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Roh YJ, Kim H, Choi DW. Metabolic Sparks in the Liver: Metabolic and Epigenetic Reprogramming in Hepatic Stellate Cells Activation and Its Implications for Human Metabolic Diseases. Diabetes Metab J 2025; 49:368-385. [PMID: 40367987 PMCID: PMC12086559 DOI: 10.4093/dmj.2025.0195] [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: 05/09/2025] [Accepted: 04/17/2025] [Indexed: 05/16/2025] Open
Abstract
The liver plays a fundamental role in metabolic homeostasis, integrating systemic fuel utilization with the progression of various metabolic diseases. Hepatic stellate cells (HSCs) are a key nonparenchymal cell type in the liver, which is essential for maintaining hepatic architecture in their quiescent state. However, upon chronic liver injury or metabolic stress, HSCs become activated, leading to excessive extracellular matrix deposition and pro-fibrotic signaling, ultimately positioning them as key players in liver pathology. Emerging evidence highlights the critical roles of metabolic reprogramming and epigenetic regulation in HSCs activation. HSCs activation is driven by both intrinsic fuel metabolism reprogramming and extrinsic metabolic cues from the microenvironment, while the metabolic intermediates actively reshape the epigenetic landscape, reinforcing fibrogenic transcriptional programs. In this review, we summarize recent advances in understanding how metabolic and epigenetic alterations drive HSCs activation, thereby shaping transcriptional programs that sustain fibrosis, and discuss potential therapeutic strategies to target these interconnected pathways in human metabolic diseases.
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Affiliation(s)
- Yeon Jin Roh
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea
| | - Hyeonki Kim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea
| | - Dong Wook Choi
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea
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2
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Chen F, Kang NW, Wungcharoen T, Jiang L, Basco CA, Garcia-Sanchez J, Lin D, Seo YA, Jang K, Myung D, Liu WW. Repurposing verteporfin and hyaluronic acid gel for ocular surface treatment to prevent corneal scarring. J Control Release 2025; 380:1141-1151. [PMID: 39986473 DOI: 10.1016/j.jconrel.2025.02.051] [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: 10/09/2024] [Revised: 02/13/2025] [Accepted: 02/18/2025] [Indexed: 02/24/2025]
Abstract
There is an unmet need for point-of-care therapies to prevent scarring and promote corneal clarity after injury, which is essential for maintaining vision. Verteporfin, an inhibitor of Yes-associated protein (YAP), has been shown to prevent fibrosis in several organs. Visudyne (VP) is an FDA-approved liposomal formulation of verteporfin used to treat abnormal blood vessels in the eye. Here, we showed that VP reduces myofibroblast formation in corneal stromal fibroblasts. To prolong the residence time of verteporfin on the ocular surface, the cohesive viscoelastic ProVisc® hyaluronic acid (HA) gel was hybridized to VP. This formulation is readily translatable because both VP and ProVisc® HA gel are FDA-approved agents. The ProVisc® HA gel increased the residence of subconjunctivally injected verteporfin 12-fold at 24 h after injection compared with pure VP. A single subconjunctival administration of VP hybridized within ProVisc® HA gel (VP/HA hydrogel) significantly reduced YAP activation, corneal fibrosis, neovascularization, and inflammation, leading to reduced opacity without compromising epithelial wound healing in mechanically injured rat corneas. This work demonstrated that VP hybridized with a viscoelastic HA gel can be readily repurposed to promote scar-less healing in the cornea.
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Affiliation(s)
- Fang Chen
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA 94303, USA
| | - Nae-Won Kang
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA 94303, USA
| | - Thitima Wungcharoen
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA 94303, USA
| | - Li Jiang
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA 94303, USA
| | - Chris A Basco
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA 94303, USA
| | - Julian Garcia-Sanchez
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA 94303, USA
| | - Danting Lin
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA 94303, USA
| | - Youngyoon Amy Seo
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA 94303, USA
| | - Kyeongwoo Jang
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA 94303, USA
| | - David Myung
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA; Division of Ophthalmology, Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA.
| | - Wendy W Liu
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA 94303, USA.
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3
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Sharip A, Kunz J. Mechanosignaling via Integrins: Pivotal Players in Liver Fibrosis Progression and Therapy. Cells 2025; 14:266. [PMID: 39996739 PMCID: PMC11854242 DOI: 10.3390/cells14040266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/05/2025] [Accepted: 02/05/2025] [Indexed: 02/26/2025] Open
Abstract
Liver fibrosis, a consequence of chronic liver injury, represents a major global health burden and is the leading cause of liver failure, morbidity, and mortality. The pathological hallmark of this condition is excessive extracellular matrix deposition, driven primarily by integrin-mediated mechanotransduction. Integrins, transmembrane heterodimeric proteins that serve as primary ECM receptors, orchestrate complex mechanosignaling networks that regulate the activation, differentiation, and proliferation of hepatic stellate cells and other ECM-secreting myofibroblasts. These mechanical signals create self-reinforcing feedback loops that perpetuate the fibrotic response. Recent advances have provided insight into the roles of specific integrin subtypes in liver fibrosis and revealed their regulation of key downstream effectors-including transforming growth factor beta, focal adhesion kinase, RhoA/Rho-associated, coiled-coil containing protein kinase, and the mechanosensitive Hippo pathway. Understanding these mechanotransduction networks has opened new therapeutic possibilities through pharmacological manipulation of integrin-dependent signaling.
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Affiliation(s)
- Aigul Sharip
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana 020000, Kazakhstan;
- Laboratory of Bioinformatics and Systems Biology, National Laboratory Astana, Astana 020000, Kazakhstan
| | - Jeannette Kunz
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana 020000, Kazakhstan;
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Gilgenkrantz H, Paradis V, Lotersztajn S. Cell metabolism-based therapy for liver fibrosis, repair, and hepatocellular carcinoma. Hepatology 2025; 81:269-287. [PMID: 37212145 PMCID: PMC11643143 DOI: 10.1097/hep.0000000000000479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 04/21/2023] [Indexed: 05/23/2023]
Abstract
Progression of chronic liver injury to fibrosis, abnormal liver regeneration, and HCC is driven by a dysregulated dialog between epithelial cells and their microenvironment, in particular immune, fibroblasts, and endothelial cells. There is currently no antifibrogenic therapy, and drug treatment of HCC is limited to tyrosine kinase inhibitors and immunotherapy targeting the tumor microenvironment. Metabolic reprogramming of epithelial and nonparenchymal cells is critical at each stage of disease progression, suggesting that targeting specific metabolic pathways could constitute an interesting therapeutic approach. In this review, we discuss how modulating intrinsic metabolism of key effector liver cells might disrupt the pathogenic sequence from chronic liver injury to fibrosis/cirrhosis, regeneration, and HCC.
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Affiliation(s)
- Hélène Gilgenkrantz
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
| | - Valérie Paradis
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
- Pathology Department, Beaujon Hospital APHP, Paris-Cité University, Clichy, France
| | - Sophie Lotersztajn
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
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5
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Islam R, Hong Z. YAP/TAZ as mechanobiological signaling pathway in cardiovascular physiological regulation and pathogenesis. MECHANOBIOLOGY IN MEDICINE 2024; 2:100085. [PMID: 39281415 PMCID: PMC11391866 DOI: 10.1016/j.mbm.2024.100085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/18/2024]
Abstract
Cardiovascular diseases (CVDs) persistently rank as a leading cause of premature death and illness worldwide. The Hippo signaling pathway, known for its highly conserved nature and integral role in regulating organ size, tissue homeostasis, and stem cell function, has been identified as a critical factor in the pathogenesis of CVDs. Recent findings underscore the significance of the Yes-associated protein (YAP) and the Transcriptional Coactivator with PDZ-binding motif (TAZ), collectively referred to as YAP/TAZ. These proteins play pivotal roles as downstream components of the Hippo pathway, in the regulation of cardiovascular development and homeostasis. YAP/TAZ can regulate various cellular processes such as cell proliferation, migration, differentiation, and apoptosis through their interactions with transcription factors, particularly those within the transcriptional enhancer associate domain (TEAD) family. The aim of this review is to provide a comprehensive overview of the current understanding of YAP/TAZ signaling in cardiovascular physiology and pathogenesis. We analyze the regulatory mechanisms of YAP/TAZ activation, explore their downstream effectors, and examine their association across numerous cardiovascular disorders, including myocardial hypertrophy, myocardial infarction, pulmonary hypertension, myocardial ischemia-reperfusion injury, atherosclerosis, angiogenesis, restenosis, and cardiac fibrosis. Furthermore, we investigate the potential therapeutic implications of targeting the YAP/TAZ pathway for the treatment of CVDs. Through this comprehensive review, our aim is to elucidate the current understanding of YAP/TAZ signaling in cardiovascular biology and underscore its potential implications for the diagnosis and therapeutic intervention of CVDs.
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Affiliation(s)
- Rakibul Islam
- Department of Mechanical Engineering, Texas Tech University, Lubbock, TX 79409, USA
| | - Zhongkui Hong
- Department of Mechanical Engineering, Texas Tech University, Lubbock, TX 79409, USA
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Hu Y, Peng L, Zhuo X, Yang C, Zhang Y. Hedgehog Signaling Pathway in Fibrosis and Targeted Therapies. Biomolecules 2024; 14:1485. [PMID: 39766192 PMCID: PMC11727624 DOI: 10.3390/biom14121485] [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: 10/23/2024] [Revised: 11/17/2024] [Accepted: 11/20/2024] [Indexed: 01/12/2025] Open
Abstract
Hedgehog (Hh) signaling is a well-established developmental pathway; it is crucial for early embryogenesis, cell differentiation, and damage-driven regeneration. It is being increasingly recognized that dysregulated Hh signaling is also involved in fibrotic diseases, which are characterized by excessive extracellular matrix deposition that compromises tissue architecture and function. As in-depth insights into the mechanisms of Hh signaling are obtained, its complex involvement in fibrosis is gradually being illuminated. Notably, some Hh-targeted inhibitors are currently under exploration in preclinical and clinical trials as a means to prevent fibrosis progression. In this review, we provide a concise overview of the biological mechanisms involved in Hh signaling. We summarize the latest advances in our understanding of the roles of Hh signaling in fibrogenesis across the liver, kidneys, airways, and lungs, as well as other tissues and organs, with an emphasis on both the shared features and, more critically, the distinct functional variations observed across these tissues and organs. We thus highlight the context dependence of Hh signaling, as well as discuss the current status and the challenges of Hh-targeted therapies for fibrosis.
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Affiliation(s)
- Yuchen Hu
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.H.); (L.P.); (X.Z.)
- Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Linrui Peng
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.H.); (L.P.); (X.Z.)
- Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xinyu Zhuo
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.H.); (L.P.); (X.Z.)
- Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chan Yang
- Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China;
| | - Yuwei Zhang
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.H.); (L.P.); (X.Z.)
- Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu 610041, China
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Yang M, Li S, Luo R, Zhao Y, Sun Y, Li H, Cui Q, Wu J, Mao L. ADAM8 promotes alcoholic liver fibrosis through the MAPK signaling pathway. J Physiol Sci 2024; 74:52. [PMID: 39407108 PMCID: PMC11481351 DOI: 10.1186/s12576-024-00943-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 09/22/2024] [Indexed: 10/19/2024]
Abstract
The effect and molecular regulatory mechanism of A Disintegrin and Metalloproteinase 8 (ADAM8) were explored in alcoholic liver fibrosis (ALF). C57BL/6N male mice were randomly divided into control, alcohol, and ADAM8-sgRNA3 plasmid groups. The control group received control liquid diet, while the alcohol and ADAM8-sgRNA3 plasmid groups were given alcohol liquid feed diet combined with ethanol gavage treatment for 8 weeks to induce ALF modeling. In addition, the ADAM8-sgRNA3 plasmid group was injected with the effective ADAM8-sgRNA3 plasmid, while the alcohol and control group mice were injected with an equivalent amount of physiological saline. LX-2 human hepatic stellate cells were divided into control, alcohol, si-ADAM8-2, and si-ADAM8-NC groups and induced for 48 h for model establishment in vitro. Serological detection, pathological staining, Western blotting, qRT-PCR and CCK8 assay were performed for experiments. Compared with the alcohol group, ADAM8 mRNA, protein and, positive area rate, serological indicators, pathological changes, and the expression of liver fibrosis marker and MAPK signaling pathway-related factors in the ADAM8-sgRNA3 plasmid group significantly decreased in vivo. Compared with the alcohol group, ADAM8 mRNA and protein expression, cell viability, and the expression of liver fibrosis markers and MAPK signaling pathway-related factors (p-ERK1/2, PCNA, Bcl-2, p-c-Jun, TGFβ1, p-p38 MAPK and HSP27) reduced significantly in the si-ADAM8-2 group. Therefore, ADAM8 promotes ALF through the MAPK signaling pathway, a promising target for treating ALF.
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Affiliation(s)
- Mengli Yang
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Sanqiang Li
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China.
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China.
| | - Renli Luo
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Yadi Zhao
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Yue Sun
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Haoyuan Li
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Qinyi Cui
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Junfei Wu
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Longfei Mao
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China.
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China.
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Zhang Y, Ren L, Tian Y, Guo X, Wei F, Zhang Y. Signaling pathways that activate hepatic stellate cells during liver fibrosis. Front Med (Lausanne) 2024; 11:1454980. [PMID: 39359922 PMCID: PMC11445071 DOI: 10.3389/fmed.2024.1454980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 08/26/2024] [Indexed: 10/04/2024] Open
Abstract
Liver fibrosis is a complex process driven by various factors and is a key feature of chronic liver diseases. Its essence is liver tissue remodeling caused by excessive accumulation of collagen and other extracellular matrix. Activation of hepatic stellate cells (HSCs), which are responsible for collagen production, plays a crucial role in promoting the progression of liver fibrosis. Abnormal expression of signaling pathways, such as the TGF-β/Smads pathway, contributes to HSCs activation. Recent studies have shed light on these pathways, providing valuable insights into the development of liver fibrosis. Here, we will review six signaling pathways such as TGF-β/Smads that have been studied more in recent years.
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Affiliation(s)
- Youtian Zhang
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Long Ren
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Yinting Tian
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Xiaohu Guo
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Fengxian Wei
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Yawu Zhang
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
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9
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Wang Y, Stoess C, Holzmann G, Mogler C, Stupakov P, Altmayr F, Schulze S, Wang B, Steffani M, Friess H, Hüser N, Holzmann B, Hartmann D, Laschinger M. Signalling of the neuropeptide calcitonin gene-related peptide (CGRP) through RAMP1 promotes liver fibrosis via TGFβ1/Smad2 and YAP pathways. Exp Cell Res 2024; 442:114193. [PMID: 39103072 DOI: 10.1016/j.yexcr.2024.114193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/07/2024]
Abstract
The liver is innervated by primary sensory nerve fibres releasing the neuropeptide calcitonin gene-related peptide (CGRP). Elevated plasma levels of CGRP have been found in patients with liver fibrosis or cirrhosis. We hypothesised that signalling of CGRP and its receptors might regulate liver fibrosis and propose a novel potential target for the treatment. In this study, hepatic expression of CGRP and its receptor component, the receptor activity-modifying protein 1 (RAMP1), was dramatically increased in diseased livers of patients. In a murine liver fibrosis model, deficiency of RAMP1 resulted in attenuated fibrogenesis characterized by less collagen deposition and decreased activity of hepatic stellate cells (HSC). Mechanistically, activity of the TGFβ1 signalling core component Smad2 was severely impaired in the absence of RAMP1, and Yes-associated protein (YAP) activity was found to be diminished in RAMP1-deficient liver parenchyma. In vitro, stimulation of the HSC line LX-2 cells with CGRP induces TGFβ1 production and downstream signalling as well as HSC activation documented by increased α-SMA expression and collagen synthesis. We further demonstrate in LX-2 cells that CGRP promotes YAP activation and its nuclear translocation subsequent to TGFβ1/Smad2 signals. These data support a promotive effect of CGRP signalling in liver fibrosis via stimulation of TGFβ1/Smad2 and YAP activity.
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Affiliation(s)
- Yang Wang
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany; Department of Hepato-Pancreato-Biliary Center, Zhongda Hospital, Southeast University School of Medicine, Dingjia Road 87, 210009, Nanjing, China
| | - Christian Stoess
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Gabriela Holzmann
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Carolin Mogler
- Technical University of Munich, TUM School of Medicine and Health, Institute of Pathology, Trogerstr. 18, 81675, Munich, Germany
| | - Pavel Stupakov
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Felicitas Altmayr
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Sarah Schulze
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Baocai Wang
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany; University Hospital of Tübingen, Department of General, Visceral and Transplantation Surgery, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany; The M3 Research Center, Eberhard Karls University, Otfried-Müller-Str. 37, 72076 Tübingen, Germany
| | - Marcella Steffani
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Helmut Friess
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Norbert Hüser
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Bernhard Holzmann
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Daniel Hartmann
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany; University Hospital of Tübingen, Department of General, Visceral and Transplantation Surgery, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany; The M3 Research Center, Eberhard Karls University, Otfried-Müller-Str. 37, 72076 Tübingen, Germany
| | - Melanie Laschinger
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany.
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10
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Wang Y, Geng X, Sun X, Cui H, Guo Z, Chu D, Li J, Li Z. Celastrol alleviates subconjunctival fibrosis induced by silicone implants mimicking glaucoma surgery. Eur J Pharm Biopharm 2024; 201:114352. [PMID: 38851459 DOI: 10.1016/j.ejpb.2024.114352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 05/29/2024] [Accepted: 06/06/2024] [Indexed: 06/10/2024]
Abstract
Subconjunctival fibrosis is critical to the outcomes of several ophthalmic conditions or procedures, such as glaucoma filtering surgery. This study aimed to investigate the anti-fibrotic effect of celastrol on subconjunctival fibrosis and to further reveal the underlying mechanisms. We used celastrol-loaded nanomicelles hydrogel hybrid as a sustained-release drug. A rabbit model of subconjunctival fibrosis following silicone implantation was used for in vivo study, and TGF-β1-induced human pterygium fibroblast (HPF) activation as an in vitro model. The effects of celastrol on inhibiting TGF-β1-induced migration and proliferation of HPFs were evaluated by scratch wound assay and CCK-8, respectively. Immunofluorescence and western blotting were used to examine the effect of celastrol on the expression of α-SMA, collagen I, fibronectin, and the targets of the Hippo signaling pathway. We found that in vivo celastrol treatment reduced the expression of YAP and TAZ in subconjunctival tissue. Moreover, celastrol alleviated collagen deposition and subconjunctival fibrosis at 8 weeks. No obvious tissue toxicity was observed in the rabbit models. Mechanistically, celastrol significantly inhibited TGF-β1-induced proliferation and migration of HPFs. Pretreatment of HPFs with celastrol also suppressed the TGF-β1-induced protein expression of α-SMA, collagen I, fibronectin, TGF-βRII, phosphorylated Smad2/3, YAP, TAZ, and TEAD1. In conclusion, celastrol effectively prevented subconjunctival fibrosis through inhibiting TGF-β1/Smad2/3-YAP/TAZ pathway. Celastrol could serve as a promising therapy for subconjunctival fibrosis.
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Affiliation(s)
- Yiwei Wang
- Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, China
| | - Xingchen Geng
- Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, China
| | - Xue Sun
- Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, China
| | - Haohao Cui
- Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, China
| | - Zhihua Guo
- Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, China
| | - Dandan Chu
- Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, China
| | - Jingguo Li
- Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, China.
| | - Zhanrong Li
- Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, China.
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11
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Chu CQ, Quan T. Fibroblast Yap/Taz Signaling in Extracellular Matrix Homeostasis and Tissue Fibrosis. J Clin Med 2024; 13:3358. [PMID: 38929890 PMCID: PMC11204269 DOI: 10.3390/jcm13123358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 06/03/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
Tissue fibrosis represents a complex pathological condition characterized by the excessive accumulation of collagenous extracellular matrix (ECM) components, resulting in impaired organ function. Fibroblasts are central to the fibrotic process and crucially involved in producing and depositing collagen-rich ECM. Apart from their primary function in ECM synthesis, fibroblasts engage in diverse activities such as inflammation and shaping the tissue microenvironment, which significantly influence cellular and tissue functions. This review explores the role of Yes-associated protein (Yap) and Transcriptional co-activator with PDZ-binding motif (Taz) in fibroblast signaling and their impact on tissue fibrosis. Gaining a comprehensive understanding of the intricate molecular mechanisms of Yap/Taz signaling in fibroblasts may reveal novel therapeutic targets for fibrotic diseases.
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Affiliation(s)
- Cong-Qiu Chu
- Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, Portland, OR 97239, USA;
- Rheumatology Section, VA Portland Health Care System, Portland, OR 97239, USA
| | - Taihao Quan
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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12
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Very N, Boulet C, Gheeraert C, Berthier A, Johanns M, Bou Saleh M, Guille L, Bray F, Strub JM, Bobowski-Gerard M, Zummo FP, Vallez E, Molendi-Coste O, Woitrain E, Cianférani S, Montaigne D, Ntandja-Wandji LC, Dubuquoy L, Dubois-Chevalier J, Staels B, Lefebvre P, Eeckhoute J. O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in myofibroblasts. Cell Death Dis 2024; 15:391. [PMID: 38830870 PMCID: PMC11148087 DOI: 10.1038/s41419-024-06773-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 05/21/2024] [Accepted: 05/23/2024] [Indexed: 06/05/2024]
Abstract
Tissue injury causes activation of mesenchymal lineage cells into wound-repairing myofibroblasts (MFs), whose uncontrolled activity ultimately leads to fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, we report that the metabolic sensor post-translational modification O-linked β-D-N-acetylglucosaminylation (O-GlcNAcylation) is increased and required for myofibroblastic activation. Inhibition of protein O-GlcNAcylation impairs archetypal myofibloblast cellular activities including extracellular matrix gene expression and collagen secretion/deposition as defined in vitro and using ex vivo and in vivo murine liver injury models. Mechanistically, a multi-omics approach combining proteomic, epigenomic, and transcriptomic data mining revealed that O-GlcNAcylation controls the MF transcriptional program by targeting the transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes-associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O-GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of the MF transcriptional regulatory landscape. We found that this involves O-GlcNAcylation of BNC2 at Thr455 and Ser490 and of TEAD4 at Ser69 and Ser99. Altogether, this study unravels protein O-GlcNAcylation as a key determinant of myofibroblastic activation and identifies its inhibition as an avenue to intervene with fibrogenic processes.
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Affiliation(s)
- Ninon Very
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Clémence Boulet
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Céline Gheeraert
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Alexandre Berthier
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Manuel Johanns
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Mohamed Bou Saleh
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
| | - Loïc Guille
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Fabrice Bray
- Miniaturization for Synthesis, Analysis & Proteomics, UAR 3290, CNRS, University of Lille, Villeneuve d'Ascq Cedex, France
| | - Jean-Marc Strub
- Laboratoire de Spectrométrie de Masse BioOrganique, CNRS UMR7178, Univ. Strasbourg, IPHC, Infrastructure Nationale de Protéomique ProFI - FR2048, Strasbourg, France
| | - Marie Bobowski-Gerard
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Francesco P Zummo
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Emmanuelle Vallez
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Olivier Molendi-Coste
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Eloise Woitrain
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Sarah Cianférani
- Laboratoire de Spectrométrie de Masse BioOrganique, CNRS UMR7178, Univ. Strasbourg, IPHC, Infrastructure Nationale de Protéomique ProFI - FR2048, Strasbourg, France
| | - David Montaigne
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Line Carolle Ntandja-Wandji
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
| | - Laurent Dubuquoy
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
| | | | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Philippe Lefebvre
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Jérôme Eeckhoute
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
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13
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Sun MT, Cotton RM, Charoenkijkajorn C, Garcia-Sanchez J, Dalal R, Xia X, Lin JH, Singh K, Goldberg JL, Liu WW. Evaluation of Verteporfin as a Novel Antifibrotic Agent in a Rabbit Model of Glaucoma Filtration Surgery: A Pilot Study. OPHTHALMOLOGY SCIENCE 2024; 4:100448. [PMID: 38261964 PMCID: PMC10797546 DOI: 10.1016/j.xops.2023.100448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 11/20/2023] [Accepted: 12/04/2023] [Indexed: 01/25/2024]
Abstract
Purpose Verteporfin is a benzoporphyrin derivative which is Food and Drug Administration-approved for treatment of choroidal neovascularization in conjunction with photodynamic therapy. It has been shown to prevent fibrosis and scar formation in several organs and represents a promising novel antifibrotic agent for glaucoma surgery. The goal of this study is to determine the effect of verteporfin on wound healing after glaucoma filtration surgery. Design Preclinical study using a rabbit model of glaucoma filtration surgery. Subjects Eight New Zealand white rabbits underwent glaucoma filtration surgery in both eyes. Methods Eyes were randomized into 4 study groups to receive a postoperative subconjunctival injection of 1 mg/mL verteporfin (n = 4), 0.4 mg/mL mitomycin C (MMC; n = 4), 0.4 mg/mL MMC + 1 mg/mL verteporfin (n = 4), or balanced salt solution (BSS) control (n = 4). Bleb survival, vascularity, and morphology were graded using a standard scale over a 30-day period, and intraocular pressure (IOP) was monitored. At 30 days postoperative or surgical failure, histology was performed to evaluate for inflammation, local toxicity, and scarring. Main Outcome Measures The primary outcome measure was bleb survival. Secondary outcome measures were IOP, bleb morphology, and bleb histology. Results Compared to BSS control blebs, verteporfin-treated blebs demonstrated a trend toward increased surgical survival (mean 9.8 vs. 7.3 days, log rank P = 0.08). Mitomycin C-treated blebs survived significantly longer than verteporfin-treated blebs (log rank P = 0.009), with all but 1 MMC-treated bleb still surviving at postoperative day 30. There were no significant differences in survival between blebs treated with combination verteporfin + MMC and MMC alone. Mitomycin C-treated blebs were less vascular than verteporfin-treated blebs (mean vascularity score 0.3 ± 0.5 for MMC vs. 1.0 ± 0.0 for verteporfin, P < 0.01). Bleb histology did not reveal any significant toxicity in verteporfin-treated eyes. There were no significant differences in inflammation or scarring across groups. Conclusions Although verteporfin remained inferior to MMC with regard to surgical survival, there was a trend toward increased survival compared with BSS control and it had an excellent safety profile. Further studies with variations in verteporfin dosage and/or application frequency are needed to assess whether this may be a useful adjunct to glaucoma surgery. Financial Disclosures Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Affiliation(s)
- Michelle T. Sun
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California
| | - Renee M. Cotton
- Department of Comparative Medicine, Stanford University, Palo Alto, California
| | - Chaow Charoenkijkajorn
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California
| | - Julian Garcia-Sanchez
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California
| | - Roopa Dalal
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California
| | - Xin Xia
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California
| | - Jonathan H. Lin
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California
| | - Kuldev Singh
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California
| | - Jeffrey L. Goldberg
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California
| | - Wendy W. Liu
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California
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14
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Zhang L, Zeng J, Wu H, Tian H, Song D, Wu W, Dong F. Knockdown of TXNDC5 alleviates CCL4-induced hepatic fibrosis in mice by enhancing endoplasmic reticulum stress. Am J Med Sci 2023; 366:449-457. [PMID: 37716602 DOI: 10.1016/j.amjms.2023.08.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 04/28/2023] [Accepted: 08/01/2023] [Indexed: 09/18/2023]
Abstract
BACKGROUND Hepatic fibrosis is a common pathological process in many chronic liver diseases. TXNDC5 has been shown to be involved in the progression of renal and pulmonary fibrosis. However, the role of TXNDC5 in hepatic fibrosis is unknown. The purpose of this study is to explore the role and mechanism of TXNDC5 in hepatic fibrosis. METHODS We used TGF-β1 to activate LX-2 cells and reduced TXNDC5 expression by short hairpin RNA. Cell viability was assessed by CCK-8 assay. Cell apoptosis was analyzed by flow cytometry or Tunel assay. The fibrosis-related proteins and endoplasmic reticulum stress (ERs)-related proteins were measured by western blot. ELISA was performed to detect COL1AL levels and MMP2/9 activities in cell medium. A mouse model of hepatic fibrosis was constructed by intraperitoneal injection of CCL4. HE and Masson staining were performed to assess fibrosis in mouse liver tissue. RESULTS The results show that TXNDC5 was up-regulated in activated LX-2 cells and CCL4-induced hepatic fibrosis mice. Knockdown of TXNDC5 inhibited the viability of activated LX-2 cells and the production of collagen COL1A1. Knockdown of TXNDC5 promoted apoptosis of activated LX-2 cells. Mechanically, inhibition of TXNDC5 enhanced ERs, and the ERs inhibitor 4-Phenylbutyric acid (4-PBA) reversed the effect of TXNDC5 on activated LX-2 cells. More importantly, knockdown of TXNDC5 alleviated CCl4-induced hepatic fibrosis in mice. CONCLUSIONS Knockdown of TXNDC5 may reduce hepatic fibrosis by regulating ERs, and targeting TXNDC5 seems to be a candidate treatment for hepatic fibrosis.
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Affiliation(s)
- Lei Zhang
- Department of Health Management, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Jieying Zeng
- Department of Ultrasound, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Huaiyu Wu
- Department of Ultrasound, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Hongtian Tian
- Department of Ultrasound, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Di Song
- Department of Ultrasound, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Weiqing Wu
- Department of Health Management, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Fajin Dong
- Department of Ultrasound, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.
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15
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Loomis T, Smith LR. Thrown for a loop: fibro-adipogenic progenitors in skeletal muscle fibrosis. Am J Physiol Cell Physiol 2023; 325:C895-C906. [PMID: 37602412 PMCID: PMC11932532 DOI: 10.1152/ajpcell.00245.2023] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/10/2023] [Accepted: 08/15/2023] [Indexed: 08/22/2023]
Abstract
Fibro-adipogenic progenitors (FAPs) are key regulators of skeletal muscle regeneration and homeostasis. However, dysregulation of these cells leads to fibro-fatty infiltration across various muscle diseases. FAPs are the key source of extracellular matrix (ECM) deposition in muscle, and disruption to this process leads to a pathological accumulation of ECM, known as fibrosis. The replacement of contractile tissue with fibrotic ECM functionally impairs the muscle and increases muscle stiffness. FAPs and fibrotic muscle form a progressively degenerative feedback loop where, as a muscle becomes fibrotic, it induces a fibrotic FAP phenotype leading to further development of fibrosis. In this review, we summarize FAPs' role in fibrosis in terms of their activation, heterogeneity, contributions to fibrotic degeneration, and role across musculoskeletal diseases. We also discuss current research on potential therapeutic avenues to attenuate fibrosis by targeting FAPs.
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Affiliation(s)
- Taryn Loomis
- Biomedical Engineering Graduate Group, University of California, Davis, California, United States
| | - Lucas R Smith
- Department of Neurobiology, Physiology, and Behavior, University of California, Davis, California, United States
- Department of Physical Medicine and Rehabilitation, University of California, Davis, California, United States
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16
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Zhao H, Zhu H, Zhang Y, Ding Y, Feng R, Li J, Ma T, Huang C. Lymphocyte-Specific Protein Tyrosine Kinase Contributes to Spontaneous Regression of Liver Fibrosis may by Interacting with Suppressor of Cytokine Signaling 1. Inflammation 2023; 46:1653-1669. [PMID: 37233920 DOI: 10.1007/s10753-023-01831-4] [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: 03/04/2023] [Revised: 05/03/2023] [Accepted: 05/04/2023] [Indexed: 05/27/2023]
Abstract
Quiescent hepatic stellate cells (qHSCs), converted to myofibroblasts, produce fibrous scars, which is an essential event during liver fibrogenesis. Clinical and experimental fibrosis undergo remarkable regression when the underlying etiological agent is removed. Some myofibroblasts revert to an inactive phenotype (iHSCs) during the regression of fibrosis. However, the mechanisms underlying HSC activation and reversal remain unclear. The present study demonstrated that the expression of lymphocyte-specific protein tyrosine kinase (LCK) was increased in fibrotic livers but decreased after spontaneous recovery in vivo and in vitro, which was correlated with the expression of α-smooth muscle actin (α-SMA) and type I collagen (COL-1). Further investigation indicated that specific knockdown of LCK by a recombination adeno-associated virus 9 (rAAV9) in C57BL/6 mice ameliorated liver fibrosis. Co-incubation of TGF-β1-induced HSC-T6 cells with LCK-siRNA inhibited cell proliferation and activation. Overexpression of LCK inhibited activated HSCs going to inactivated phenotype. Interestingly, we found that LCK may interact with suppressor of cytokine signaling 1 (SOCS1) and may influence the expression of p-JAK1 and p-STAT1/3. These data suggest that LCK may play a regulatory role in liver fibrosis by inhibiting SOCS1, indicating that LCK is a potential therapeutic target for liver fibrosis treatment.
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Affiliation(s)
- Huizi Zhao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Hong Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yuan Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yuhao Ding
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Rui Feng
- 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
| | - Taotao Ma
- 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.
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17
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Siapoush S, Rezaei R, Alavifard H, Hatami B, Zali MR, Vosough M, Lorzadeh S, Łos MJ, Baghaei K, Ghavami S. Therapeutic implications of targeting autophagy and TGF-β crosstalk for the treatment of liver fibrosis. Life Sci 2023; 329:121894. [PMID: 37380126 DOI: 10.1016/j.lfs.2023.121894] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 06/19/2023] [Accepted: 06/25/2023] [Indexed: 06/30/2023]
Abstract
Liver fibrosis is characterized by the excessive deposition and accumulation of extracellular matrix components, mainly collagens, and occurs in response to a broad spectrum of triggers with different etiologies. Under stress conditions, autophagy serves as a highly conserved homeostatic system for cell survival and is importantly involved in various biological processes. Transforming growth factor-β1 (TGF-β1) has emerged as a central cytokine in hepatic stellate cell (HSC) activation and is the main mediator of liver fibrosis. A growing body of evidence from preclinical and clinical studies suggests that TGF-β1 regulates autophagy, a process that affects various essential (patho)physiological aspects related to liver fibrosis. This review comprehensively highlights recent advances in our understanding of cellular and molecular mechanisms of autophagy, its regulation by TGF-β, and the implication of autophagy in the pathogenesis of progressive liver disorders. Moreover, we evaluated crosstalk between autophagy and TGF-β1 signalling and discussed whether simultaneous inhibition of these pathways could represent a novel approach to improve the efficacy of anti-fibrotic therapy in the treatment of liver fibrosis.
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Affiliation(s)
- Samaneh Siapoush
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ramazan Rezaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Helia Alavifard
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research center, Research institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research center, Research institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Marek J Łos
- Biotechnology Center, Silesian University of Technology, 8 Krzywousty St., 44-100 Gliwice, Poland; Autophagy Research Center, Department of Biochemistry; Shiraz University of Medical Sciences, Shiraz, Iran; LinkoCare Life Sciences AB, Linkoping, Sweden
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research center, Research institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, 41-800 Zabrze, Poland; Research Institute of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, Manitoba, Canada; Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, Manitoba, Canada.
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18
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Wei Y, Hui VLZ, Chen Y, Han R, Han X, Guo Y. YAP/TAZ: Molecular pathway and disease therapy. MedComm (Beijing) 2023; 4:e340. [PMID: 37576865 PMCID: PMC10412783 DOI: 10.1002/mco2.340] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 06/27/2023] [Accepted: 07/04/2023] [Indexed: 08/15/2023] Open
Abstract
The Yes-associated protein and its transcriptional coactivator with PDZ-binding motif (YAP/TAZ) are two homologous transcriptional coactivators that lie at the center of a key regulatory network of Hippo, Wnt, GPCR, estrogen, mechanical, and metabolism signaling. YAP/TAZ influences the expressions of downstream genes and proteins as well as enzyme activity in metabolic cycles, cell proliferation, inflammatory factor expression, and the transdifferentiation of fibroblasts into myofibroblasts. YAP/TAZ can also be regulated through epigenetic regulation and posttranslational modifications. Consequently, the regulatory function of these mechanisms implicates YAP/TAZ in the pathogenesis of metabolism-related diseases, atherosclerosis, fibrosis, and the delicate equilibrium between cancer progression and organ regeneration. As such, there arises a pressing need for thorough investigation of YAP/TAZ in clinical settings. In this paper, we aim to elucidate the signaling pathways that regulate YAP/TAZ and explore the mechanisms of YAP/TAZ-induce diseases and their potential therapeutic interventions. Furthermore, we summarize the current clinical studies investigating treatments targeting YAP/TAZ. We also address the limitations of existing research on YAP/TAZ and propose future directions for research. In conclusion, this review aims to provide fresh insights into the signaling mediated by YAP/TAZ and identify potential therapeutic targets to present innovative solutions to overcome the challenges associated with YAP/TAZ.
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Affiliation(s)
- Yuzi Wei
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduSichuanChina
| | - Victoria Lee Zhi Hui
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduSichuanChina
| | - Yilin Chen
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduSichuanChina
- Department of OrthodonticsWest China Hospital of StomatologySichuan UniversityChengduSichuanChina
| | - Ruiying Han
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduSichuanChina
- Department of OrthodonticsWest China Hospital of StomatologySichuan UniversityChengduSichuanChina
| | - Xianglong Han
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduSichuanChina
- Department of OrthodonticsWest China Hospital of StomatologySichuan UniversityChengduSichuanChina
| | - Yongwen Guo
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduSichuanChina
- Department of OrthodonticsWest China Hospital of StomatologySichuan UniversityChengduSichuanChina
- Department of OrthodonticsLanzhou Stomatological HospitalLanzhouGansuChina
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Ishikane S, Arioka M, Takahashi-Yanaga F. Promising small molecule anti-fibrotic agents: Newly developed or repositioned drugs targeting myofibroblast transdifferentiation. Biochem Pharmacol 2023; 214:115663. [PMID: 37336252 DOI: 10.1016/j.bcp.2023.115663] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/11/2023] [Accepted: 06/13/2023] [Indexed: 06/21/2023]
Abstract
Fibrosis occurs in all organs and tissues except the brain, and its progression leads to dysfunction of affected organs. Fibrosis-induced organ dysfunction results from the loss of elasticity, strength, and functionality of tissues due to the extracellular matrix secreted by myofibroblasts that express smooth muscle-type actin as a marker. Myofibroblasts, which play a major role in fibrosis, were once thought to originate exclusively from activated fibroblasts; however, it is now clear that myofibroblasts are diverse in origin, from epithelial cells, endothelial cells, adipocytes, macrophages, and other cells. Fibrosis of vital organs, such as the heart, lungs, kidneys, and liver, is a serious chronic disease that ultimately leads to death. Currently, anti-cancer drugs have made remarkable progress, as evidenced by the development of many molecular-targeted drugs, and are making a significant contribution to improving the prognosis of cancer treatment. However, the development of anti-fibrotic agents, which also play an important role in prognosis, has lagged. In this review, the current knowledge regarding myofibroblasts is summarized, with particular attention given to their origin and transdifferentiation signaling pathways (e.g., TGF-β, Wnt/β-catenin, YAP/TAZ and AMPK signaling pathways). The development of new small molecule anti-fibrotic agents and the repositioning of existing drugs targeting myofibroblast transdifferentiation are discussed.
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Affiliation(s)
- Shin Ishikane
- Department of Pharmacology, Faculty of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan
| | - Masaki Arioka
- Department of Pharmacology, Faculty of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan
| | - Fumi Takahashi-Yanaga
- Department of Pharmacology, Faculty of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.
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20
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Ye B, Yu M, Yue M, Yin M, Zhang C, Wang Q, Ding X, Shen W, Zhao Z. Role of PDLIM1 in hepatic stellate cell activation and liver fibrosis progression. Sci Rep 2023; 13:10946. [PMID: 37414929 PMCID: PMC10326060 DOI: 10.1038/s41598-023-38144-3] [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: 02/14/2023] [Accepted: 07/04/2023] [Indexed: 07/08/2023] Open
Abstract
Liver fibrosis is caused by chronic hepatic injury and may lead to cirrhosis, and even hepatocellular carcinoma. When hepatic stellate cells (HSCs) are activated by liver injury, they transdifferentiate into myofibroblasts, which secrete extracellular matrix proteins that generate the fibrous scar. Therefore, it is extremely urgent to find safe and effective drugs for HSCs activation treatment to prevent liver against fibrosis. Here, we reported that PDZ and LIM domain protein 1 (PDLIM1), a highly conserved cytoskeleton organization regulator, was significantly up-regulated in fibrotic liver tissues and TGF-β-treated HSC-T6 cells. Through transcriptome analysis, we found that knockdown of PDLIM1 resulted in a significant downregulation of genes related to inflammation and immune-related pathways in HSC-T6 cells. Moreover, PDLIM1 knockdown significantly inhibited the activation of HSC-T6 cells and the trans-differentiation of HSC-T6 cells into myofibroblasts. Mechanistically, PDLIM1 is involved in the regulation of TGF-β-mediated signaling pathways in HSCs activation. Thus, targeting PDLIM1 may provide an alternative method to suppress HSCs activation during liver injury. CCCTC-binding factor (CTCF), a master regulator of genome architecture, is upregulated during HSCs activation. PDLIM1 knockdown also indirectly reduced CTCF protein expression, however, CTCF binding to chromatin was not significantly altered by CUT&Tag analysis. We speculate that CTCF may cooperate with PDLIM1 to activate HSCs in other ways. Our results suggest that PDLIM1 can accelerate the activation of HSCs and liver fibrosis progression and could be a potential biomarker for monitoring response to anti-fibrotic therapy.
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Affiliation(s)
- Bingyu Ye
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, 453007, China.
| | - Mengli Yu
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, 453007, China
| | - Meijuan Yue
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, 453007, China
| | - Man Yin
- Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Chunyan Zhang
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, 453007, China
| | - Qiwen Wang
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, 453007, China
| | - Xinru Ding
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, 453007, China
| | - Wenlong Shen
- Beijing Institute of Biotechnology, No. 20, Dongdajie Street, Fengtai District, Beijing, 100071, China.
| | - Zhihu Zhao
- Beijing Institute of Biotechnology, No. 20, Dongdajie Street, Fengtai District, Beijing, 100071, China.
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21
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Zhao Y, Wang H, He T, Ma B, Chen G, Tzeng C. Knockdown of Yap attenuates TAA-induced hepatic fibrosis by interaction with hedgehog signals. J Cell Commun Signal 2023:10.1007/s12079-023-00775-6. [PMID: 37338798 DOI: 10.1007/s12079-023-00775-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 06/05/2023] [Indexed: 06/21/2023] Open
Abstract
Liver fibrosis is an aberrant wound healing response to tissue injury characterized by excessive extracellular matrix deposition and loss of normal liver architecture. Hepatic stellate cells (HSCs) activation is regards to be the major process in liver fibrogenesis which is dynamic and reversible. Both Hippo signaling core factor Yap and Hedgehog (Hh) signaling promote HSCs transdifferentiation thereby regulating the repair process of liver injury. However, the molecular function of YAP and the regulation between Yap and Hh during fibrogenesis remain uncertain. In this study, the essential roles of Yap in liver fibrosis were investigated. Yap was detected to be increased in liver fibrotic tissue by the thioacetamide (TAA)-induced zebrafish embryonic and adult models. Inhibition of Yap by both embryonic morpholino interference and adult's inhibitor treatment was proved to alleviate TAA-induced liver lesions by and histology and gene expression examination. Transcriptomic analysis and gene expression detection showed that Yap and Hh signaling pathway have a cross talking upon TAA-induced liver fibrosis. In addition, TAA induction promoted the nuclear colocalization of YAP and Hh signaling factor GLI2α. This study demonstrates that Yap and Hh play synergistic protective roles in liver fibrotic response and provides new theoretical insight concerning the mechanisms of fibrosis progression.
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Affiliation(s)
- Ye Zhao
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211800, China.
| | - Huiling Wang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211800, China
| | - Tianhua He
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211800, China
| | - Bo Ma
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211800, China
| | - Guoguang Chen
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211800, China
| | - Chimeng Tzeng
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361005, China.
- Translational Medicine Research Center-Key Laboratory for Cancer T-Cell Theragnostic and Clinical Translation, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China.
- Xiamen Chang Gung Hospital Medical Research Center, Xiamen, Fujian, China.
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22
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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).
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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.
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23
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Zhao YQ, Deng XW, Xu GQ, Lin J, Lu HZ, Chen J. Mechanical homeostasis imbalance in hepatic stellate cells activation and hepatic fibrosis. Front Mol Biosci 2023; 10:1183808. [PMID: 37152902 PMCID: PMC10157180 DOI: 10.3389/fmolb.2023.1183808] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 04/12/2023] [Indexed: 05/09/2023] Open
Abstract
Chronic liver disease or repeated damage to hepatocytes can give rise to hepatic fibrosis. Hepatic fibrosis (HF) is a pathological process of excessive sedimentation of extracellular matrix (ECM) proteins such as collagens, glycoproteins, and proteoglycans (PGs) in the hepatic parenchyma. Changes in the composition of the ECM lead to the stiffness of the matrix that destroys its inherent mechanical homeostasis, and a mechanical homeostasis imbalance activates hepatic stellate cells (HSCs) into myofibroblasts, which can overproliferate and secrete large amounts of ECM proteins. Excessive ECM proteins are gradually deposited in the Disse gap, and matrix regeneration fails, which further leads to changes in ECM components and an increase in stiffness, forming a vicious cycle. These processes promote the occurrence and development of hepatic fibrosis. In this review, the dynamic process of ECM remodeling of HF and the activation of HSCs into mechanotransduction signaling pathways for myofibroblasts to participate in HF are discussed. These mechanotransduction signaling pathways may have potential therapeutic targets for repairing or reversing fibrosis.
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Affiliation(s)
- Yuan-Quan Zhao
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xi-Wen Deng
- Graduate School of Youjiang Medical University for Nationalities, Baise, China
| | - Guo-Qi Xu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jie Lin
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Hua-Ze Lu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jie Chen
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
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24
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Zhao Y, Zhang X, Wang G, Wu H, Chen R, Zhang Y, Yang S, Liu L. LXA4 inhibits TGF-β1-induced airway smooth muscle cells proliferation and migration by suppressing the Smad/YAP pathway. Int Immunopharmacol 2023; 118:110144. [PMID: 37030120 DOI: 10.1016/j.intimp.2023.110144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/29/2023] [Accepted: 03/31/2023] [Indexed: 04/10/2023]
Abstract
The aims of the present study were to examine the signaling mechanisms for transforming growth factor-β1 (TGF-β1)-induced rat airway smooth muscle cells (ASMCs) proliferation and migration and to determine the effect of lipoxin A4 (LXA4) on TGF-β1-induced rat ASMCs proliferation and migration and its underlying mechanisms. TGF-β1 upregulated transcriptional coactivator Yes-associated protein (YAP) expression by activating Smad2/3 and then upregulated cyclin D1, leading to rat ASMCs proliferation and migration. This effect was reversed after treatment with the TGF-β1 receptor inhibitor SB431542. YAP is a critical mediator of TGF-β1-induced ASMCs proliferation and migration. Knockdown of YAP disrupted the pro-airway remodeling function of TGF-β1. Preincubation of rat ASMCs with LXA4 blocked TGF-β1-induced activation of Smad2/3 and changed its downstream targets, YAP and cyclin D1, resulting in the inhibition of rat ASMCs proliferation and migration. Our study suggests that LXA4 suppresses Smad/YAP signaling to inhibit rat ASMCs proliferation and migration and therefore has potential value in the prevention and treatment of asthma by negatively modulating airway remodeling.
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Affiliation(s)
- Yali Zhao
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Xiangli Zhang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Guizuo Wang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Hua Wu
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Ruilin Chen
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Yongqing Zhang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Shumei Yang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Lu Liu
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China.
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25
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Xiong Y, Wu B, Guo X, Shi D, Xia H, Xu H, Liu X. Galangin delivered by retinoic acid-modified nanoparticles targeted hepatic stellate cells for the treatment of hepatic fibrosis. RSC Adv 2023; 13:10987-11001. [PMID: 37033441 PMCID: PMC10077338 DOI: 10.1039/d2ra07561j] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 03/17/2023] [Indexed: 04/11/2023] Open
Abstract
Hepatic fibrosis (HF) is a chronic hepatic pathological process induced by various liver injuries, with few available therapies. Previous research studies revealed that HF is characterized by the accumulation of excess extracellular matrix in the liver, mainly overexpressed by activated hepatic stellate cells (HSC). Therefore, HSC have been targeted in clinical trials for the management of HF. The aim of the present study was to develop an anti-HF drug delivery system with acrylic resin (Eudragit® RS100, Eud RS100) nanoparticles (NPs) through modification by retinoic acid (RA), modified for binding the retinol-binding protein reporter (RBPR) in HSC. Galangin (GA), is a multiple effects flavonoid which has demonstrated an anti-HF effect in our previous studies. In this study, GA was utilized for the treatment of HF. The results revealed that the NPs were well formed (diameter: 70 nm), spherical in shape, and exhibited uniform distribution and a high encapsulation efficiency. Moreover, a prominent controlled release effect and a significant increase in bioavailability was observed following the encapsulation of GA in NPs. These findings indicated that the limitation of low bioavailability due to the hydrophobic feature of GA was overcome. Furthermore, the pharmacodynamics studies demonstrated that NPs could drastically influence the anti-HF effects of GA after modification with retinoic acid. The results of the present study suggested that retinoic acid-modified GA NPs represent a promising candidate in the development of an anti-HF drug delivery system for the treatment of HF.
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Affiliation(s)
- Yuanguo Xiong
- Department of Pharmacy, Renmin Hospital of Wuhan University Wuhan 430060 China
- School of Pharmaceuticals, Hubei University of Chinese Medicine, No. 1 HuangJiahu Road West Wuhan 430065 China +86 27 68890239
| | - Bing Wu
- Department of Cardiology, Renmin Hospital, Hubei University of Medicine Shiyan 442000 China
- Department of Cardiology, Renmin Hospital of Wuhan University Jiefang Road 238 Wuhan 430060 China +86 27 88041911 +86 27 88041911
- Cardiovascular Research Institute, Wuhan University Jiefang Road 238 Wuhan 430060 China
- Hubei Key Laboratory of Cardiology Wuhan 430060 China
| | - Xianxi Guo
- Department of Pharmacy, Renmin Hospital of Wuhan University Wuhan 430060 China
| | - Dong Shi
- School of Pharmaceuticals, Hubei University of Chinese Medicine, No. 1 HuangJiahu Road West Wuhan 430065 China +86 27 68890239
| | - Hao Xia
- Department of Cardiology, Renmin Hospital of Wuhan University Jiefang Road 238 Wuhan 430060 China +86 27 88041911 +86 27 88041911
- Cardiovascular Research Institute, Wuhan University Jiefang Road 238 Wuhan 430060 China
- Hubei Key Laboratory of Cardiology Wuhan 430060 China
| | - Hanlin Xu
- School of Pharmaceuticals, Hubei University of Chinese Medicine, No. 1 HuangJiahu Road West Wuhan 430065 China +86 27 68890239
| | - Xiaoxiong Liu
- Department of Cardiology, Renmin Hospital of Wuhan University Jiefang Road 238 Wuhan 430060 China +86 27 88041911 +86 27 88041911
- Cardiovascular Research Institute, Wuhan University Jiefang Road 238 Wuhan 430060 China
- Hubei Key Laboratory of Cardiology Wuhan 430060 China
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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.
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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
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27
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Salah N, Eissa S, Mansour A, El Magd NMA, Hasanin AH, El Mahdy MM, Hassan MK, Matboli M. Evaluation of the role of kefir in management of non-alcoholic steatohepatitis rat model via modulation of NASH linked mRNA-miRNA panel. Sci Rep 2023; 13:236. [PMID: 36604518 PMCID: PMC9816104 DOI: 10.1038/s41598-022-27353-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 12/30/2022] [Indexed: 01/07/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is the clinically aggressive variant of non-alcoholic fatty liver disease. Hippo pathway dysregulation can contribute to NASH development and progression. The use of probiotics is effective in NASH management. Our aim is to investigate the efficacy of kefir Milk in NASH management via modulation of hepatic mRNA-miRNA based panel linked to NAFLD/NASH Hippo signaling and gut microbita regulated genes which was identified using bioinformatics tools. Firstly, we analyzed mRNAs (SOX11, SMAD4 and AMOTL2), and their epigenetic regulator (miR-6807) followed by validation of target effector proteins (TGFB1, IL6 and HepPar1). Molecular, biochemical, and histopathological, analyses were used to evaluate the effects of kefir on high sucrose high fat (HSHF) diet -induced NASH in rats. We found that administration of Kefir proved to prevent steatosis and development of the inflammatory component of NASH. Moreover, Kefir improved liver function and lipid panel. At the molecular level, kefir down-regulated the expression of miR 6807-5p with subsequent increase in the expression of SOX 11, AMOTL2 associated with downregulated SMAD4, resulting in reduction in the expression of the inflammatory and fibrotic markers, IL6 and TGF-β1 in the treated and prophylactic groups compared to the untreated rats. In conclusion, Kefir suppressed NASH progression and improved both fibrosis and hepatic inflammation. The produced effect was correlated with modulation of SOX11, SMAD4 and AMOTL2 mRNAs) - (miR-6807-5p) - (TGFB, IL6 and, HepPar1) expression.
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Affiliation(s)
- Noha Salah
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Abbassia, P.O. box 11381, Cairo, Egypt
| | - Sanaa Eissa
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Abbassia, P.O. box 11381, Cairo, Egypt.
- MASRI institute of research, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Amal Mansour
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Abbassia, P.O. box 11381, Cairo, Egypt
| | - Nagwa M Abo El Magd
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Amany Helmy Hasanin
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Manal M El Mahdy
- Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed Kamel Hassan
- Department of Biology, Faculty of Science, Port Said University, Port Said, Egypt
- Center for Genomics, Helmy Institute for Medical Science, Zewail City for Science & Technology, Giza, Egypt
| | - Marwa Matboli
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Abbassia, P.O. box 11381, Cairo, Egypt.
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28
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Chen G, Deng Y, Xia B, Lv Y. In Situ Regulation and Mechanisms of 3D Matrix Stiffness on the Activation and Reversion of Hepatic Stellate Cells. Adv Healthc Mater 2022; 12:e2202560. [PMID: 36519640 DOI: 10.1002/adhm.202202560] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/08/2022] [Indexed: 12/23/2022]
Abstract
Activated hepatic stellate cells (HSCs) is a key event in the progression of liver fibrosis. HSCs transdifferentiate into myofibroblasts and secrete large amounts of extracellular matrix, resulting in increased liver stiffness. It is difficult for platforms constructed in vitro to simulate the structure, composition, and stiffness of the 3D microenvironment of HSCs in vivo. Here, 3D scaffolds with different stiffness are constructed by decellularizing rat livers at different stages of fibrosis. The effects of matrix stiffness on the proliferation, activation, and reversion of HSCs are studied. The results demonstrate these scaffolds have good cytocompatibility. It is also found that the high stiffness can significantly promote the activation of HSCs, and this process is accompanied by the activation of integrin β1 as well as the nucleation and activation of Yes-associated protein (YAP). Moreover, the low stiffness of the scaffold can promote the reversion of activated HSCs, which is associated with cell apoptosis and accompanied by the inactivation of integrin β1 and YAP. These results suggest that YAP may be a potential therapeutic target for the treatment of liver fibrosis and the theoretical feasibility of inducing activated HSCs reversion to the resting state by regulating matrix stiffness of liver.
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Affiliation(s)
- Guobao Chen
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, P. R. China.,Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, P. R. China.,Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College, Chongqing University, Chongqing, 400044, P. R. China
| | - Yaxin Deng
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, P. R. China.,Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, P. R. China
| | - Bin Xia
- Engineering Research Center for Waste Oil Recovery Technology and Equipment, Ministry of Education, Chongqing Technology and Business University, Chongqing, 400067, P. R. China
| | - Yonggang Lv
- State Key Laboratory of New Textile Materials and Advanced Processing Technologies, Wuhan Textile University, Wuhan, 430200, P. R. China
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HBO1 as an Important Target for the Treatment of CCL4-Induced Liver Fibrosis and Aged-Related Liver Aging and Fibrosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:1881519. [PMID: 36524217 PMCID: PMC9747301 DOI: 10.1155/2022/1881519] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 10/26/2022] [Accepted: 11/08/2022] [Indexed: 12/12/2022]
Abstract
The liver is the largest digestive organ in the human body. The increasing incidence of chronic liver fibrosis is one of the major health challenges in the world. Liver fibrosis is a wound-healing response to acute or chronic cellular damage of liver tissue. At present, despite a series of research progress on the pathophysiological mechanism of fibrosis that has been made, there is still a gap in identifying antifibrotic targets and converting them into effective treatments. Therefore, it is extremely important to seek a molecular target that can alleviate or reverse liver fibrosis, which has important scientific and clinical significance. In the current study, to evaluate the therapeutic effect of HBO1 as a molecular target on liver aging and fibrosis, naturally-aged mice and CCL4-induced liver fibrosis mice were used as animal models, and multiple experiments were performed. Experimental results showed that HBO1 knockdown could strongly mitigate the accumulation of hepatic collagen by Masson and Sirius Red staining. Further study showed that HBO1 knockdown reduced the expression of fibrosis-related marker molecules (α-SMA, collagen type I (ColI), and fibronectin). Further work showed that HBO1 knockdown could significantly alleviate HSC activation. On this basis, we analyzed the underlying mechanism by which HBO1 alleviates liver fibrosis. It was found that HBO1 knockdown may modulate liver fibrosis by regulating the processes of EMT, inflammation, and oxidative stress. We further studied the effect of HBO1 knockdown on liver aging and aging-related liver fibrosis, and the results showed that HBO1 knockdown could significantly reduce the level of aging-related liver fibrosis and relieve liver aging. In conclusion, we systematically investigated the potential of HBO1 as a therapeutic target to attenuate liver fibrosis and liver aging. The current study found a crucial target for liver fibrosis and liver-aging therapy, which has laid a solid foundation for the liver fibrosis-related research.
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Chowdhury K, Huang M, Kim HG, Dong XC. Sirtuin 6 protects against hepatic fibrogenesis by suppressing the YAP and TAZ function. FASEB J 2022; 36:e22529. [PMID: 36036554 PMCID: PMC9542050 DOI: 10.1096/fj.202200522r] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 07/29/2022] [Accepted: 08/19/2022] [Indexed: 11/11/2022]
Abstract
Hepatic fibrosis occurs in response to prolonged tissue injury in the liver, which results in abnormal accumulation of extracellular matrix. Hepatic stellate cells (HSCs) have been suggested to play a major role in liver fibrosis. However, the molecular mechanisms remain incompletely understood. Sirtuin 6 (SIRT6), an NAD+ -dependent deacetylase, has been previously implicated in the regulation of the transforming growth factor β (TGFβ)-SMAD3 pathway that plays a significant role in liver fibrosis. In this work, we aimed to identify other important players during hepatic fibrogenesis, which are modulated by SIRT6. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ or WWTR1), key players in the Hippo pathway, have been implicated in the promotion of hepatic fibrosis. Our data show that HSC-specific Sirt6 knockout mice are more susceptible to high-fat-cholesterol-cholate diet-induced hepatic fibrosis than their wildtype counterparts. Our signaling analyses suggest that in addition to the TGFβ-SMAD3 pathway, YAP and TAZ are also highly activated in the SIRT6-deficient HSCs. As it is not clear how SIRT6 might regulate YAP and TAZ, we have decided to elucidate the mechanism underlying the regulation of YAP and TAZ by SIRT6 in HSCs. Overexpression or knockdown of SIRT6 corroborates the role of SIRT6 in the negative regulation of YAP and TAZ. Further biochemical analyses reveal that SIRT6 deacetylates YAP and TAZ and reprograms the composition of the TEA domain transcription factor complex to suppress their downstream target genes, particularly those involved in hepatic fibrosis. In conclusion, our data suggest that SIRT6 plays a critical role in the regulation of the Hippo pathway to protect against hepatic fibrosis.
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Affiliation(s)
- Kushan Chowdhury
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Menghao Huang
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Hyeong-Geug Kim
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - X Charlie Dong
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
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31
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Puerta Cavanzo N, Riesmeijer SA, Holt-Kedde IL, Werker PMN, Piersma B, Olinga P, Bank RA. Verteporfin ameliorates fibrotic aspects of Dupuytren's disease nodular fibroblasts irrespective the activation state of the cells. Sci Rep 2022; 12:13940. [PMID: 35977978 PMCID: PMC9386017 DOI: 10.1038/s41598-022-18116-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 08/05/2022] [Indexed: 11/28/2022] Open
Abstract
Dupuytren’s disease is a chronic, progressive fibroproliferative condition of the hand fascia which results in digital contraction. So far, treatments do not directly interfere with the (myo)fibroblasts that are responsible for the formation of the collagen-rich cords and its contraction. Here we investigated whether verteporfin (VP) is able to inhibit the activation and subsequent differentiation of DD nodular fibroblasts into myofibroblasts. Fibroblasts were isolated from nodules of 7 Dupuytren patients. Cells are treated (1) for 48 h with 5 ng/ml transforming growth factor β1 (TGF-β1) followed by 48 h with/without 250 nM VP in the absence of TGF-β1, or treated (2) for 48 h with TGF-β1 followed by 48 h with/without VP in the presence of TGF-β1. mRNA levels were measured by means of Real-Time PCR, and proteins were visualized by means of Western blotting and/or immunofluorescence. Quantitative data were statistically analyzed with GraphPad Prism using the paired t-test. We found that fibroblasts activated for 48 h with TGF-β1 show a decrease in mRNA levels of COL1A1, COL3A1, COL4A1, PLOD2, FN1EDA, CCN2 and SERPINE1 when exposed for another 48 h with VP, whereas no decrease is seen for ACTA2, YAP1, SMAD2 and SMAD3 mRNA levels. Cells exposed for an additional 48 h with TGF-β1, but now in the presence of VP, are not further activated anymore, whereas in the absence of VP the cells continue to differentiate into myofibroblasts. Collagen type I, fibronectin-extra domain A, α-smooth muscle actin, YAP1, Smad2 and Smad3 protein levels were attenuated by both VP treatments. We conclude that VP has strong anti-fibrotic properties: it is able to halt the differentiation of fibroblasts into myofibroblasts, and is also able to reverse the activation status of fibroblasts. The decreased protein levels of YAP1, Smad2 and Smad3 in the presence of VP explain in part the strong anti-fibrotic properties of VP. Verteporfin is clinically used as a photosensitizer for photodynamic therapy to eliminate abnormal blood vessels in the eye to attenuate macular degeneration. The antifibrotic properties of VP do not rely on photo-activation, as we used the molecule in its non-photoinduced state.
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Affiliation(s)
- Nataly Puerta Cavanzo
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.,MATRIX Research Group, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
| | - Sophie A Riesmeijer
- Department of Plastic Surgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
| | - Iris L Holt-Kedde
- Department of Plastic Surgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
| | - Paul M N Werker
- Department of Plastic Surgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
| | - Bram Piersma
- MATRIX Research Group, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
| | - Peter Olinga
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands
| | - Ruud A Bank
- MATRIX Research Group, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
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32
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New Insights into Hippo/YAP Signaling in Fibrotic Diseases. Cells 2022; 11:cells11132065. [PMID: 35805148 PMCID: PMC9265296 DOI: 10.3390/cells11132065] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/25/2022] [Accepted: 06/26/2022] [Indexed: 12/20/2022] Open
Abstract
Fibrosis results from defective wound healing processes often seen after chronic injury and/or inflammation in a range of organs. Progressive fibrotic events may lead to permanent organ damage/failure. The hallmark of fibrosis is the excessive accumulation of extracellular matrix (ECM), mostly produced by pathological myofibroblasts and myofibroblast-like cells. The Hippo signaling pathway is an evolutionarily conserved kinase cascade, which has been described well for its crucial role in cell proliferation, apoptosis, cell fate decisions, and stem cell self-renewal during development, homeostasis, and tissue regeneration. Recent investigations in clinical and pre-clinical models has shown that the Hippo signaling pathway is linked to the pathophysiology of fibrotic diseases in many organs including the lung, heart, liver, kidney, and skin. In this review, we have summarized recent evidences related to the contribution of the Hippo signaling pathway in the development of organ fibrosis. A better understanding of this pathway will guide us to dissect the pathophysiology of fibrotic disorders and develop effective tissue repair therapies.
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33
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Ding M, Huang Z, Wang X, Liu X, Xu L, Chen P, Liu J, Liu Y, Guan H, Chu Y, Liu H. Heparan sulfate proteoglycans-mediated targeted delivery of TGF-β1-binding peptide to liver for improved anti-liver fibrotic activity in vitro and in vivo. Int J Biol Macromol 2022; 209:1516-1525. [PMID: 35452701 DOI: 10.1016/j.ijbiomac.2022.04.085] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 04/11/2022] [Accepted: 04/11/2022] [Indexed: 11/05/2022]
Abstract
Elevated expressions of transforming growth factor β1 (TGF-β1) have been implicated in the pathogenesis of liver fibrosis, thus attenuating the excessive TGF-β1's activity by TGF-β1-binding peptide is an ideal strategy for the treatment of liver fibrosis. However, the application of small peptide as a pharmaceutical agent is obstacle due to difficult preparation and non-selective delivery. The I-plus sequences of circumsporozoite protein (CSP-I) possesses high affinity for heparan sulfate proteoglycans, which are primarily located on liver tissues. TGF-β1-binding peptide P15 holds specific ability of binding to TGF-β1. In this study, we describe an approach to efficiently preparing liver-targeting peptide P15-CSP-I, which is conjugation of the sequences of P15 to the N-terminus of CSP-I, from the cleavage of biological macromolecule SUMO-tagged P15-CSP-I. In vitro and ex vivo binding assay showed that P15-CSP-I specifically targeted to the hepatocytes and liver tissues. Moreover, P15-CSP-I inhibited cell proliferation, migration and invasion, and decreased fibrosis-related proteins expression in TGF-β1-activated HSCs in vitro. Furthermore, P15-CSP-I ameliorated liver morphology and decreased the fibrosis responses in vivo. Taken together, P15-CSP-I may be a potential candidate for targeting therapy on liver fibrosis due to its high efficient preparation, specific liver-targeting potential and improved anti-liver fibrotic activity.
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Affiliation(s)
- Minglu Ding
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang 157011, PR China
| | - Zhen Huang
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang 157011, PR China; Department of Pediatrics Nursing, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China
| | - Xiaohua Wang
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang 157011, PR China; Laboratory of Pathogenic Microbiology and Immunology, Mudanjiang Medical University, Mudanjiang 157011, PR China.
| | - Xiaohui Liu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang 157011, PR China
| | - Liming Xu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang 157011, PR China
| | - Peijian Chen
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang 157011, PR China
| | - Jieting Liu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang 157011, PR China
| | - Yong Liu
- Medical Research Center, Mudanjiang Medical University, Mudanjiang 157011, PR China
| | - Huilin Guan
- Medical Research Center, Mudanjiang Medical University, Mudanjiang 157011, PR China
| | - Yanhui Chu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang 157011, PR China
| | - Haifeng Liu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang 157011, PR China; Laboratory of Pathogenic Microbiology and Immunology, Mudanjiang Medical University, Mudanjiang 157011, PR China.
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34
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Yu S, Ericson M, Fanjul A, Erion DM, Paraskevopoulou M, Smith EN, Cole B, Feaver R, Holub C, Gavva N, Horman SR, Huang J. Genome-wide CRISPR Screening to Identify Drivers of TGF-β-Induced Liver Fibrosis in Human Hepatic Stellate Cells. ACS Chem Biol 2022; 17:918-929. [PMID: 35274923 PMCID: PMC9016707 DOI: 10.1021/acschembio.2c00006] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver fibrosis progression in chronic liver disease leads to cirrhosis, liver failure, or hepatocellular carcinoma and often ends in liver transplantation. Even with an increased understanding of liver fibrogenesis and many attempts to generate therapeutics specifically targeting fibrosis, there is no approved treatment for liver fibrosis. To further understand and characterize the driving mechanisms of liver fibrosis, we developed a high-throughput genome-wide CRISPR/Cas9 screening platform to identify hepatic stellate cell (HSC)-derived mediators of transforming growth factor (TGF)-β-induced liver fibrosis. The functional genomics phenotypic screening platform described here revealed the novel biology of TGF-β-induced fibrogenesis and potential drug targets for liver fibrosis.
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Affiliation(s)
- Shan Yu
- Takeda Development Center Americas, Inc., San Diego, California 92121, United States
| | - Matthew Ericson
- Takeda Development Center Americas, Inc., San Diego, California 92121, United States
| | - Andrea Fanjul
- Takeda Development Center Americas, Inc., San Diego, California 92121, United States
| | - Derek M. Erion
- Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts 02139, United States
| | - Maria Paraskevopoulou
- Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts 02139, United States
| | - Erin N. Smith
- Takeda Development Center Americas, Inc., San Diego, California 92121, United States
| | - Banumathi Cole
- HemoShear Therapeutics, Inc., Charlottesville, Virginia 22902, United States
| | - Ryan Feaver
- HemoShear Therapeutics, Inc., Charlottesville, Virginia 22902, United States
| | - Corine Holub
- Takeda Development Center Americas, Inc., San Diego, California 92121, United States
| | - Narender Gavva
- Takeda Development Center Americas, Inc., San Diego, California 92121, United States
| | - Shane R. Horman
- Takeda Development Center Americas, Inc., San Diego, California 92121, United States
| | - Jie Huang
- Takeda Development Center Americas, Inc., San Diego, California 92121, United States
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35
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Gallego-Durán R, Albillos A, Ampuero J, Arechederra M, Bañares R, Blas-García A, Berná G, Caparrós E, Delgado TC, Falcón-Pérez JM, Francés R, Fernández-Barrena MG, Graupera I, Iruzubieta P, Nevzorova YA, Nogueiras R, Macías RIR, Marín F, Sabio G, Soriano G, Vaquero J, Cubero FJ, Gracia-Sancho J. Metabolic-associated fatty liver disease: from simple steatosis towards liver cirrhosis and potential complications. Proceedings of the Third Translational Hepatology Meeting, endorsed by the Spanish Association for the Study of the Liver (AEEH). GASTROENTEROLOGIA Y HEPATOLOGIA 2022; 45:724-734. [PMID: 35248669 DOI: 10.1016/j.gastrohep.2022.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 02/21/2022] [Indexed: 11/28/2022]
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36
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Abstract
Non-alcoholic fatty liver disease is comprised of either simple steatosis (non-alcoholic fatty liver) or a more advanced inflammatory and fibrogenic stage (non-alcoholic steatohepatitis [NASH]). NASH affects a growing proportion of the global adult and pediatric population, leading to rising rates of liver fibrosis and hepatocellular carcinoma. NASH is a multifactorial disease that is part of a systemic metabolic disorder. Here, we provide an overview of the metabolic underpinnings of NASH pathogenesis and established drivers of inflammation and fibrosis. Clarification of underlying fibrogenic and inflammatory mechanisms will advance the development of novel treatment strategies as there are no approved therapies at present. We discuss emerging experimental approaches and potential novel investigational strategies derived from animal models including the inflammasome, epigenetic reprogramming, Hippo signaling, Notch signaling, engineered T cells to remove fibrogenic HSCs, and HSC-specific targeting therapies. Recently completed and ongoing clinical trials and antifibrotics are discussed, illuminating the growing expectation that one or more therapies will yield clinical benefit in NASH in the coming years.
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Affiliation(s)
- Youngmin A. Lee
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Scott L. Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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37
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Zhang J, Liu Q, He J, Li Y. Novel Therapeutic Targets in Liver Fibrosis. Front Mol Biosci 2021; 8:766855. [PMID: 34805276 PMCID: PMC8602792 DOI: 10.3389/fmolb.2021.766855] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/18/2021] [Indexed: 02/05/2023] Open
Abstract
Liver fibrosis is end-stage liver disease that can be rescued. If irritation continues due to viral infection, schistosomiasis and alcoholism, liver fibrosis can progress to liver cirrhosis and even cancer. The US Food and Drug Administration has not approved any drugs that act directly against liver fibrosis. The only treatments currently available are drugs that eliminate pathogenic factors, which show poor efficacy; and liver transplantation, which is expensive. This highlights the importance of clarifying the mechanism of liver fibrosis and searching for new treatments against it. This review summarizes how parenchymal, nonparenchymal cells, inflammatory cells and various processes (liver fibrosis, hepatic stellate cell activation, cell death and proliferation, deposition of extracellular matrix, cell metabolism, inflammation and epigenetics) contribute to liver fibrosis. We highlight discoveries of novel therapeutic targets, which may provide new insights into potential treatments for liver fibrosis.
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Affiliation(s)
- Jinhang Zhang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, China
| | - Qinhui Liu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, China
| | - Jinhan He
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, China.,Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan, China
| | - Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, China
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38
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Zhang G, Jiang Y, Liu X, Deng Y, Wei B, Shi L. Lingonberry Anthocyanins Inhibit Hepatic Stellate Cell Activation and Liver Fibrosis via TGFβ/Smad/ERK Signaling Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:13546-13556. [PMID: 34735147 DOI: 10.1021/acs.jafc.1c05384] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Phytochemicals from lingonberry have rich pharmacological value and may play an essential role in treating liver diseases. We investigated the regulatory role of lingonberry anthocyanins (LA) on HSC activation in vitro and liver fibrogenesis in vivo. The viability of HSCs treated with LA was significantly reduced in a dose-dependent manner at the concentration of 25-100 μg/mL, in which the monomers of LA also reduced the proliferation of HSCs via IC50 assay. The inducer transforming growth factor β1 (TGFβ1) and the effector α-smooth muscle actin (α-SMA) of HSC activation were all decreased both in protein and RNA levels treated by LA. Moreover, LA alleviated CCl4-induced liver fibrosis in rats, reducing collagen aggregation and production and decreasing the hydroxyproline (HYP) and malondialdehyde (MDA) levels in the liver tissue. Moreover, LA reduced the indexes of serum liver fibrosis and reversed the index of serum liver function in CCl4-induced rats. Furthermore, the antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT), in the liver tissue and serum were significantly increased upon treatment with LA. Importantly, LA promoted hepatic parenchymal cell proliferation and inhibited the expression of TGFβ/Smad/extracellular regulated protein kinase (ERK) signaling pathway-related genes. This study demonstrates the anti-liver fibrosis activity of LA and investigates its mechanism, which may provide a novel strategy for treating liver fibrosis using lingonberry.
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Affiliation(s)
- Guokun Zhang
- Changchun Sci-Tech University, Changchun, Jilin 130600, China
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences (CAAS), Changchun, Jilin 130112, China
| | - Yunyao Jiang
- Changchun Sci-Tech University, Changchun, Jilin 130600, China
| | - Xin Liu
- Shenyang Ligong University, Shenyang, Liaoning 110159, China
| | - Yongyan Deng
- Changchun Sci-Tech University, Changchun, Jilin 130600, China
| | - Bin Wei
- Jilin Province Product Quality Supervision and Inspection Institute, Changchun, Jilin 130000, China
| | - Liyan Shi
- Changchun Sci-Tech University, Changchun, Jilin 130600, China
- China-Japan Union Hospital of Jilin University, Changchun, Jilin 130031, China
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39
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Zhang W, Li J. Yes-associated protein is essential for proliferative vitreoretinopathy development via the epithelial-mesenchymal transition in retinal pigment epithelial fibrosis. J Cell Mol Med 2021; 25:10213-10223. [PMID: 34598306 PMCID: PMC8572794 DOI: 10.1111/jcmm.16958] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 09/09/2021] [Accepted: 09/19/2021] [Indexed: 12/16/2022] Open
Abstract
This study was aim to investigate whether the progression of proliferative vitreoretinopathy (PVR) depended on the activation of Yes‐associated protein (YAP) and the subsequent epithelial‐mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cell. The effect of YAP activation on retinal fibrosis in a PVR mouse model and in human ARPE‐19 cells in vitro was studied. After treated with transforming growth factor‐β2(TGF‐β2), the expressions of fibrogenic molecules, YAP activation and the TGF‐β2‐Smad signalling pathway in ARPE‐19 cells were detected by Western blot and immunocytochemical analyses. The effect of YAP on change in fibrosis and EMT was tested by knockdown experiment using verteporfin (YAP inhibitor). YAP was upregulated in the PVR mouse model and during TGF‐β2–induced RPE cell EMT. In an in vivo study, verteporfin attenuated PVR progression in a mouse model. Additionally, YAP knockdown retained phenotype of RPE cells and ameliorated TGF‐β2–induced migration, gel contraction and EMT in vitro. YAP knockdown inhibited the TGF‐β2–induced upregulation of connective tissue growth factor (CTGF), smooth muscle actin (SMA‐α) and fibronectin. YAP was essential for the TGF‐β2–induced nuclear translocation and phosphorylation of Smad2/3. Our work provides direct evidence that YAP is an essential regulator of EMT and profibrotic responses in PVR and indicates that YAP inhibition could be a potential target in PVR therapeutic intervention.
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Affiliation(s)
- Wei Zhang
- Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Clinical College of Ophthalmology Tianjin Medical University, Tianjin, China.,Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jing Li
- Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Clinical College of Ophthalmology Tianjin Medical University, Tianjin, China
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Antifibrotic Effects of Kangxian Ruangan Capsule on Rats with Nonalcoholic Fatty Liver Fibrosis and Hepatic Stellate Cells through Regulation of TGF- β and TLR4 Signaling Pathways. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5649575. [PMID: 34422075 PMCID: PMC8371615 DOI: 10.1155/2021/5649575] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 05/07/2021] [Accepted: 07/22/2021] [Indexed: 01/18/2023]
Abstract
Kangxian ruangan (KXRG) is a traditional Chinese medicine (TCM) formula consisting of 12 herbs. TCM syndrome differentiation proposes that KXRG exerts pharmacological effects against nonalcoholic fatty liver disease (NAFLD) fibrosis. This work investigates the effect of KXRG on NAFLD fibrosis in vivo and in vitro. In vivo, the NAFLD fibrosis model was constructed in Wistar rats using methionine- and choline-deficient (MCD) diet, followed by KXRG (0.92 g/kg/d) treatment for 8 weeks. In vitro, primary hepatic stellate cells (HSCs) were activated using platelet-derived growth factor (PDGF) and treated with KXRG. Molecular mechanisms underlying fibrosis were investigated. After 8 weeks, compared with the control groups, the histological lesions, degree of fibrosis, and inflammatory reaction increased with the MCD diet as demonstrated by histological changes and increased fibrosis-related (α-SMA, TGF-β, COL1A1, and desmin, P < 0.01) and inflammation-related factors (TNF-α, MCP-1, and F4/80, P < 0.01), whereas they decreased with KXRG treatment (P < 0.01). KXRG not only inhibited the proliferation of activated HSCs and promoted their apoptosis but also resulted in G0-G1 arrest. Furthermore, KXRG suppressed HSC activation (P < 0.01), collagen synthesis (P < 0.01), and α-SMA expression (P < 0.01) with PDGF stimulation. In both the MCD diet-induced animal model and PDGF-induced cell model, KXRG inhibited TGF-β and TLR4 signaling (P < 0.01), similar to corresponding small-molecule inhibitors. These results demonstrated that KXRG might exert suppressive effects against NAFLD fibrosis via regulating TGF-β and TLR4 signaling. KXRG may act as a natural and potent therapeutic agent against NAFLD.
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Yan Y, Zeng J, Xing L, Li C. Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation. Biomedicines 2021; 9:biomedicines9081014. [PMID: 34440218 PMCID: PMC8391653 DOI: 10.3390/biomedicines9081014] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/09/2021] [Accepted: 08/11/2021] [Indexed: 12/18/2022] Open
Abstract
Hepatic fibrosis is characterized by the pathological accumulation of extracellular matrix (ECM) in the liver resulting from the persistent liver injury and wound-healing reaction induced by various insults. Although hepatic fibrosis is considered reversible after eliminating the cause of injury, chronic injury left unchecked can progress to cirrhosis and liver cancer. A better understanding of the cellular and molecular mechanisms controlling the fibrotic response is needed to develop novel clinical strategies. It is well documented that activated hepatic stellate cells (HSCs) is the most principal cellular players promoting synthesis and deposition of ECM components. In the current review, we discuss pathways of HSC activation, emphasizing emerging extra- and intra-cellular signals that drive this important cellular response to hepatic fibrosis. A number of cell types and external stimuli converge upon HSCs to promote their activation, including hepatocytes, liver sinusoidal endothelial cells, macrophages, cytokines, altered ECM, hepatitis viral infection, enteric dysbiosis, lipid metabolism disorder, exosomes, microRNAs, alcohol, drugs and parasites. We also discuss the emerging signaling pathways and intracellular events that individually or synergistically drive HSC activation, including TGFβ/Smad, Notch, Wnt/β-catenin, Hedgehog and Hippo signaling pathways. These findings will provide novel potential therapeutic targets to arrest or reverse fibrosis and cirrhosis.
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Liang T, Qiu J, Li S, Deng Z, Qiu X, Hu W, Li P, Chen T, Liang Z, Zhou H, Gao B, Huang D, Liang A, Gao W. Inverse Agonist of Retinoid-Related Orphan Receptor-Alpha Prevents Apoptosis and Degeneration in Nucleus Pulposus Cells via Upregulation of YAP. Mediators Inflamm 2021; 2021:9954909. [PMID: 34366712 PMCID: PMC8337132 DOI: 10.1155/2021/9954909] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 06/17/2021] [Accepted: 07/08/2021] [Indexed: 12/18/2022] Open
Abstract
Intervertebral disc degenerative disease (IDD) is the most common degenerative spine disease, which leads to chronic low back pain and symptoms in the lower extremities. In this study, we found that RORα, a member of the retinoid-related orphan receptor family, is significantly elevated in nucleus pulposus tissue in IDD patients. The elevation of RORα is associated with increased apoptosis of nucleus pulposus (NP) cells. Therefore, we applicated a well-established inverse agonist of RORα, SR3335, to investigate its role in regulating NP cell metabolism and apoptosis. To further investigate the mechanism that SR3335 regulates the pathogenesis of IDD in vitro, tumor necrosis factor alpha (TNF-α) stimulation was used in human NP cells to mimic the hostile environment that leads to degeneration. We found that SR3335 treatment reversed the trend of increased apoptosis in NP cells induced by TNF-α treatment. Next, TNF-α treatment upregulated the expression of type II collagen and aggrecan and downregulated MMP13 (matrix-degrading enzyme matrix metalloproteinase 13) and ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4). However, these effects were reversed after SR3335 treatment. Furthermore, we find that SR3335 mediated the effect in NP cells by regulating the YAP signaling pathway, especially by affecting the phosphorylation state of YAP. In conclusion, the reduction of matrix degradation enzymes and apoptosis upon SR3335 treatment suggests that SR3335 is a promising drug in reversing the deleterious microenvironment in IDD patients.
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Affiliation(s)
- Tongzhou Liang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yan Jiang Road, Guangzhou, Guangdong 510120, China
| | - Jincheng Qiu
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yan Jiang Road, Guangzhou, Guangdong 510120, China
| | - Shaoguang Li
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yan Jiang Road, Guangzhou, Guangdong 510120, China
| | - Zhihuai Deng
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yan Jiang Road, Guangzhou, Guangdong 510120, China
| | - Xianjian Qiu
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yan Jiang Road, Guangzhou, Guangdong 510120, China
| | - Wenjun Hu
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yan Jiang Road, Guangzhou, Guangdong 510120, China
| | - Pengfei Li
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yan Jiang Road, Guangzhou, Guangdong 510120, China
| | - Taiqiu Chen
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yan Jiang Road, Guangzhou, Guangdong 510120, China
| | - Zhancheng Liang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yan Jiang Road, Guangzhou, Guangdong 510120, China
| | - Hang Zhou
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yan Jiang Road, Guangzhou, Guangdong 510120, China
| | - Bo Gao
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yan Jiang Road, Guangzhou, Guangdong 510120, China
| | - Dongsheng Huang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yan Jiang Road, Guangzhou, Guangdong 510120, China
| | - Anjing Liang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yan Jiang Road, Guangzhou, Guangdong 510120, China
| | - Wenjie Gao
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yan Jiang Road, Guangzhou, Guangdong 510120, China
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Wu Q, Miao X, Zhang J, Xiang L, Li X, Bao X, Du S, Wang M, Miao S, Fan Y, Wang W, Xu X, Shen X, Yang D, Wang X, Fang Y, Hu L, Pan X, Dong H, Wang H, Wang Y, Li J, Huang Z. Astrocytic YAP protects the optic nerve and retina in an experimental autoimmune encephalomyelitis model through TGF-β signaling. Theranostics 2021; 11:8480-8499. [PMID: 34373754 PMCID: PMC8344002 DOI: 10.7150/thno.60031] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 07/06/2021] [Indexed: 02/07/2023] Open
Abstract
Rationale: Optic neuritis is one of main symptoms in multiple sclerosis (MS) that causes visual disability. Astrocytes are pivotal regulators of neuroinflammation in MS, and astrocytic yes-associated protein (YAP) plays a critical role in neuroinflammation. Meanwhile, YAP signaling is involved in visual impairment, including glaucoma, retinal choroidal atrophy and retinal detachment. However, the roles and underlying mechanisms of astrocytic YAP in neuroinflammation and demyelination of MS-related optic neuritis (MS-ON) remains unclear. Methods: To assess the functions of YAP in MS-ON, experimental autoimmune encephalomyelitis (EAE, a common model of MS) was established, and mice that conditional knockout (CKO) of YAP in astrocytes, YAPGFAP-CKO mice, were successfully generated. Behavior tests, immunostaining, Nissl staining, Hematoxylin-Eosin (HE) staining, TUNEL staining, Luxol Fast Blue (LFB) staining, electron microscopy (EM), quantitative real-time PCR (qPCR), gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) by RNA sequencing were used to examine the function and mechanism of YAP signaling based on these YAPGFAP-CKO mice and EAE model mice. To further explore the potential treatment of YAP signaling in EAE, EAE mice were treated with various drugs, including SRI-011381 that is an agonist of transforming growth factor-β (TGF-β) pathway, and XMU-MP-1 which inhibits Hippo kinase MST1/2 to activate YAP. Results: We found that YAP was significantly upregulated and activated in the astrocytes of optic nerve in EAE mice. Conditional knockout of YAP in astrocytes caused more severe inflammatory infiltration and demyelination in optic nerve, and damage of retinal ganglion cells (RGCs) in EAE mice. Moreover, YAP deletion in astrocytes promoted the activation of astrocytes and microglia, but inhibited the proliferation of astrocytes of optic nerve in EAE mice. Mechanically, TGF-β signaling pathway was significantly down-regulated after YAP deletion in astrocytes. Additionally, both qPCR and immunofluorescence assays confirmed the reduction of TGF-β signaling pathway in YAPGFAP-CKO EAE mice. Interestingly, SRI-011381 partially rescued the deficits in optic nerve and retina of YAPGFAP-CKO EAE mice. Finally, activation of YAP signaling by XMU-MP-1 relieved the neuroinflammation and demyelination in optic nerve of EAE mice. Conclusions: These results suggest astrocytic YAP may prevent the neuroinflammatory infiltration and demyelination through upregulation of TGF-β signaling and provide targets for the development of therapeutic strategies tailored for MS-ON.
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Affiliation(s)
- Qian Wu
- School of pharmacy and Holistic Integrative Pharmacy Institutes, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xuemeng Miao
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Jingjing Zhang
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Ludan Xiang
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xiuchun Li
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xiaomei Bao
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Siyu Du
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Mianxian Wang
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Shuangda Miao
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Yiren Fan
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Wei Wang
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xingxing Xu
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xiya Shen
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Danlu Yang
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xiwu Wang
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Yuanyuan Fang
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Lixin Hu
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xuyi Pan
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Haoru Dong
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Hui Wang
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Ying Wang
- Phase I Clinical Research Center, Zhejiang Provincial People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310053, China
| | - Jia Li
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Zhihui Huang
- School of pharmacy and Holistic Integrative Pharmacy Institutes, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
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Zhu S, Chen X, Wang JN, Xu JJ, Wang A, Li JJ, Wu S, Wu YY, Li XF, Huang C, Li J. Circular RNA circUbe2k promotes hepatic fibrosis via sponging miR-149-5p/TGF-β2 axis. FASEB J 2021; 35:e21622. [PMID: 33982351 DOI: 10.1096/fj.202002738r] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 03/25/2021] [Accepted: 04/12/2021] [Indexed: 12/12/2022]
Abstract
Abundant regulatory genes and complex circuits involving non-coding RNAs (ncRNAs) monitor the formation and development of hepatic fibrosis (HF). Circular RNAs (circRNAs) are a class of RNAs generated from protein coding genes by back-splicing, playing crucial roles in various pathological processes, including HF. However, little is known about mechanisms of action of circRNAs, let alone in HF. In this study, we found circUbe2k enhanced in CCl4 -induced HF mice and LX-2 cells stimulated with TGF-β1, regulating the development of HF. Restraining the expression of circUbe2k inhibited α-SMA and Col1α1 expression in CCl4 -induced HF mice and in LX-2 cells stimulated with TGF-β1. Furthermore, inhibiting circUbe2k expression reduced hepatic stellate cells (HSCs) activation and proliferation in vivo and in vitro. Mechanistically, we demonstrated a direct interaction between circUbe2k and miR-149-5p, which results in the modulation of TGF-β2 expressions. Together, circUbe2k may act as a "catalyst" of HSCs activation and HF through the circUbe2k/miR-149-5p/TGF-β2 axis. Our results provide unprecedented evidence for a significant role for circUbe2k to serve as a potential biomarker for HF therapy.
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Affiliation(s)
- Sai Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xin Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jia-Nan Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jin-Jin Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Ao Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Juan-Juan Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Sha Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yuan-Yuan Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xiao-Feng Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
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You H, Wang L, Bu F, Meng H, Pan X, Li J, Zhang Y, Wang A, Yin N, Huang C, Li J. The miR-455-3p/HDAC2 axis plays a pivotal role in the progression and reversal of liver fibrosis and is regulated by epigenetics. FASEB J 2021; 35:e21700. [PMID: 34105828 DOI: 10.1096/fj.202002319rrr] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 01/29/2021] [Accepted: 05/11/2021] [Indexed: 12/29/2022]
Abstract
Histone deacetylases (HDACs), especially HDAC2, play a role in alleviating liver fibrosis; however, the specific upstream regulation mechanism is unknown. Herein, TargetScan was used to predict the potential upstream targets of HDAC2, and the role of miR-455-3p was explored. The dual luciferase reporter assay showed that miR-455-3p binds to the 3' UTR of HDAC2 mRNA. Additionally, miR-455-3p was downregulated in the liver tissues of patients with cirrhosis and mice with liver fibrosis, as well as in primary HSCs isolated from fibrotic mouse livers and TGF-β-treated LX-2 cells. In contrast, it is highly expressed in the reversal stage of hepatic fibrosis and MDI-cultured LX-2 cells. Our functional analyses showed that miR-455-3p overexpression facilitated apoptosis and reduced the expression of pro-fibrotic markers and the proliferation of activated LX-2 cells. On the contrary, miR-455-3p inhibition converted inactivated LX-2 cells into activated, proliferative, fibrogenic cells. Interestingly, restoration of HDAC2 expression partially blocked the function of miR-455-3p. Downregulated miR-455-3p expression can be restored by DNA methyltransferases in activated LX-2 cells. Methylation-specific PCR, bisulfite sequencing PCR, and chromatin immunoprecipitation assays indicated that the methylation level of miR-455-3p promoter CpG islands was elevated in TGF-β-treated LX-2 cells and that miR-455-3p was downregulated in activated LX-2 cells by DNA hypermethylation, which is mediated by DNMT3b and DNMT1. In conclusion, miR-455-3p acts as a liver fibrosis suppressor by targeting HDAC2, and its deficiency further aggravates the reversal phase of fibrosis. Thus, the epigenetics mediated miR-455-3p/HDAC2 axis may serve as a novel potential therapeutic target for clinical treatment of hepatic fibrosis.
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Affiliation(s)
- Hongmei You
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Ling Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Fangtian Bu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hongwu Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xueyin Pan
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Juanjuan Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yafei Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Ao Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Nana Yin
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
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Khurana A, Sayed N, Allawadhi P, Weiskirchen R. It's all about the spaces between cells: role of extracellular matrix in liver fibrosis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:728. [PMID: 33987426 PMCID: PMC8106070 DOI: 10.21037/atm-20-2948] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 07/22/2020] [Indexed: 12/19/2022]
Abstract
Liver fibrosis is one of the leading complications of a variety of chronic liver disorders, including the nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, liver cirrhosis and liver failure. The progression of liver fibrosis is driven by chronic inflammation, which activates the secretory fibroblasts to the myofibroblast phenotype. These specialized liver cells are called as hepatic stellate cells (HSCs). The excessive extracellular matrix (ECM) secretion creates a large number of complications. Fibrosis is the result of imbalance between the matrix synthesizing and matrix degrading factors. The major ECM proteins include the matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), lysyl oxidases (LOX), lysyl oxidase-like (LOXLs) enzymes, tenascins and others. These ECM proteins present novel avenues for the therapeutics of liver fibrosis. The current review highlights the major role played by these critical matrix proteins in liver fibrosis. Further, some of the targeted formulations used against these proteins are discussed and suggestions are provided to select the course of research for successful clinical translation of basic research findings for the amelioration of liver fibrosis.
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Affiliation(s)
- Amit Khurana
- Center for Biomedical Engineering (CBME), Indian Institute of Technology (IIT), Hauz Khas, New Delhi, India
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
| | - Nilofer Sayed
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science, Rajendranagar, Hyderabad, Telangana, India
| | - Prince Allawadhi
- Department of Biotechnology, Indian Institute of Technology (IIT), Roorkee, Uttarakhand, India
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
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MicroRNA-92b-3p promotes the progression of liver fibrosis by targeting CREB3L2 through the JAK/STAT signaling pathway. Pathol Res Pract 2021; 219:153367. [PMID: 33618248 DOI: 10.1016/j.prp.2021.153367] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/23/2022]
Abstract
Liver fibrosis is a common feature of almost all chronic liver diseases, which eventually leads to cirrhosis and even hepatocellular carcinoma (HCC). The current study showed that miR-92b plays an important role in the progression of HCC but its role in liver fibrosis is still unclear. Here we aimed to explore the role and underlying molecular mechanism of miR-92b-3p in the activated hepatic stellate cells (HSCs) and the pathological process of hepatic fibrosis. We found that miR-92b-3p was highly expressed both in fibrotic liver tissues from patients and model mice and in activated LX-2 cells stimulated with TGF-β1. However, the expression of miR-92b-3p was downregulated in inactivated LX-2 cells treated with adipogenic differentiation mixture (MDI). In addition, we found that miR-92b-3p mimic could promote the activation, proliferation, and migration of LX-2 and HSC-T6 cells, while miR-92b-3p inhibitor could reverse this process. From the TargetScan databases, we found that CREB3L2 is a potential target of miR-92b-3p and the luciferase assay revealed the suppressed CREB3L2 expression by miR-92b-3p. Mechanistically, we found that miR-92b-3p promotes the activation of HSCs and thereby the progression of liver fibrosis by activating JAK/STAT pathway via targeting CREB3L2, providing a new target for the diagnosis and treatment of liver fibrosis.
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Li S, Ji J, Zhang Z, Peng Q, Hao L, Guo Y, Zhou W, Cui Q, Shi X. Cisplatin promotes the expression level of PD-L1 in the microenvironment of hepatocellular carcinoma through YAP1. Mol Cell Biochem 2020; 475:79-91. [PMID: 32761300 DOI: 10.1007/s11010-020-03861-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 07/26/2020] [Indexed: 12/26/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. However, the immune tolerance limits the effect of chemotherapeutic drugs. Therefore, the mechanism of cisplatin in promoting PD-L1 expression by YAP1 was investigated in the present study, and we found that cisplatin increased the expression level of YAP1 in the mouse liver with H22 cells. Meanwhile, cisplatin improved the expression level of PD-L1, IL-1β and CCL2 in the tumor microenvironment. Further, cisplatin also enhanced the expression level of YAP1 in shYAP1 HepG2215 cells. The expression of PD-L1 was decreased by Verteporfin, YAP1 inhibitor, during the treatment of DEN/TCPOBOP-induced liver cancer in C57BL/6 mice. These results suggested that cisplatin could deteriorate the immunosuppressive microenvironment through increasing PD-L1, CCL2, IL-1β by upregulated YAP1 expression. Therefore, the study suggested that YAP1 blockade destroyed the immunosuppressive microenvironment of cancer to improve the effect of chemotherapy in HCC.
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MESH Headings
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism
- Animals
- Antineoplastic Agents/pharmacology
- B7-H1 Antigen/biosynthesis
- B7-H1 Antigen/genetics
- B7-H1 Antigen/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Cisplatin/pharmacology
- Hep G2 Cells
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Neoplasms, Experimental/drug therapy
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/pathology
- Male
- Mice
- Mice, Inbred BALB C
- Photosensitizing Agents/pharmacology
- Signal Transduction
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Tumor Microenvironment
- Verteporfin/pharmacology
- YAP-Signaling Proteins
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Affiliation(s)
- Shenghao Li
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, No.3 Xingyuan Road, Shijiazhuang, 050200, Hebei, China
- Hebei Key Laboratory of Integrative Medicine On Liver Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
| | - Jingmin Ji
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, No.3 Xingyuan Road, Shijiazhuang, 050200, Hebei, China
| | - Zhiqin Zhang
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, No.3 Xingyuan Road, Shijiazhuang, 050200, Hebei, China
| | - Qing Peng
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, No.3 Xingyuan Road, Shijiazhuang, 050200, Hebei, China
| | - Liyuan Hao
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, No.3 Xingyuan Road, Shijiazhuang, 050200, Hebei, China
| | - Yinglin Guo
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, No.3 Xingyuan Road, Shijiazhuang, 050200, Hebei, China
| | - Wenhan Zhou
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, No.3 Xingyuan Road, Shijiazhuang, 050200, Hebei, China
| | - Qingzhuo Cui
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, No.3 Xingyuan Road, Shijiazhuang, 050200, Hebei, China
| | - Xinli Shi
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, No.3 Xingyuan Road, Shijiazhuang, 050200, Hebei, China.
- Hebei Key Laboratory of Integrative Medicine On Liver Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
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49
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Bruschi FV, Tardelli M, Einwallner E, Claudel T, Trauner M. PNPLA3 I148M Up-Regulates Hedgehog and Yap Signaling in Human Hepatic Stellate Cells. Int J Mol Sci 2020; 21:E8711. [PMID: 33218077 PMCID: PMC7698885 DOI: 10.3390/ijms21228711] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 11/13/2020] [Accepted: 11/16/2020] [Indexed: 12/16/2022] Open
Abstract
Liver fibrosis represents the wound healing response to sustained hepatic injury with activation of hepatic stellate cells (HSCs). The I148M variant of the PNPLA3 gene represents a risk factor for development of severe liver fibrosis. Activated HSCs carrying the I148M variant display exacerbated pro-inflammatory and pro-fibrogenic features. We aimed to examine whether the I148M variant may impair Hedgehog and Yap signaling, as key pathways implicated in the control of energy expenditure and maintenance of myofibroblastic traits. First, we show that TGF-β rapidly up-regulated the PNPLA3 transcript and protein and Yap/Hedgehog target gene expression. In addition, HSCs overexpressing PNPLA3 I148M boosted anaerobic glycolysis, as supported by higher lactate release and decreased phosphorylation of the energy sensor AMPK. These cells displayed higher Yap and Hedgehog signaling, due to accumulation of total Yap protein, Yap promoter activity and increased downstream targets expression, compared to WT cells. HSCs exposed to TGF-β and leptin rapidly increased total Yap, together with a reduction in its inhibited form, phosphorylated Yap. In line, Yap-specific inhibitor Verteporfin strongly abolished Yap-mediated genes expression, at baseline as well as after TGF-β and leptin treatments in HSCs with I148M PNPLA3. Finally, Yap transcriptional activity was strongly reduced by a combination of Verteporfin and Rosiglitazone, a PPARγ synthetic agonist. In conclusion, HSCs carrying the PNPLA3 variant show activated Yap/Hedgehog pathways, resulting in altered anaerobic glycolysis and enhanced synthesis of Hedgehog markers and sustained Yap signaling. TGF-β and leptin exacerbate Yap/Hedgehog-related fibrogenic genes expression, while Yap inhibitors and PPARγ agonists abrogate these effects in PNPLA3 I148M carrying HSCs.
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Affiliation(s)
- Francesca Virginia Bruschi
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (F.V.B.); (M.T.); (T.C.)
| | - Matteo Tardelli
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (F.V.B.); (M.T.); (T.C.)
- Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Cornell Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA
| | - Elisa Einwallner
- Department of Laboratory Medicine, Center of Translational Research, Medical University of Vienna, 1090 Vienna, Austria;
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (F.V.B.); (M.T.); (T.C.)
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (F.V.B.); (M.T.); (T.C.)
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50
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Jia WQ, Zhou TC, Dai JW, Liu ZN, Zhang YF, Zang DD, Lv XW. CD73 regulates hepatic stellate cells activation and proliferation through Wnt/β-catenin signaling pathway. Eur J Pharmacol 2020; 890:173667. [PMID: 33121948 DOI: 10.1016/j.ejphar.2020.173667] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/16/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023]
Abstract
Alcoholic liver fibrosis (ALF) is commonly associated with long-term alcohol consumption and the activation of hepatic stellate cells (HSCs). Inhibiting the activation and proliferation of HSCs is a critical step to alleviate liver fibrosis. Increasing evidence indicates that ecto-5'-nucleotidase (CD73) plays a vital role in liver disease as a critical component of extracellular adenosine pathway. However, the regulatory role of CD73 in ALF has not been elucidated. In this study, both ethanol plus CCl4-induced liver fibrosis mice model and acetaldehyde-activated HSC-T6 cell model were employed and the expression of CD73 was consistently elevated in vivo and in vitro. C57BL/6 J mice were intraperitoneally injected with CD73 inhibitor Adenosine 5'-(α, β-methylene) diphosphate sodium salt (APCP) from 5th week to the 8th week in the development of ALF. The results showed APCP could inhibit the activation of HSCs, reduce fibrogenesis marker expression and thus alleviate ALF. Silencing of CD73 inhibited the activation of HSC-T6 cells and promoted apoptosis of activated HSC-T6 cells. What's more, the proliferation of HSC-T6 cells was inhibited, which was characterized by decreased cell viability and cycle arrest. Mechanistically, Wnt/β-catenin pathway was activated in acetaldehyde-activated HSC-T6 cells and CD73 silencing or overexpression could regulate Wnt/β-catenin signaling pathway. Collectively, our study unveils the role of CD73 in HSCs activation, and Wnt/β-catenin signaling pathway might be involved in this progression.
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Affiliation(s)
- Wen-Qian Jia
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Tao-Cheng Zhou
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Jing-Wen Dai
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Zhen-Ni Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Ya-Fei Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Dan-Dan Zang
- The Center for Scientific Research of Anhui Medical University, China
| | - Xiong-Wen Lv
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
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