelular y la desregulación de diversos mecanismos fisiológicos. En los estadios iniciales de las patologías crónicas, el hígado posee una elevada capacidad de regeneración, por lo que la detección temprana de la fibrosis hepática resulta esencial. En este contexto, es preciso contar con herramientas sencillas y económicas que permitan detectar la fibrosis hepática en sus fases iniciales. Para evaluar la fibrosis hepática, se han propuesto multitud de biomarcadores séricos no invasivos, tanto directos, como el ácido hialurónico o las metaloproteasas, como indirectos. Así mismo, se han desarrollado diversas fórmulas que combinan dichos biomarcadores junto con parámetros demográficos, como el índice FIB-4, el índice de fibrosis en la enfermedad de hígado graso no alcohólico (NFS, por sus siglas en inglés), la prueba ELF o el score de fibrosis Hepamet (HFS, por sus siglas en inglés). En el presente manuscrito, realizamos una revisión crítica del valor diagnóstico y pronóstico de los diferentes biomarcadores séricos y fórmulas actualmente existentes.
Collapse
Affiliation(s)
- Julia Maroto-García
- Departamento de Bioquímica, Clínica Universidad de Navarra, Pamplona, España
| | - Ana Moreno-Álvarez
- Departamento de Bioquímica, Clínica Universidad de Navarra, Pamplona, España
| | | | - Antonio Buño-Soto
- Departamento de Análisis Clínicos, Hospital Universitario La Paz, Madrid, España
- Instituto de investigación en salud del Hospital La (IdiPaz), Madrid, España
| | - Álvaro González
- Departamento de Bioquímica, Clínica Universidad de Navarra, Pamplona, España
- Instituto Navarro de investigación en salud (IdiSNA), Pamplona, España
| |
Collapse
|
25
|
Wegrzyniak O, Lechi F, Mitran B, Cheung P, Bitzios A, Persson J, Löfblom J, Nordström H, Eriksson J, Frejd FY, Korsgren O, Zhang B, Eriksson O. Non-invasive PET imaging of liver fibrogenesis using a RESCA-conjugated Affibody molecule. iScience 2024; 27:109688. [PMID: 38660405 PMCID: PMC11039342 DOI: 10.1016/j.isci.2024.109688] [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: 12/02/2023] [Revised: 02/02/2024] [Accepted: 04/05/2024] [Indexed: 04/26/2024] Open
Abstract
Non-invasive assessment of fibrogenic activity, rather than fibrotic scars, could significantly improve the management of fibrotic diseases and the development of anti-fibrotic drugs. This study explores the potential of an Affibody molecule (Z09591) labeled with the Al(18)F-restrained complexing agent (RESCA) method as a tracer for the non-invasive detection of fibrogenic cells. Z09591 was functionalized with the RESCA chelator for direct labeling with [18F]AlF. In vivo positron emission tomography/magnetic resonance imaging scans on U-87 tumor-bearing mice exhibited high selectivity of the resulting radiotracer, [18F]AlF-RESCA-Z09591, for platelet-derived growth factor receptor β (PDGFRβ), with minimal non-specific background uptake. Evaluation in a mouse model with carbon tetrachloride-induced fibrotic liver followed by a disease regression phase, revealed the radiotracer's high affinity and specificity for fibrogenic cells in fibrotic livers (standardized uptake value [SUV] 0.43 ± 0.05), with uptake decreasing during recovery (SUV 0.29 ± 0.03) (p < 0.0001). [18F]AlF-RESCA-Z09591 accurately detects PDGFRβ, offering non-invasive assessment of fibrogenic cells and promising applications in precise liver fibrogenesis diagnosis, potentially contributing significantly to anti-fibrotic drug development.
Collapse
Affiliation(s)
- Olivia Wegrzyniak
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| | - Francesco Lechi
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| | - Bogdan Mitran
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
- Antaros Medical AB, Mölndal, Sweden
| | - Pierre Cheung
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| | - Athanasios Bitzios
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| | - Jonas Persson
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
- Department of Protein Science, Division of Protein Engineering, KTH Royal Institute of Technology, Stockholm, Sweden
| | - John Löfblom
- Department of Protein Science, Division of Protein Engineering, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Helena Nordström
- Science for Life Laboratory, Drug Discovery & Development Platform, Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden
| | - Jonas Eriksson
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
- PET Center, Uppsala University Hospital, Uppsala, Sweden
| | - Fredrik Y. Frejd
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Affibody AB, Solna, Sweden
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Bo Zhang
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| | - Olof Eriksson
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
- Antaros Medical AB, Mölndal, Sweden
| |
Collapse
|
26
|
Kong M, Zhou J, Kang A, Kuai Y, Xu H, Li M, Miao X, Guo Y, Fan Z, Xu Y, Li Z. Histone methyltransferase Suv39h1 regulates hepatic stellate cell activation and is targetable in liver fibrosis. Gut 2024; 73:810-824. [PMID: 38176898 DOI: 10.1136/gutjnl-2023-329671] [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: 02/08/2023] [Accepted: 12/15/2023] [Indexed: 01/06/2024]
Abstract
OBJECTIVE Liver fibrosis is a prelude to a host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source for excessive production of extracellular matrix proteins. In the present study, we investigated the role of Suv39h1, a lysine methyltransferase, in HSC-myofibroblast transition and the implication in liver fibrosis. DESIGN HSC-specific or myofibroblast-specific Suv39h1 deletion was achieved by crossbreeding the Suv39h1 f/f mice to the Lrat-Cre mice or the Postn-CreERT2 mice. Liver fibrosis was induced by CCl4 injection or bile duct ligation. RESULTS We report that Suv39h1 expression was universally upregulated during HSC-myofibroblast transition in different cell and animal models of liver fibrosis and in human cirrhotic liver tissues. Consistently, Suv39h1 knockdown blocked HSC-myofibroblast transition in vitro. HSC-specific or myofibroblast-specific deletion of Suv39h1 ameliorated liver fibrosis in mice. More importantly, Suv39h1 inhibition by a small-molecule compound chaetocin dampened HSC-myofibroblast transition in cell culture and mitigated liver fibrosis in mice. Mechanistically, Suv39h1 bound to the promoter of heme oxygenase 1 (HMOX1) and repressed HMOX1 transcription. HMOX1 depletion blunted the effects of Suv39h1 inhibition on HSC-myofibroblast transition in vitro and liver fibrosis in vivo. Transcriptomic analysis revealed that HMOX1 might contribute to HSC-myofibroblast transition by modulating retinol homeostasis. Finally, myofibroblast-specific HMOX1 overexpression attenuated liver fibrosis in both a preventive scheme and a therapeutic scheme. CONCLUSIONS Our data demonstrate a previously unrecognised role for Suv39h1 in liver fibrosis and offer proof-of-concept of its targetability in the intervention of cirrhosis.
Collapse
Affiliation(s)
- Ming Kong
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Junjing Zhou
- Department of Hepatobiliary Surgery, Affiliated Hospital of JiangnanUniversity, Wuxi, People's Republic of China
| | - Aoqi Kang
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Yameng Kuai
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Huihui Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Min Li
- Department of Pathophysiology, Jiangsu Health Vocational College, Nanjing, People's Republic of China
| | - Xiulian Miao
- Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, People's Republic of China
| | - Yan Guo
- Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, People's Republic of China
| | - Zhiwen Fan
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People's Republic of China
| | - Yong Xu
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Zilong Li
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, People's Republic of China
| |
Collapse
|
27
|
Osna NA, Tikhanovich I, Ortega-Ribera M, Mueller S, Zheng C, Mueller J, Li S, Sakane S, Weber RCG, Kim HY, Lee W, Ganguly S, Kimura Y, Liu X, Dhar D, Diggle K, Brenner DA, Kisseleva T, Attal N, McKillop IH, Chokshi S, Mahato R, Rasineni K, Szabo G, Kharbanda KK. Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression. Biomolecules 2024; 14:404. [PMID: 38672422 PMCID: PMC11048648 DOI: 10.3390/biom14040404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 03/20/2024] [Accepted: 03/24/2024] [Indexed: 04/28/2024] Open
Abstract
Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide and represents a spectrum of liver injury beginning with hepatic steatosis (fatty liver) progressing to inflammation and culminating in cirrhosis. Multiple factors contribute to ALD progression and disease severity. Here, we overview several crucial mechanisms related to ALD end-stage outcome development, such as epigenetic changes, cell death, hemolysis, hepatic stellate cells activation, and hepatic fatty acid binding protein 4. Additionally, in this review, we also present two clinically relevant models using human precision-cut liver slices and hepatic organoids to examine ALD pathogenesis and progression.
Collapse
Affiliation(s)
- Natalia A. Osna
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68106, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68106, USA
| | - Irina Tikhanovich
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA;
| | - Martí Ortega-Ribera
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (M.O.-R.); (G.S.)
| | - Sebastian Mueller
- Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany; (S.M.); (C.Z.); (J.M.); (S.L.)
- Viscera AG Bauchmedizin, 83011 Bern, Switzerland
| | - Chaowen Zheng
- Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany; (S.M.); (C.Z.); (J.M.); (S.L.)
| | - Johannes Mueller
- Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany; (S.M.); (C.Z.); (J.M.); (S.L.)
| | - Siyuan Li
- Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany; (S.M.); (C.Z.); (J.M.); (S.L.)
| | - Sadatsugu Sakane
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Raquel Carvalho Gontijo Weber
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Hyun Young Kim
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Wonseok Lee
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Souradipta Ganguly
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Yusuke Kimura
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Xiao Liu
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Debanjan Dhar
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
| | - Karin Diggle
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - David A. Brenner
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.S.); (R.C.G.W.); (H.Y.K.); (W.L.); (S.G.); (Y.K.); (X.L.); (D.D.); (K.D.); (D.A.B.)
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA;
| | - Neha Attal
- Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC 28203, USA; (N.A.); (I.H.M.)
| | - Iain H. McKillop
- Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC 28203, USA; (N.A.); (I.H.M.)
| | - Shilpa Chokshi
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE59NT, UK;
- School of Microbial Sciences, King’s College, London SE59NT, UK
| | - Ram Mahato
- Department of Pharmaceutical Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68106, USA;
| | - Karuna Rasineni
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68106, USA;
| | - Gyongyi Szabo
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (M.O.-R.); (G.S.)
| | - Kusum K. Kharbanda
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68106, USA
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68106, USA;
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
| |
Collapse
|
28
|
Shree Harini K, Ezhilarasan D. Flavonoids-based nanomedicines for the treatment of liver fibrosis: A recent progress. J Drug Deliv Sci Technol 2024; 93:105467. [DOI: 10.1016/j.jddst.2024.105467] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
29
|
Imaduddin UK, Berbudi A, Rohmawaty E. The Effect of Physalis angulata L. Administration on Gene Expressions Related to Lung Fibrosis Resolution in Mice-Induced Bleomycin. J Exp Pharmacol 2024; 16:49-60. [PMID: 38317831 PMCID: PMC10840535 DOI: 10.2147/jep.s439932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 01/05/2024] [Indexed: 02/07/2024] Open
Abstract
Purpose To explore the potential therapeutic effects of Physalis angulata L. (Ciplukan) extract on lung fibrosis resolution in a Bleomycin-induced mouse model, researchers conducted a comprehensive study. The study focused on key genes associated with fibrosis progression, including Nox4, Mmp8, Klf4, and FAS, and assessed their mRNA expression levels following the administration of Ciplukan extract. Methods A Bleomycin-induced mice model was divided into seven groups to investigate the effects of ciplukan extract on fibrosis-related gene expressions. Mice were induced with subcutaneously injected Bleomycin to generate lung fibrosis and given different doses of the Ciplukan extract for four weeks. Lung fibrosis mRNA expression was analyzed by semi-quantitative PCR for Nox4, Klf4, Mmp8, and FAS. Results The administration of ciplukan extract resulted in a significant decrease in mRNA expression of Nox4 with p-value=0.000, Mmp8 with p-value =0.002, and Klf4 with p-value =0.007, indicating potential antifibrotic effects. However, FAS expression remained unchanged (p-value=0.127). Conclusion Ciplukan extract exhibited promising effects on fibrosis-related gene expressions, particularly Nox4, Mmp8, and Klf4. This study suggests that the extract has the potential to intervene in fibrosis progression, offering a potential avenue for therapeutic strategies.
Collapse
Affiliation(s)
- Ummul Khair Imaduddin
- Graduate School of Master Program in Anti Aging and Aesthetic Medicine, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia
| | - Afiat Berbudi
- Parasitology Division, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia
| | - Enny Rohmawaty
- Pharmacology & Therapy Division, Departement of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia
| |
Collapse
|
30
|
Choi HJ, Kim YA, Ryu J, Park KK, Lee SJ, Kim BS, Song JE, Kim JD. STAT3 Decoy Oligodeoxynucleotides Suppress Liver Inflammation and Fibrosis in Liver Cancer Cells and a DDC-Induced Liver Injury Mouse Model. Molecules 2024; 29:593. [PMID: 38338338 PMCID: PMC10856653 DOI: 10.3390/molecules29030593] [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: 11/22/2023] [Revised: 12/28/2023] [Accepted: 01/15/2024] [Indexed: 02/12/2024] Open
Abstract
Liver damage caused by various factors results in fibrosis and inflammation, leading to cirrhosis and cancer. Fibrosis results in the accumulation of extracellular matrix components. The role of STAT proteins in mediating liver inflammation and fibrosis has been well documented; however, approved therapies targeting STAT3 inhibition against liver disease are lacking. This study investigated the anti-fibrotic and anti-inflammatory effects of STAT3 decoy oligodeoxynucleotides (ODN) in hepatocytes and liver fibrosis mouse models. STAT3 decoy ODN were delivered into cells using liposomes and hydrodynamic tail vein injection into 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice in which liver injury was induced. STAT3 target gene expression changes were verified using qPCR and Western blotting. Liver tissue fibrosis and bile duct proliferation were assessed in animal experiments using staining techniques, and macrophage and inflammatory cytokine distribution was verified using immunohistochemistry. STAT3 decoy ODN reduced fibrosis and inflammatory factors in liver cancer cell lines and DDC-induced liver injury mouse model. These results suggest that STAT3 decoy ODN may effectively treat liver fibrosis and must be clinically investigated.
Collapse
Affiliation(s)
- Hye Jin Choi
- Department of Surgery, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea;
| | - Young-Ah Kim
- Seoul Clinical Laboratories of Daegu, Daegu 41238, Republic of Korea
| | - Junghwa Ryu
- Department of Radiology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea;
| | - Kwan-Kyu Park
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (K.-K.P.)
| | - Sun-Jae Lee
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (K.-K.P.)
| | - Byung Seok Kim
- Department of Internal Medicine, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (B.S.K.)
| | - Jeong-En Song
- Department of Internal Medicine, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (B.S.K.)
| | - Joo Dong Kim
- Department of Surgery, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea;
| |
Collapse
|
31
|
Fareed MM, Khalid H, Khalid S, Shityakov S. Deciphering Molecular Mechanisms of Carbon Tetrachloride- Induced Hepatotoxicity: A Brief Systematic Review. Curr Mol Med 2024; 24:1124-1134. [PMID: 37818557 DOI: 10.2174/0115665240257603230919103539] [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: 05/02/2023] [Revised: 08/07/2023] [Accepted: 08/11/2023] [Indexed: 10/12/2023]
Abstract
The liver plays a critical role in metabolic processes, making it vulnerable to injury. Researchers often study carbon tetrachloride (CCl4)-induced hepatotoxicity in model organisms because it closely resembles human liver damage. This toxicity occurs due to the activation of various cytochromes, including CYP2E1, CYP2B1, CYP2B2, and possibly CYP3A, which produce the trichloromethyl radical (CCl3*). CCl3* can attach to biological molecules such as lipids, proteins, and nucleic acids, impairing lipid metabolism and leading to fatty degeneration. It can also combine with DNA to initiate hepatic carcinogenesis. When exposed to oxygen, CCl3* generates more reactive CCl3OO*, which leads to lipid peroxidation and membrane damage. At the molecular level, CCl4 induces the release of several inflammatory cytokines, including TNF-α and NO, which can either help or harm hepatotoxicity through cellular apoptosis. TGF-β contributes to fibrogenesis, while IL-6 and IL-10 aid in recovery by minimizing anti-apoptotic activity and directing cells toward regeneration. To prevent liver damage, different interventions can be employed, such as antioxidants, mitogenic agents, and the maintenance of calcium sequestration. Drugs that prevent CCl4- induced cytotoxicity and proliferation or enhance CYP450 activity may offer a protective response against hepatic carcinoma.
Collapse
Affiliation(s)
- Muhammad Mazhar Fareed
- School of Science and Engineering, Department of Computer Science, Università degli Studi di Verona, Verona, Italy
- Laboratorio di Bioinformatica Applicata, Department of Biotechnology, Università degli Studi di Verona, Verona, Italy
| | - Hina Khalid
- Faculty of Life Sciences, Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Sana Khalid
- School of Life Science and Medicine, Shandong University of Technology, Zibo, China
| | - Sergey Shityakov
- Laboratory of Chemoinformatics, Infochemistry Scientific Center, ITMO University, Saint-Petersburg, Russian Federation
| |
Collapse
|
32
|
Wells RG. Liver fibrosis: Our evolving understanding. Clin Liver Dis (Hoboken) 2024; 23:e0243. [PMID: 38961878 PMCID: PMC11221862 DOI: 10.1097/cld.0000000000000243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 03/29/2024] [Indexed: 07/05/2024] Open
|
33
|
Gong L, Zhou H, Zhang Y, Wang C, Fu K, Ma C, Li Y. Preparation of Phillygenin-Hyaluronic acid composite milk-derived exosomes and its anti-hepatic fibrosis effect. Mater Today Bio 2023; 23:100804. [PMID: 37753374 PMCID: PMC10518489 DOI: 10.1016/j.mtbio.2023.100804] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/23/2023] [Accepted: 09/15/2023] [Indexed: 09/28/2023] Open
Abstract
Liver fibrosis remains a serious problem affecting the health of millions of people worldwide. Hepatic stellate cells (HSCs) are the main effector cells in liver fibrosis and their activation could lead to extracellular matrix deposition, which may aggravate the development of liver fibrosis and inflammation. Previous studies have reported the potential of Phillygenin (PHI) as a hepatoprotective agent to inhibit HSCs activation and fibrosis development. However, the poor water solubility of PHI hinders its clinical application as a potential anti-liver fibrosis therapy. Milk-derived exosomes (mEXO) serve as scalable nanocarriers for delivering chemotherapeutic agents due to their excellent biocompatibility. Here, we developed a PHI-Hyaluronic acid (HA) composite mEXO (PHI-HA-mEXO) drug delivery system, in which DSPE-PEG2000-HA was conjugated to the surface of mEXO to prepare HA-mEXO, and PHI was encapsulated into HA-mEXO to form PHI-HA-mEXO. As a specific receptor for HA, CD44 is frequently over-expressed during liver fibrosis and highly expressed on the surface of activated HSCs (aHSCs). PHI-HA-mEXO can bind to CD44 and enter aHSCs through endocytosis and release PHI. PHI-HA-mEXO drug delivery system can significantly induce aHSCs death without affecting quiescent HSCs (qHSCs) and hepatocytes. Furthermore, we carried out in vitro and in vivo experiments and found that PHI-HA-mEXO could alleviate liver fibrosis through aHSCs-targeted mechanism. In conclusion, the favorable biosafety and superior anti-hepatic fibrosis effects suggest a promising potential of PHI-HA-mEXO in the treatment of hepatic fibrosis. However, detailed pharmokinetics and dose-responsive experiments of PHI-HA-mEXO and the mechanism of mEXO loading drugs are still required before PHI-HA-mEXO can be applied clinically.
Collapse
Affiliation(s)
| | | | - Yafang Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of StandardizatAion for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Cheng Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of StandardizatAion for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Ke Fu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of StandardizatAion for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Cheng Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of StandardizatAion for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of StandardizatAion for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| |
Collapse
|
34
|
Brennan PN, Elsharkawy AM, Kendall TJ, Loomba R, Mann DA, Fallowfield JA. Antifibrotic therapy in nonalcoholic steatohepatitis: time for a human-centric approach. Nat Rev Gastroenterol Hepatol 2023; 20:679-688. [PMID: 37268740 PMCID: PMC10236408 DOI: 10.1038/s41575-023-00796-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/09/2023] [Indexed: 06/04/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) might soon become the leading cause of end-stage liver disease and indication for liver transplantation worldwide. Fibrosis severity is the only histological predictor of liver-related morbidity and mortality in NASH identified to date. Moreover, fibrosis regression is associated with improved clinical outcomes. However, despite numerous clinical trials of plausible drug candidates, an approved antifibrotic therapy remains elusive. Increased understanding of NASH susceptibility and pathogenesis, emerging human multiomics profiling, integration of electronic health record data and modern pharmacology techniques hold enormous promise in delivering a paradigm shift in antifibrotic drug development in NASH. There is a strong rationale for drug combinations to boost efficacy, and precision medicine strategies targeting key genetic modifiers of NASH are emerging. In this Perspective, we discuss why antifibrotic effects observed in NASH pharmacotherapy trials have been underwhelming and outline potential approaches to improve the likelihood of future clinical success.
Collapse
Affiliation(s)
- Paul N Brennan
- Institute for Regeneration & Repair, University of Edinburgh, Edinburgh, UK
- Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK
| | - Ahmed M Elsharkawy
- Liver Unit and NIHR Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Timothy J Kendall
- Institute for Regeneration & Repair, University of Edinburgh, Edinburgh, UK
- Edinburgh Pathology, University of Edinburgh, Edinburgh, UK
| | - Rohit Loomba
- NAFLD Research Centre, Division of Gastroenterology and Hepatology, UC San Diego School of Medicine, La Jolla, CA, USA
| | - Derek A Mann
- Fibrosis Research Group, Newcastle University, Newcastle, UK.
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
| | | |
Collapse
|
35
|
Kim HY, Sakane S, Eguileor A, Carvalho Gontijo Weber R, Lee W, Liu X, Lam K, Ishizuka K, Rosenthal SB, Diggle K, Brenner DA, Kisseleva T. The Origin and Fate of Liver Myofibroblasts. Cell Mol Gastroenterol Hepatol 2023; 17:93-106. [PMID: 37743012 PMCID: PMC10665929 DOI: 10.1016/j.jcmgh.2023.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 09/14/2023] [Accepted: 09/14/2023] [Indexed: 09/26/2023]
Abstract
Liver fibrosis of different etiologies is a serious health problem worldwide. There is no effective therapy available for liver fibrosis except the removal of the underlying cause of injury or liver transplantation. Development of liver fibrosis is caused by fibrogenic myofibroblasts that are not present in the normal liver, but rather activate from liver resident mesenchymal cells in response to chronic toxic or cholestatic injury. Many studies indicate that liver fibrosis is reversible when the causative agent is removed. Regression of liver fibrosis is associated with the disappearance of activated myofibroblasts and resorption of the fibrous scar. In this review, we discuss the results of genetic tracing and cell fate mapping of hepatic stellate cells and portal fibroblasts, their specific characteristics, and potential phenotypes. We summarize research progress in the understanding of the molecular mechanisms underlying the development and reversibility of liver fibrosis, including activation, apoptosis, and inactivation of myofibroblasts.
Collapse
Affiliation(s)
- Hyun Young Kim
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Sadatsugu Sakane
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Alvaro Eguileor
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Raquel Carvalho Gontijo Weber
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - Wonseok Lee
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Xiao Liu
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - Kevin Lam
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Kei Ishizuka
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Sara Brin Rosenthal
- Center for Computational Biology and Bioinformatics, University of California San Diego, La Jolla, California
| | - Karin Diggle
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - David A Brenner
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego School of Medicine, La Jolla, California.
| |
Collapse
|
36
|
Abubakr S, Hazem NM, Sherif RN, Elhawary AA, Botros KG. Correlation between SDF-1α, CD34 positive hematopoietic stem cells and CXCR4 expression with liver fibrosis in CCl4 rat model. BMC Gastroenterol 2023; 23:323. [PMID: 37730560 PMCID: PMC10512633 DOI: 10.1186/s12876-023-02932-y] [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: 04/22/2023] [Accepted: 08/25/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND One of the most frequent disorders is liver fibrosis. An improved understanding of the different events during the process of liver fibrosis & its reversibility could be helpful in its staging and in finding potential therapeutic agents. AIM The goal of this research was to evaluate the relationship among CD34 + HPSCs, SDF-1α, and CXCR4 receptor expression with the percentage of the area of hepatic fibrosis. MATERIALS AND METHODS Thirty-six male Sprague-Dawley rats were separated into the control group, liver injury group & spontaneous reversion group. The liver injury was induced by using 2 ml/kg CCl4 twice a week. Flow cytometric examination of CD34 + cells in the blood & liver was performed. Bone marrow & liver samples were taken for evaluation of the SDF-1α mRNA by PCR. Liver specimens were stained for histopathological and CXCR4 immuno-expression evaluation. RESULTS In the liver injury group, the hepatic enzymes, fibrosis area percentage, CXCR4 receptor expression in the liver, CD34 + cells in the blood and bone marrow & the level SDF-1α in the liver and its concentration gradient were statistically significantly elevated with the progression of the liver fibrosis. On the contrary, SDF-1α in the bone marrow was statistically significantly reduced with the development of liver fibrosis. During the spontaneous reversion group, all the studied parameters apart from SDF-1α in the bone marrow were statistically substantially decreased compared with the liver injury group. We found a statistically substantial positive correlation between fibrosis area and all of the following: liver enzymes, CXCR4 receptor expression in the liver, CD34 + cells in the blood and liver, and SDF- 1α in the liver and its concentration gradient. In conclusion, in CCl4 rat model, the fibrosis area is significantly correlated with many parameters in the blood, bone marrow, and liver, which can be used during the process of follow-up during the therapeutic interventions.
Collapse
Affiliation(s)
- Sara Abubakr
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Noha M Hazem
- Medical Biochemistry and Molecular Biology Department, Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Algomhoria Street, Mansoura, 35516, Egypt.
- Pathological Sciences Department, Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia.
| | - R N Sherif
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Adel Abdelmohdy Elhawary
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Kamal G Botros
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| |
Collapse
|
37
|
Zhang C, Teng Y, Li F, Ho W, Bai X, Xu X, Zhang XQ. Nanoparticle-Mediated RNA Therapy Attenuates Nonalcoholic Steatohepatitis and Related Fibrosis by Targeting Activated Hepatic Stellate Cells. ACS NANO 2023; 17:14852-14870. [PMID: 37490628 DOI: 10.1021/acsnano.3c03217] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/27/2023]
Abstract
Chronic liver injury and inflammation triggered by metabolic abnormalities initiate the activation of hepatic stellate cells (HSCs), driving fibrosis and parenchymal dysfunction, culminating in disorders such as nonalcoholic steatohepatitis (NASH). Unfortunately, there are currently no approved drugs capable of effectively treating NASH due to the challenges in addressing fibrosis and restoring extracellular matrix (ECM) homeostasis. We discovered a significant up-regulation of interleukin-11 (IL-11) in fibrotic livers using two well-established murine models of NASH. To leverage this signaling pathway, we developed a nanoparticle (NP)-assisted RNA interfering approach that specifically targets activated HSCs (aHSCs), blocking IL-11/ERK signaling to regulate HSC transdifferentiation along with fibrotic remodeling. The most potent NP, designated NP-AEAA, showed enhanced accumulation in fibrotic livers with NASH and was primarily enriched in aHSCs. We further investigated the therapeutic efficacy of aHSC-targeting NP-AEAA encapsulating small interfering RNA (siRNA) against IL11 or its cognate receptor IL11ra1 (termed siIL11@NP-AEAA or siIL11ra1@NP-AEAA, respectively) for resolving fibrosis and NASH. Our results demonstrate that both siIL11@NP-AEAA and siIL11ra1@NP-AEAA effectively inhibit HSC activation and resolve fibrosis and inflammation in two well-established murine models of NASH. Notably, siIL11ra1@NP-AEAA exhibits a superior therapeutic effect over siIL11@NP-AEAA, in terms of reducing liver steatosis and fibrosis as well as recovering liver function. These results constitute a targeted nanoparticulate siRNA therapeutic approach against the IL-11 signaling pathway of aHSCs in the fibrotic liver, offering a promising therapeutic intervention for NASH and other diseases.
Collapse
Affiliation(s)
- Chenshuang Zhang
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Yilong Teng
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | | | | | - Xin Bai
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | | | - Xue-Qing Zhang
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| |
Collapse
|
38
|
Jia X, Li R, Zhang X, Zhou T, Sun D, Yang N, Luo Z. Increased age, bilirubin, international normalized ratio, and creatinine score to triglyceride ratio are associated with alcohol-associated primary liver carcinoma: a single-centered retrospective study. Lipids Health Dis 2023; 22:117. [PMID: 37537579 PMCID: PMC10401853 DOI: 10.1186/s12944-023-01888-y] [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: 05/25/2023] [Accepted: 07/28/2023] [Indexed: 08/05/2023] Open
Abstract
BACKGROUND This study analyzed the clinical features and biomarkers of alcohol-associated liver disease (ALD) to investigate the diagnostic value of age, bilirubin, international normalized ratio (INR), and creatinine (ABIC) score to triglyceride (TG) ratio (ABIC/TG) in ALD-associated primary liver carcinoma (PLC). MATERIALS AND METHODS Data were collected from 410 participants with ALD, and the epidemiological and clinical records of 266 participants were analyzed. Participants were divided into ALD-without-PLC and ALD-associated-PLC groups. Relationships between clinical characteristics, biomarkers and ALD-associated PLC were estimated. Serum lipid levels and liver function were compared between ALD patients without PLC and patients with ALD-associated PLC. Scoring systems were calculated to investigate ALD severity. The robustness of the relationship was analyzed by the receiver operating characteristic (ROC) curve. RESULTS Age and dyslipidemia were more strongly associated with ALD-associated PLC than with ALD-without PLC, with AORs of 2.39 and 0.25, respectively, with P less than 0.05. Drinking time and average daily intake, ABIC score, and ABIC/TG ratio were significantly higher in the ALD-associated-PLC group than in the ALD-without-PLC group. The AUC for the ABIC/TG ratio predicting the incidence of PLC was 0.80 (P < 0.01), which was higher than that of the ABIC and TG scores alone; additionally, the specificity and Youden index for the ABIC/TG ratio were also higher, and the cutoff value was 6.99. CONCLUSIONS In ALD patients, age, drinking time, and average daily intake were risk factors for PLC. Drinking time, average daily intake, TG and ABIC score have diagnostic value for ALD-associated PLC. The ABIC/TG ratio had a higher AUC value and Youden index than the ABIC score and TG level.
Collapse
Affiliation(s)
- Xiaoqing Jia
- Department of Gastroenterology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, 250010, P.R. China
| | - Rong Li
- Department of Geriatric Medicine, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, 250010, P.R. China
| | - Xiaoting Zhang
- Department of Geriatric Medicine, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, 250010, P.R. China
| | - Tao Zhou
- Department of Geriatric Medicine, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, 250010, P.R. China
| | - Dalong Sun
- Department of Geriatric Medicine, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, 250010, P.R. China
| | - Na Yang
- Department of Geriatric Medicine, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, 250010, P.R. China
| | - Zheng Luo
- Department of Geriatric Medicine, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, 250010, P.R. China.
| |
Collapse
|
39
|
Toya K, Tomimaru Y, Kobayashi S, Harada A, Sasaki K, Iwagami Y, Yamada D, Noda T, Takahashi H, Kado T, Imamura H, Takaichi S, Chijimatsu R, Asaoka T, Tanemura M, Miyagawa S, Doki Y, Eguchi H. Efficacy of Autologous Skeletal Myoblast Cell Sheet Transplantation for Liver Regeneration in Liver Failure. Transplantation 2023; 107:e190-e200. [PMID: 37046371 DOI: 10.1097/tp.0000000000004567] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
BACKGROUND No effective therapies have yet been established for liver regeneration in liver failure. Autologous skeletal myoblast cell sheet transplantation has been proven to improve cardiac function in patients with heart failure, and one of the mechanisms has been reported to be a paracrine effect by various growth factors associated with liver regeneration. Therefore, the present study focused on the effect of myoblast cells on liver regeneration in vitro and in vivo. METHODS We assessed the effect of myoblast cells on the cells comprising the liver in vitro in association with liver regeneration. In addition, we examined in vivo effect of skeletal myoblast cell sheet transplantation in C57/BL/6 mouse models of liver failure, such as liver fibrosis induced by thioacetamide and hepatectomy. RESULTS In vitro, the myoblast cells exhibited a capacity to promote the proliferation of hepatic epithelial cells and the angiogenesis of liver sinusoidal endothelial cells, and suppress the activation of hepatic stellate cells. In vivo, sheet transplantation significantly suppressed liver fibrosis in the induced liver fibrosis model and accelerated liver regeneration in the hepatectomy model. CONCLUSIONS Autologous skeletal myoblast cell sheet transplantation significantly improved the liver failure in the in vitro and in vivo models. Sheet transplantation is expected to have the potential to be a clinically therapeutic option for liver regeneration in liver failure.
Collapse
Affiliation(s)
- Keisuke Toya
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yoshito Tomimaru
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Akima Harada
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kazuki Sasaki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takeshi Kado
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hiroki Imamura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shohei Takaichi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Ryota Chijimatsu
- Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan
| | - Tadafumi Asaoka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Masahiro Tanemura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| |
Collapse
|
40
|
Han Y, Akhtar J, Liu G, Li C, Wang G. Early warning and diagnosis of liver cancer based on dynamic network biomarker and deep learning. Comput Struct Biotechnol J 2023; 21:3478-3489. [PMID: 38213892 PMCID: PMC10782000 DOI: 10.1016/j.csbj.2023.07.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 06/19/2023] [Accepted: 07/01/2023] [Indexed: 01/13/2024] Open
Abstract
Background Early detection of complex diseases like hepatocellular carcinoma remains challenging due to their network-driven pathology. Dynamic network biomarkers (DNB) based on monitoring changes in molecular correlations may enable earlier predictions. However, DNB analysis often overlooks disease heterogeneity. Methods We integrated DNB analysis with graph convolutional neural networks (GCN) to identify critical transitions during hepatocellular carcinoma development in a mouse model. A DNB-GCN model was constructed using transcriptomic data and gene expression levels as node features. Results DNB analysis identified a critical transition point at 7 weeks of age despite histological examinations being unable to detect cancerous changes at that time point. The DNB-GCN model achieved 100% accuracy in classifying healthy and cancerous mice, and was able to accurately predict the health status of newly introduced mice. Conclusion The integration of DNB analysis and GCN demonstrates potential for the early detection of complex diseases by capturing network structures and molecular features that conventional biomarker discovery methods overlook. The approach warrants further development and validation.
Collapse
Affiliation(s)
- Yukun Han
- Institute of Modern Biology, Nanjing University, Nanjing 210023, China
- Guangdong Provincial Key Laboratory of Computational Science and Material Design, Shenzhen 518055, China
- Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China
| | - Javed Akhtar
- Biomedical Science and Engineering, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
- Center for Endocrinology and Metabolic Diseases, Second Affiliated Hospital, The Chinese University of Hong Kong, Shenzhen 518172, China
- Guangdong Provincial Key Laboratory of Computational Science and Material Design, Shenzhen 518055, China
- Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China
| | - Guozhen Liu
- Biomedical Science and Engineering, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
| | - Chenzhong Li
- Biomedical Science and Engineering, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
| | - Guanyu Wang
- Biomedical Science and Engineering, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
- Center for Endocrinology and Metabolic Diseases, Second Affiliated Hospital, The Chinese University of Hong Kong, Shenzhen 518172, China
- Guangdong Provincial Key Laboratory of Computational Science and Material Design, Shenzhen 518055, China
- Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China
| |
Collapse
|
41
|
Li L, Diao S, Chen Z, Zhang J, Chen W, Wang T, Chen X, Zhao Y, Xu T, Huang C, Li J. DNMT3a-mediated methylation of TCF21/hnRNPA1 aggravates hepatic fibrosis by regulating the NF-κB signaling pathway. Pharmacol Res 2023; 193:106808. [PMID: 37268177 DOI: 10.1016/j.phrs.2023.106808] [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: 05/27/2023] [Revised: 05/28/2023] [Accepted: 05/28/2023] [Indexed: 06/04/2023]
Abstract
Hepatic fibrosis is caused by liver damage as a consequence of wound healing response. Recent studies have shown that hepatic fibrosis could be effectively reversed, partly through regression of activated hepatic stellate cells (HSCs). Transcription factor 21 (TCF21), a member of the basic helix-loop-helix (bHLH) transcription factor, is involved in epithelial-mesenchymal transformation in various diseases. However, the mechanism by which TCF21 regulates epithelial-mesenchymal transformation in hepatic fibrosis has not been elucidated. In this research, we found that hnRNPA1, the downstream binding protein of TCF21, accelerates hepatic fibrosis reversal by inhibiting the NF-κB signaling pathway. Furthermore, the combination of DNMT3a with TCF21 promoter results in TCF21 hypermethylation. Our results suggest that DNMT3a regulation of TCF21 is a significant event in reversing hepatic fibrosis. In conclusion, this research identifies a novel signaling axis, DNMT3a-TCF21-hnRNPA1, that regulates HSCs activation and hepatic fibrosis reversal, providing a novel treatment strategy for hepatic fibrosis. The clinical trial was registered in the Research Registry (researchregistry9079).
Collapse
Affiliation(s)
- Liangyun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University
| | - Shaoxi Diao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University
| | - Zixiang Chen
- The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Jintong Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University
| | - Wei Chen
- The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Tianqi Wang
- The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Xin Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University
| | - Yuxin Zhao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University
| | - Tao Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University.
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University.
| |
Collapse
|
42
|
McElhinney K, Irnaten M, O’Brien C. p53 and Myofibroblast Apoptosis in Organ Fibrosis. Int J Mol Sci 2023; 24:ijms24076737. [PMID: 37047710 PMCID: PMC10095465 DOI: 10.3390/ijms24076737] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/23/2023] [Accepted: 03/28/2023] [Indexed: 04/07/2023] Open
Abstract
Organ fibrosis represents a dysregulated, maladaptive wound repair response that results in progressive disruption of normal tissue architecture leading to detrimental deterioration in physiological function, and significant morbidity/mortality. Fibrosis is thought to contribute to nearly 50% of all deaths in the Western world with current treatment modalities effective in slowing disease progression but not effective in restoring organ function or reversing fibrotic changes. When physiological wound repair is complete, myofibroblasts are programmed to undergo cell death and self-clearance, however, in fibrosis there is a characteristic absence of myofibroblast apoptosis. It has been shown that in fibrosis, myofibroblasts adopt an apoptotic-resistant, highly proliferative phenotype leading to persistent myofibroblast activation and perpetuation of the fibrotic disease process. Recently, this pathological adaptation has been linked to dysregulated expression of tumour suppressor gene p53. In this review, we discuss p53 dysregulation and apoptotic failure in myofibroblasts and demonstrate its consistent link to fibrotic disease development in all types of organ fibrosis. An enhanced understanding of the role of p53 dysregulation and myofibroblast apoptosis may aid in future novel therapeutic and/or diagnostic strategies in organ fibrosis.
Collapse
Affiliation(s)
- Kealan McElhinney
- UCD Clinical Research Centre, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
| | - Mustapha Irnaten
- UCD Clinical Research Centre, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
| | - Colm O’Brien
- UCD Clinical Research Centre, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
| |
Collapse
|
43
|
Zhao W, Lei M, Li J, Zhang H, Zhang H, Han Y, Ba Z, Zhang M, Li D, Liu C. Yes-associated protein inhibition ameliorates liver fibrosis and acute and chronic liver failure by decreasing ferroptosis and necroptosis. Heliyon 2023; 9:e15075. [PMID: 37151632 PMCID: PMC10161368 DOI: 10.1016/j.heliyon.2023.e15075] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 03/23/2023] [Accepted: 03/27/2023] [Indexed: 04/05/2023] Open
Abstract
Background/aims This study aims to determine which cell death modes contribute most in the progression of cirrhosis and acute-on-chronic liver failure (ACLF), and to investigate whether Yes associated protein (YAP) affects the disease process by regulating cell death. Materials and methods 30C57BL/6 male mice were divided into five groups: control, carbon tetrachloride (CCl4)-induced liver fibrosis model, CCl4+verteporfin, CCl4+lipopolysaccharides (LPS) combined with the D-(+)-Galactosamine (LPS/D-GalN)-induced ACLF model, and ACLF + verteporfin. Patients with chronic hepatitis B (CHB), hepatitis B virus (HBV) related liver cirrhosis or ACLF were enrolled. Histology, immunohistochemistry, transmission electron microscopy, Western blot and ELISA were conducted to assess the roles of YAP and cell death in liver cirrhosis and ACLF, and to explore the effect of YAP inhibition on cell deaths. Results YAP was markedly increased in mice with liver fibrosis and ACLF, along with ferroptosis and necroptosis. Furthermore, YAP inhibition significantly suppressed fibrosis in CCl4-mediated liver fibrosis and ACLF-associated liver injury. Notably, CCl4 induced up-regulation of ACSL4 and RIPK3 and down-regulation of SLC7A11, key factors in ferroptosis and necroptosis. This was significantly abrogated by verteporfin treatment. Similar changes in ferroptosis and necroptosis were found in ACLF and ACLF + verteporfin groups. Consistent with the above findings in mice, we found that plasma YAP levels were gradually increased with the development of HBV-related liver fibrosis and ACLF. Conclusion Ferroptosis and necroptosis are involved in the development of liver cirrhosis and ACLF. Inhibition of YAP improved liver fibrosis and liver damage in ACLF through a reduction in ferroptosis and necroptosis. Our findings may help better understanding the role of YAP in liver fibrosis and ACLF.
Collapse
Affiliation(s)
- Wen Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Miao Lei
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Jinfeng Li
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Hailin Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Hongkun Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Yuxin Han
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Zhiwei Ba
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Manli Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Dongdong Li
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Chuanmiao Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| |
Collapse
|
44
|
Cheng M, Li JJ, Niu XN, Zhu L, Liu JY, Jia PC, Zhu S, Meng HW, Lv XW, Huang C, Li J. BRD4 promotes hepatic stellate cells activation and hepatic fibrosis via mediating P300/H3K27ac/PLK1 axis. Biochem Pharmacol 2023; 210:115497. [PMID: 36907496 DOI: 10.1016/j.bcp.2023.115497] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 03/03/2023] [Accepted: 03/06/2023] [Indexed: 03/14/2023]
Abstract
Hepatic fibrosis (HF) is a reversible wound-healing response characterized by excessive extracellular matrix (ECM) deposition and secondary to persistent chronic injury. Bromodomain protein 4 (BRD4) commonly functions as a "reader" to regulate epigenetic modifications involved in various biological and pathological events, but the mechanism of HF remains unclear. In this study, we established a CCl4-induced HF model and spontaneous recovery model in mice and found aberrant BRD4 expression, which was consistent with the results in human hepatic stellate cells (HSCs)- LX2 cells in vitro. Subsequently, we found that distriction and inhibition of BRD4 restrained TGFβ-induced trans-differentiation of LX2 cells into activated, proliferative myofibroblasts and accelerated apoptosis, and BRD4 overexpression blocked MDI-induced LX2 cells inactivation and promoted the proliferation and inhibited apoptosis of inactivated cells. Additionally, adeno-associated virus serotype 8-loaded short hairpin RNA-mediated BRD4 knockdown in mice significantly attenuated CCl4-induced fibrotic responses including HSCs activation and collagen deposition. Mechanistically, BRD4 deficiency inhibited PLK1 expression in activated LX2 cells, and ChIP and Co-IP assays revealed that BRD4 regulation of PLK1 was dependent on P300-mediated acetylation modification for H3K27 on the PLK1 promoter. In conclusion, BRD4 deficiency in the liver alleviates CCl4-induced HF in mice, and BRD4 participates in the activation and reversal of HSCs through positively regulating the P300/H3K27ac/PLK1 axis, providing a potential insight for HF therapy.
Collapse
Affiliation(s)
- Miao Cheng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Juan-Juan Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Xue-Ni Niu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Lin Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Jin-Yu Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Peng-Cheng Jia
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Sai Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Hong-Wu Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Xiong-Wen Lv
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
| |
Collapse
|
45
|
Li Y, Guha C, Asp P, Wang X, Tchaikovskya TL, Kim K, Mendel M, Cost GJ, Perlmutter DH, Roy-Chowdhury N, Fox IJ, Conway A, Roy-Chowdhury J. Resolution of hepatic fibrosis after ZFN-mediated gene editing in the PiZ mouse model of human α1-antitrypsin deficiency. Hepatol Commun 2023; 7:e0070. [PMID: 36848094 PMCID: PMC9974076 DOI: 10.1097/hc9.0000000000000070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 12/21/2022] [Indexed: 03/01/2023] Open
Abstract
BACKGROUND α1-antitrypsin deficiency is most commonly caused by a mutation in exon-7 of SERPINA1 (SA1-ATZ), resulting in hepatocellular accumulation of a misfolded variant (ATZ). Human SA1-ATZ-transgenic (PiZ) mice exhibit hepatocellular ATZ accumulation and liver fibrosis. We hypothesized that disrupting the SA1-ATZ transgene in PiZ mice by in vivo genome editing would confer a proliferative advantage to the genome-edited hepatocytes, enabling them to repopulate the liver. METHODS To create a targeted DNA break in exon-7 of the SA1-ATZ transgene, we generated 2 recombinant adeno-associated viruses (rAAV) expressing a zinc-finger nuclease pair (rAAV-ZFN), and another rAAV for gene correction by targeted insertion (rAAV-TI). PiZ mice were injected i.v. with rAAV-TI alone or the rAAV-ZFNs at a low (7.5×1010vg/mouse, LD) or a high dose (1.5×1011vg/mouse, HD), with or without rAAV-TI. Two weeks and 6 months after treatment, livers were harvested for molecular, histological, and biochemical analyses. RESULTS Two weeks after treatment, deep sequencing of the hepatic SA1-ATZ transgene pool showed 6%±3% or 15%±4% nonhomologous end joining in mice receiving LD or HD rAAV-ZFN, respectively, which increased to 36%±12% and 36%±12%, respectively, 6 months after treatment. Two weeks postinjection of rAAV-TI with LD or HD of rAAV-ZFN, repair by targeted insertion occurred in 0.10%±0.09% and 0.25%±0.14% of SA1-ATZ transgenes, respectively, which increased to 5.2%±5.0% and 33%±13%, respectively, 6 months after treatment. Six months after rAAV-ZFN administration, there was a marked clearance of ATZ globules from hepatocytes, and resolution of liver fibrosis, along with reduction of hepatic TAZ/WWTR1, hedgehog ligands, Gli2, a TIMP, and collagen content. CONCLUSIONS ZFN-mediated SA1-ATZ transgene disruption provides a proliferative advantage to ATZ-depleted hepatocytes, enabling them to repopulate the liver and reverse hepatic fibrosis.
Collapse
Affiliation(s)
- Yanfeng Li
- Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA
| | - Chandan Guha
- Department of Radiation Oncology, Albert Einstein College of Medicine, New York, New York, USA
- Department of Pathology, Albert Einstein College of Medicine, New York, New York, USA
- Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, New York, USA
| | - Patrik Asp
- Department of Radiation Oncology, Albert Einstein College of Medicine, New York, New York, USA
- Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, New York, USA
| | - Xia Wang
- Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA
| | - Tatyana L. Tchaikovskya
- Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA
- Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, New York, USA
| | - Kenneth Kim
- Sangamo Therapeutics, Richmond, California, USA
| | | | | | - David H. Perlmutter
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Namita Roy-Chowdhury
- Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA
- Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, New York, USA
- Department of Genetics, Albert Einstein College of Medicine, New York, New York, USA
| | - Ira J. Fox
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | | | - Jayanta Roy-Chowdhury
- Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA
- Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, New York, USA
- Department of Genetics, Albert Einstein College of Medicine, New York, New York, USA
| |
Collapse
|
46
|
Hildreth AD, Padilla ET, Tafti RY, Legala AR, O'Sullivan TE. Sterile liver injury induces a protective tissue-resident cDC1-ILC1 circuit through cDC1-intrinsic cGAS-STING-dependent IL-12 production. Cell Rep 2023; 42:112141. [PMID: 36807146 PMCID: PMC10435668 DOI: 10.1016/j.celrep.2023.112141] [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: 08/17/2022] [Revised: 11/02/2022] [Accepted: 02/06/2023] [Indexed: 02/22/2023] Open
Abstract
Tissue-resident immune cells are critical to the initiation and potentiation of inflammation. However, the tissue-protective cellular communication networks initiated by resident immunity during sterile inflammation are not well understood. Using single-cell transcriptomic analysis, we show the liver-resident cell connectome and signalome during acute liver injury. These analyses identify Il12b as a central regulator of liver injury-associated changes in gene expression. Interleukin (IL)-12 produced by conventional type 1 dendritic cells (cDC1s) is required for protection during acute injury through activation of interferon (IFN)-γ production by liver-resident type 1 innate lymphoid cells (ILC1s). Using a targeted in vivo CRISPR-Cas9 screen of innate immune sensing pathways, we find that cDC1-intrinsic cGAS-STING signaling acts upstream of IL-12 production to initiate early protective immune responses. Our study identifies the core communication hubs initiated by tissue-resident innate immune cells during sterile inflammation in vivo and implicates cDC1-derived IL-12 as an important regulator of this process.
Collapse
Affiliation(s)
- Andrew D Hildreth
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Eddie T Padilla
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Rana Yakhshi Tafti
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Akshara R Legala
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Timothy E O'Sullivan
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
| |
Collapse
|
47
|
Iwanaga T, Chiba T, Nakamura M, Kaneko T, Ao J, Qiang N, Ma Y, Zhang J, Kogure T, Yumita S, Ishino T, Ogawa K, Kan M, Nakagawa M, Fujiwara K, Fujita N, Sakuma T, Kanzaki H, Koroki K, Kusakabe Y, Inoue M, Kobayashi K, Kanogawa N, Kiyono S, Kondo T, Nakagawa R, Ogasawara S, Nakamoto S, Muroyama R, Kato J, Kanda T, Maruyama H, Mimura N, Honda T, Murayama T, Nakamura H, Kato N. Miglustat, a glucosylceramide synthase inhibitor, mitigates liver fibrosis through TGF-β/Smad pathway suppression in hepatic stellate cells. Biochem Biophys Res Commun 2023; 642:192-200. [PMID: 36586187 DOI: 10.1016/j.bbrc.2022.12.025] [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: 11/17/2022] [Revised: 11/30/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022]
Abstract
Transforming growth factor (TGF)-β/Smad pathway is implicated in the pathogenesis of liver fibrosis, a condition characterized by excessive deposition of extracellular matrix (ECM) proteins such as collagen in response to chronic inflammation. It has been reported that ceramide regulates collagen production through TGF-β/Smad pathway activation. In this study, we examined whether miglustat, an inhibitor of glucosylceramide synthase, can suppress liver fibrosis by reducing TGF-β/Smad pathway activity. Human hepatic stellate cells (HHSteCs) were cultured with TGF-β and multiple miglustat concentrations to examine dose-dependent effects on the expression levels of ECM-related genes and Smad proteins. To evaluate the efficacy of miglustat for fibrosis mitigation, C57BL/6 mice were treated with carbon tetrachloride (CCl4) for 4 weeks to induce liver fibrosis, followed by combined CCl4 plus miglustat for a further 2 weeks. To examine if miglustat can also prevent fibrosis, mice were treated with CCl4 for 2 weeks, followed by CCl4 plus miglustat for 2 weeks. Miglustat dose-dependently downregulated expression of α-smooth muscle actin and ECM components in TGF-β-treated HHSteCs. Both phosphorylation and nuclear translocation of Smad2 and Smad3 were also suppressed by miglustat treatment. Sirius-Red staining and hydroxyproline assays of model mouse liver samples revealed that miglustat reduced fibrosis, an effect accompanied by decreased expression of ECM. Our findings suggest that miglustat can both prevent and reverse liver fibrosis by inhibiting TGF-β/Smad pathway.
Collapse
Affiliation(s)
- Terunao Iwanaga
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tatsuya Kaneko
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Junjie Ao
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Na Qiang
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yaojia Ma
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Jiaqi Zhang
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tadayoshi Kogure
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Sae Yumita
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takamasa Ishino
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keita Ogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Motoyasu Kan
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Miyuki Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kisako Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoto Fujita
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takafumi Sakuma
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keisuke Koroki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yuko Kusakabe
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masanori Inoue
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kanogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryo Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryosuke Muroyama
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Hitoshi Maruyama
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoya Mimura
- Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan
| | - Takuya Honda
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Toshihiko Murayama
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Hiroyuki Nakamura
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| |
Collapse
|
48
|
Reolizo L, Matsuda M, Seki E. Experimental Workflow for Preclinical Studies of Human Antifibrotic Therapies. Methods Mol Biol 2023; 2669:285-306. [PMID: 37247068 DOI: 10.1007/978-1-0716-3207-9_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Chronic liver diseases accompanied by liver fibrosis have caused significant morbidity and mortality in the world with increasing prevalence. Nonetheless, there are no approved antifibrotic therapies. Although numerous preclinical studies showed satisfactory results in targeting fibrotic pathways, these animal studies have not led to success in humans. In this chapter, we summarize the experimental approaches currently available, including in vitro cell culture models, in vivo animal models, and new experimental tools relevant to humans, and discuss how we translate laboratory results to clinical trials. We will also address the obstacles in transitioning promising therapies from preclinical studies to human antifibrotic treatments.
Collapse
Affiliation(s)
- Lien Reolizo
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Michitaka Matsuda
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ekihiro Seki
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| |
Collapse
|
49
|
Secretin alleviates biliary and liver injury during late-stage primary biliary cholangitis via restoration of secretory processes. J Hepatol 2023; 78:99-113. [PMID: 35987275 DOI: 10.1016/j.jhep.2022.07.034] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 07/22/2022] [Accepted: 07/29/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND & AIMS Primary biliary cholangitis (PBC) is characterised by ductopenia, ductular reaction, impairment of anion exchanger 2 (AE2) and the 'bicarbonate umbrella'. Ductulo-canalicular junction (DCJ) derangement is hypothesised to promote PBC progression. The secretin (Sct)/secretin receptor (SR) axis regulates cystic fibrosis transmembrane receptor (CFTR) and AE2, thus promoting choleresis. We evaluated the role of Sct/SR signalling on biliary secretory processes and subsequent injury in a late-stage PBC mouse model and human samples. METHODS At 32 weeks of age, female and male wild-type and dominant-negative transforming growth factor beta receptor II (late-stage PBC model) mice were treated with Sct for 1 or 8 weeks. Bulk RNA-sequencing was performed in isolated cholangiocytes from mouse models. RESULTS Biliary Sct/SR/CFTR/AE2 expression and bile bicarbonate levels were reduced in late-stage PBC mouse models and human samples. Sct treatment decreased bile duct loss, ductular reaction, inflammation, and fibrosis in late-stage PBC models. Sct reduced hepatic bile acid levels, modified bile acid composition, and restored the DCJ and 'bicarbonate umbrella'. RNA-sequencing identified that Sct promoted mature epithelial marker expression, specifically anterior grade protein 2 (Agr2). Late-stage PBC models and human samples exhibited reduced biliary mucin 1 levels, which were enhanced by Sct treatment. CONCLUSION Loss of Sct/SR signalling in late-stage PBC results in a faulty 'bicarbonate umbrella' and reduced Agr2-mediated mucin production. Sct restores cholangiocyte secretory processes and DCJ formation through enhanced mature cholangiocyte phenotypes and bile duct growth. Sct treatment may be beneficial for individuals with late-stage PBC. IMPACT AND IMPLICATIONS Secretin (Sct) regulates biliary proliferation and bicarbonate secretion in cholangiocytes via its receptor, SR, and in mouse models and human samples of late-stage primary biliary cholangitis (PBC), the Sct/SR axis is blunted along with loss of the protective 'bicarbonate umbrella'. We found that both short- and long-term Sct treatment ameliorated ductular reaction, immune cell influx, and liver fibrosis in late-stage PBC mouse models. Importantly, Sct treatment promoted bicarbonate and mucin secretion and hepatic bile acid efflux, thus reducing cholestatic and toxic bile acid-associated injury in late-stage PBC mouse models. Our work perpetuates the hypothesis that PBC pathogenesis hinges on secretory defects, and restoration of secretory processes that promote the 'bicarbonate umbrella' may be important for amelioration of PBC-associated damage.
Collapse
|
50
|
Sharma A, Kudira R, Wang J, Miethke A, Gandhi CR. Differential recruitment of monocyte-derived macrophages in control and stellate cell-depleted mice during recurrent carbon tetrachloride-induced acute liver injury. J Cell Physiol 2022; 237:4215-4225. [PMID: 36098042 PMCID: PMC11296225 DOI: 10.1002/jcp.30877] [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: 04/11/2022] [Revised: 08/04/2022] [Accepted: 08/23/2022] [Indexed: 11/07/2022]
Abstract
Liver depleted of hepatic stellate cells (HSCs) is resistant to ischemia/reperfusion-, concanavalin A-, and acetaminophen-induced acute injury. Whether HSCs regulate carbon tetrachloride (CCl4 )-induced acute liver injury is not known. CCl4 treatment damages pericentral hepatocytes that express CCl4 -metabolizing Cyp2E1 and activates HSCs. We investigated whether HSC-depletion in mice transgenic for thymidine kinase under the glial fibrillary acidic protein promoter (GFAP-TK-Tg) confers resistance to injury and inflammation due to CCl4 rechallenge. GFAP-TK-Tg or wild type (WT) mice were administered 0.16 ml/kg CCl4 (3× at 3 days intervals), then 40 μg/g/day ganciclovir for 10 days. The treatment depletes ~70%-75% HSCs from GFAP-TK-Tg but not WT mice while the liver recovers from earlier CCl4 -induced injury. Mice were then administered CCl4 , and liver injury and inflammation were determined at 24 h. HSC-depleted and HSC-sufficient mice showed similar CCl4 -induced hepatocyte necrosis and oxidative stress. However, increase in F4/80+ macrophages, but not CD68+ cells, was greater in CCl4 rechallenged HSC-depleted compared to HSC-sufficient mice. Expression of tumor necrosis factor-α (TNF-α), CCL2, and CXCL1 increased similarly, whereas increase in interleukin-6 (IL6), IL1β, and IL10 expression was higher in CCl4 rechallenged HSC-depleted compared to HSC-sufficient mice. CCl4 rechallenge of HSC-sufficient mice rapidly activated HSCs causing significant fibrosis with increased expression of Col1a1, transforming growth factor β1 (TGFβ1), tissue inhibitors of metalloproteinases 1 (TIMP1); increase in TIPM1 was much lower and metalloproteinases 13 (MMP13) greater in CCl4 rechallenged HSC-depleted mice. Interestingly, hepatic recruitment of both profibrogenic (Ly6Chi ) and antifibrogenic restorative (Ly6Clo ) macrophages, and neutrophils was significantly greater in CCl4 rechallenged HSC-depleted mice. These data suggest that CCl4 directly damages hepatocytes but HSCs regulate inflammation. Rapid fibrogenesis in CCl4 rechallenged HSC-sufficient mice recovered from earlier injury indicates that even transiently activated HSCs that had reverted to the quiescent phenotype remain primed to become reactivated.
Collapse
Affiliation(s)
- Akanksha Sharma
- Department of Pediatrics, Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
- Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
| | - Ramesh Kudira
- Department of Pediatrics, Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Jiang Wang
- Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Alexander Miethke
- Department of Pediatrics, Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Chandrashekhar R. Gandhi
- Department of Pediatrics, Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
- Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA
| |
Collapse
|