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1
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Borrello MT, Ruzic D, Paish H, Graham E, Collins AL, Scott R, Higginbotham S, Radovic B, Nelson G, Bulmer D, Borthwick LA, Robinson SM, French J, Moir J, White SA, Wilson C, Pandanaboyana S, Hammond J, Thakkar R, Alrawashdeh W, Figueiredo R, Petkovic M, Nikolic K, Oakley F, Mann DA, Mann J. Pharmacological manipulation of liver fibrosis progression using novel HDAC6 inhibitors. FEBS J 2025. [PMID: 40084612 DOI: 10.1111/febs.70062] [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: 07/19/2024] [Revised: 11/15/2024] [Accepted: 02/28/2025] [Indexed: 03/16/2025]
Abstract
Chronic liver injury characterized by unresolved hepatitis leads to fibrosis, potentially progressing to cirrhosis and hepatocellular carcinoma. Effective treatments for halting or reversing liver fibrosis are currently lacking. This study investigates the potential of HDAC6 as a therapeutic target in liver fibrosis. We synthesized two selective HDAC6 inhibitors, DR-3 and FDR2, and assessed their effects on hepatic stellate cell (HSC) activation and liver fibrosis using human precision cut liver slices (hPCLS). Molecular docking, deacetylation inhibition assays, and various cellular assays were employed to evaluate the specificity and anti-fibrotic efficacy of these inhibitors. DR-3 and FDR2 demonstrated high selectivity for HDAC6 over HDAC1, significantly inhibiting HSC activation markers and fibrogenic gene expression. Both inhibitors increased acetylation of α-tubulin and suppressed TGF-β1-induced SMAD signaling in HSCs. In human precision cut liver slices (hPCLS), DR-3 and FDR2 reduced fibrogenic protein levels and collagen deposition. The selective inhibition of HDAC6 by DR-3 and FDR2 effectively reduces HSC activation and fibrogenesis in liver models, supporting further investigation of HDAC6 inhibitors as potential anti-fibrotic therapies.
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Affiliation(s)
- Maria Teresa Borrello
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, UK
- School of Pharmacy and Pharmaceutics, Faculty of Health Sciences and Wellbeing, University of Sunderland, UK
| | - Dusan Ruzic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Serbia
| | - Hannah Paish
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, UK
| | - Eleanor Graham
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, UK
| | - Amy L Collins
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, UK
| | - Rebecca Scott
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, UK
| | - Sam Higginbotham
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, UK
| | - Branko Radovic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Serbia
| | - Glyn Nelson
- Bioimaging Unit, Faculty of Medical Sciences, Newcastle University, UK
| | - David Bulmer
- Bioimaging Unit, Faculty of Medical Sciences, Newcastle University, UK
| | - Lee A Borthwick
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, UK
- FibroFind, Newcastle upon Tyne, UK
| | - Stuart M Robinson
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK
| | - Jeremy French
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK
| | - John Moir
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK
| | - Steve A White
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK
| | - Colin Wilson
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK
| | - Sanjay Pandanaboyana
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK
| | - John Hammond
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK
| | - Rohan Thakkar
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK
| | - Wasfi Alrawashdeh
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK
| | - Rodrigo Figueiredo
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK
| | - Milos Petkovic
- Department of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, Serbia
| | - Katarina Nikolic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Serbia
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, UK
- Newcastle University Centre for Cancer, Newcastle University, UK
| | - Jelena Mann
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, UK
- FibroFind, Newcastle upon Tyne, UK
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2
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Chen T, Yang W, Dong R, Yao H, Sun M, Wang J, Zhou Q, Xu J. The effect and application of adiponectin in hepatic fibrosis. Gastroenterol Rep (Oxf) 2024; 12:goae108. [PMID: 39737222 PMCID: PMC11683834 DOI: 10.1093/gastro/goae108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/04/2024] [Accepted: 09/24/2024] [Indexed: 01/01/2025] Open
Abstract
Hepatic fibrosis, a degenerative liver lesion, significantly contributes to the deterioration and mortality among patients with chronic liver diseases. The condition arises from various factors including toxins, such as alcohol, infections like different types of viral hepatitis, and metabolic diseases. Currently, there are no effective treatments available for liver fibrosis. Recent research has shown that adiponectin (ADPN) exhibits inhibitory effects on hepatic fibrosis. ADPN, an adipocytokine secreted by mature adipocytes, features receptors that are widely distributed across multiple tissues, especially the liver. In the liver, direct effects of ADPN on liver fibrosis include reducing inflammation and regulating hepatic stellate cell proliferation and migration. And its indirect effects include alleviating hepatic endoplasmic reticulum stress and reducing inflammation in hepatic lobules, thereby mitigating hepatic fibrosis. This review aims to elucidate the regulatory role of ADPN in liver fibrosis, explore how ADPN and its receptors alleviate endoplasmic reticulum stress, summarize ADPN detection methods, and discuss its potential as a novel marker and therapeutic agent in combating hepatic fibrosis.
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Affiliation(s)
- Taoran Chen
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Wenjing Yang
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Rongrong Dong
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Han Yao
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Miao Sun
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Jiaxin Wang
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Qi Zhou
- Department of Pediatrics, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Jiancheng Xu
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
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3
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Cheng Z, Li F, Qie Y, Sun J, Wang Y, Zhao Y, Nie G. Hepatic Stellate Cell Membrane-Camouflaged Nanoparticles for Targeted Delivery of an Antifibrotic Agent to Hepatic Stellate Cells with Enhanced Antifibrosis Efficacy. NANO LETTERS 2024; 24:15827-15836. [PMID: 39585320 DOI: 10.1021/acs.nanolett.4c04820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2024]
Abstract
Liver fibrosis is characterized by the excessive accumulation of extracellular matrix proteins primarily produced by activated hepatic stellate cells (HSCs). The activation of HSCs plays a pivotal role in driving the progression of liver fibrosis. Achieving specific targeted delivery of antifibrotic agents toward activated HSCs remains a formidable challenge. Here, we developed an HSC membrane-camouflaged nanosystem, named HSC-PLGA-BAY, for the precise delivery of the antifibrosis agent BAY 11-7082 to activated HSCs in the treatment of liver fibrosis. The designed HSC-PLGA-BAY nanosystem exhibited selective targeting toward activated HSCs, with internalization mediated by homologous cell adhesion molecules from the HSC membrane, namely integrins and N-cadherin. Furthermore, our findings demonstrate that treatment with HSC-PGA-BAY significantly increased apoptosis of activated HSCs and ameliorated liver fibrosis progression in a bile duct ligation (BDL)-induced fibrotic mice model. Collectively, the HSCs-targeted therapeutic platform holds promising potential as an effective strategy for liver fibrosis treatment.
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Affiliation(s)
- Zhaoxia Cheng
- College of Chemistry, Zhengzhou University, Zhengzhou 450001, China
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
| | - Fenfen Li
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yunkai Qie
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Jingyi Sun
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
| | - Yazhou Wang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ying Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
| | - Guangjun Nie
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
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DeJesus J, Wang X, Gu Y, Mao RM, Zhou J, Radhakrishnan R. Novel Compound HJC0416 Attenuates Hepatic Fibrosis via HSP90/NF-κB-Associated Mechanism. J Surg Res 2024; 304:305-314. [PMID: 39579470 DOI: 10.1016/j.jss.2024.09.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 08/19/2024] [Accepted: 09/14/2024] [Indexed: 11/25/2024]
Abstract
INTRODUCTION Chronic liver disease is driven by a prolonged wound healing response leading to fibrogenesis, potentially progressing to cirrhosis. Hepatic stellate cells (HSCs) are the primary cells driving hepatic fibrosis because they are major producers of extracellular matrix. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ΚB) pathway is a key regulator of inflammatory signaling, and survival of activated HSCs has been found to be NF-KB dependent. Our team previously synthesized HJC0416-a signal transducer and activator of transcription three inhibitor with potent anti-inflammatory effects. In HSCs, HJC0416 reduced cell viability, extracellular matrix production, and-notably-NF-KB activation. However, HJC0416's antifibrogenetic mechanism remains unknown. This study examined the effects of HJC0416 on NF-KB and its associate factor HSP-90 in HSCs. METHODS The activated human HSC line LX-2 was treated with either HJC0416 or 17-AAG, then exposed to TNFα as indicated. Nuclear and cytosolic proteins were isolated for Western blot or immunofluorescence assay. RESULTS HJC0416 significantly attenuated TNFα-induced IκBα phosphorylation, NF-KBp65 nuclear translocation, and DNA binding activity. Endogenous and TNFα-induced p65 phosphorylation of S536 was suppressed by HJC0416. Notably, HJC0416 dose-dependently attenuated the expression of FAK, IKKα, and signal transducer and activator of transcription three which are Heat Shock Protein 90 (HSP90) interacting proteins. The expression of other HSP90 interacting proteins-RIP1, AKT, FAK, and cyclin-dependent kinase nine-were decreased. HSP90-specific inhibitor 17-AAG significantly attenuated TNFα-induced IκBα phosphorylation and degradation, p65 nuclear translocation, DNA binding, and production of collagen type I and fibronectin. CONCLUSIONS The HSP90 chaperone protein may be a key intermediary linking HJC0416's ability to inhibit NF-κB activity. HJC0416 may be a promising drug candidate for liver fibrosis.
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Affiliation(s)
- Jana DeJesus
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas
| | - Xiaofu Wang
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas
| | - Yanping Gu
- Department of Neurobiology, University of Texas Medical Branch, Galveston, Texas
| | - Rui-Min Mao
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas
| | - Jia Zhou
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas
| | - Ravi Radhakrishnan
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas.
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5
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Calvillo-Robledo A, Samson-Soleil, Marichal-Cancino BA, Medina-Pizaño MY, Ibarra-Martínez D, Ventura-Juárez J, Muñoz-Ortega M. Rapid liver self-recovery: A challenge for rat models of tissue damage. Life Sci 2024; 357:122975. [PMID: 39142508 DOI: 10.1016/j.lfs.2024.122975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/11/2024] [Accepted: 08/10/2024] [Indexed: 08/16/2024]
Abstract
Animal models, mainly murine, stay as a fundamental resource in diverse research pursuits, notably contributing to significant strides in discovering novel treatments for therapeutic applications. Preclinical assays must consider the existence of self-recovery mechanisms in the murine species to achieve a well-designed control group. This study focuses on unveiling the innate rapid regenerative capacity of rat liver by utilizing the thioacetamide-induced sub-chronic liver injury model. Employing histopathological, biochemical, and molecular liver function tests, we assessed the recovery of liver tissue functionality. Moreover, animals were housed with voluntary running wheels and locomotory activity was recorded and employed as an indirect index of overall animal recuperation. Remarkably, basal locomotory activity reestablished to normal levels only two weeks post-thioacetamide exposure. Our results raise vital considerations about the importance of temporal synchronicity in comparative assays to validate the real action of treatments, emphasizing the role of the rapid rat liver endogenous self-recovery.
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Affiliation(s)
- Argelia Calvillo-Robledo
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Samson-Soleil
- Departamento de Morfología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Bruno A Marichal-Cancino
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | | | - David Ibarra-Martínez
- Departamento de Química, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Javier Ventura-Juárez
- Departamento de Morfología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Martin Muñoz-Ortega
- Departamento de Química, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico.
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6
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Yang X, Yue R, Zhao L, Huang X, Wang Q. Banxia Xiexin Tang attenuates high glucose-induced hepatocyte injury by activating SOD2 to scavenge ROS via PGC-1α/IGFBP1. 3 Biotech 2024; 14:216. [PMID: 39220826 PMCID: PMC11358567 DOI: 10.1007/s13205-024-04060-0] [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: 07/09/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024] Open
Abstract
This study aimed to explore the protective mechanism of Banxia Xiexin Tang (BXXXT) on liver cell damage caused by high glucose (H-G) and to clarify its molecular regulatory pathways. First, the main components in BXXXT-containing serum were analyzed by high-performance liquid chromatography (HPLC) to provide basic data for subsequent experiments. Subsequently, the effect of BXXXT on high glucose (H-G)-induced hepatocyte activity was evaluated through screening of the optimal concentration of drug-containing serum. Experimental results showed that BXXXT significantly reduced the loss of cell activity caused by high glucose. Further research focuses on the regulatory effect of BXXXT on high glucose-induced hepatocyte apoptosis, especially its effect on the PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) pathway. Experimental results showed that BXXXT reduced high-glucose-induced hepatocyte apoptosis and exerted its protective effect by upregulating the activity of the PGC-1α pathway. BXXXT significantly increased the expression level of IGFBP1 (insulin-like growth factor-binding proteins) in hepatocytes under a high-glucose environment. It cleared mitochondrial ROS (reactive oxygen species) by enhancing SOD2 (superoxide dismutase) enzyme activity and maintained the survival of hepatocytes under a high-glucose environment. Finally, the regulation of PGC-1α by BXXXT is indeed involved in the regulation of IGFBP1 expression in hepatocytes and its downstream SOD2 effector signaling. Taken together, this study provides an in-depth explanation of the protective mechanism of BXXXT on hepatocytes in a high-glucose environment, focusing on regulating the expression of the PGC-1α pathway and IGFBP1, and reducing cell damage by scavenging ROS. This provides an experimental basis for further exploring the potential of BXXXT in the treatment of diabetes-related liver injury. Supplementary Information The online version contains supplementary material available at 10.1007/s13205-024-04060-0.
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Affiliation(s)
- Xu Yang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Rensong Yue
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - LiangBin Zhao
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiushen Huang
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiyue Wang
- Chengdu Jinniu Hospital of Traditional Chinese Medicine, Chengdu, China
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7
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Yang Z, Xiong Z, Wang Q, Zhou N. A bibliometric analysis of macrophages associated with non-alcoholic fatty liver disease research from 2005 to 2023. Heliyon 2024; 10:e24187. [PMID: 38293366 PMCID: PMC10827458 DOI: 10.1016/j.heliyon.2024.e24187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 01/03/2024] [Accepted: 01/04/2024] [Indexed: 02/01/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition associated with the risk of progressing to decompensated cirrhosis and hepatocellular carcinoma. While macrophages play a crucial role in the development of NAFLD, their heterogeneity and plasticity allow them to undertake diverse roles in immune response, tissue repair, and maintaining tissue homeostasis. Thus, the exact involvement of macrophages in the onset and progression of NAFLD remains to be further explored. This study aims to employ bibliometric analysis to elucidate the role of macrophages in the pathogenesis of NAFLD, analyze research focal points in this domain, and speculate on future research trends. The literature search, conducted using the Web of Science Core Collection, encompassed articles and reviews related to macrophages and NAFLD published between 2005 and 2023. A bibliometric analysis of 1264 extracted publications was performed using VOSviewer 1.6.17 and Citespace 6.1. R2, evaluating parameters such as spatial and temporal distribution, authors, thematic categories, topic distribution, references, and keywords. The findings revealed a steady global increase in publications in this field, with the United States contributing the most followed by China. The University of California System produced the highest volume of publications, while the Journal of Hepatology had the highest impact factors among the top 10 publishing journals. Tacke Frank emerged as both the most prolific author and the most cited. Co-occurrence and burst analysis of keywords and references highlighted the hotspots in this research area, emphasizing the mechanisms of NAFLD pathogenesis, metabolic regulation, immune modulation, and oxidative stress. Maintaining hepatic homeostasis by liver macrophages and macrophage polarization were identified as trending research directions in this field. Based on the bibliometric analysis, continued attention toward NAFLD therapeutic research involving hepatic macrophages is anticipated. As the mechanisms underlying NAFLD pathogenesis are further elucidated, the development of more treatment approaches related to macrophage immunology and metabolic regulation may expand therapeutic options. This study offers valuable insights into the current state and future trends in the field, providing beneficial guidance to researchers aiming to make significant contributions.
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Affiliation(s)
- Zhen Yang
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Zhiwei Xiong
- Department of Liver Transplantation, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Qiuguo Wang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ning Zhou
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
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8
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Medina Pizaño MY, Loera Arias MDJ, Montes de Oca Luna R, Saucedo Cárdenas O, Ventura Juárez J, Muñoz Ortega MH. Neuroimmunomodulation of adrenoblockers during liver cirrhosis: modulation of hepatic stellate cell activity. Ann Med 2023; 55:543-557. [PMID: 36826975 PMCID: PMC9970206 DOI: 10.1080/07853890.2022.2164047] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
Abstract
The sympathetic nervous system and the immune system are responsible for producing neurotransmitters and cytokines that interact by binding to receptors; due to this, there is communication between these systems. Liver immune cells and nerve fibres are systematically distributed in the liver, and the partial overlap of both patterns may favour interactions between certain elements. Dendritic cells are attached to fibroblasts, and nerve fibres are connected via the dendritic cell-fibroblast complex. Receptors for most neuroactive substances, such as catecholamines, have been discovered on dendritic cells. The sympathetic nervous system regulates hepatic fibrosis through sympathetic fibres and adrenaline from the adrenal glands through the blood. When there is liver damage, the sympathetic nervous system is activated locally and systemically through proinflammatory cytokines that induce the production of epinephrine and norepinephrine. These neurotransmitters bind to cells through α-adrenergic receptors, triggering a cellular response that secretes inflammatory factors that stimulate and activate hepatic stellate cells. Hepatic stellate cells are key in the fibrotic process. They initiate the overproduction of extracellular matrix components in an active state that progresses from fibrosis to liver cirrhosis. It has also been shown that they can be directly activated by norepinephrine. Alpha and beta adrenoblockers, such as carvedilol, prazosin, and doxazosin, have recently been used to reverse CCl4-induced liver cirrhosis in rodent and murine models.KEY MESSAGESNeurotransmitters from the sympathetic nervous system activate and increase the proliferation of hepatic stellate cells.Hepatic fibrosis and cirrhosis treatment might depend on neurotransmitter and hepatic nervous system regulation.Strategies to reduce hepatic stellate cell activation and fibrosis are based on experimentation with α-adrenoblockers.
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Affiliation(s)
| | | | | | - Odila Saucedo Cárdenas
- Histology Department, Faculty of Medicine, Autonomous University of Nuevo León, Monterrey, México
| | - Javier Ventura Juárez
- Department of Morphology, Autonomous University of Aguascalientes, Aguascalientes, México
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9
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Borrello MT, Mann D. Chronic liver diseases: From development to novel pharmacological therapies: IUPHAR Review 37. Br J Pharmacol 2023; 180:2880-2897. [PMID: 35393658 DOI: 10.1111/bph.15853] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 03/16/2022] [Accepted: 03/30/2022] [Indexed: 12/10/2022] Open
Abstract
Chronic liver diseases comprise a broad spectrum of burdensome diseases that still lack effective pharmacological therapies. Our research group focuses on fibrosis, which is a major precursor of liver cirrhosis. Fibrosis consists in a progressive disturbance of liver sinusoidal architecture characterised by connective tissue deposition as a reparative response to tissue injury. Multifactorial events and several types of cells participate in fibrosis initiation and progression, and the process still needs to be completely understood. The development of experimental models of liver fibrosis alongside the identification of critical factors progressing fibrosis to cirrhosis will facilitate the development of more effective therapeutic approaches for such condition. This review provides an overlook of the main process leading to hepatic fibrosis and therapeutic approaches that have emerged from a deep knowledge of the molecular regulation of fibrogenesis in the liver. LINKED ARTICLES: This article is part of a themed issue on Translational Advances in Fibrosis as a Therapeutic Target. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.22/issuetoc.
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Affiliation(s)
- Maria Teresa Borrello
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Derek Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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10
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Ruiz de Galarreta M, Arriazu E, Pérez de Obanos MP, Ansorena E, Iraburu MJ. Antifibrogenic and apoptotic effects of Ocoxin in cultured rat hepatic stellate cells. J Physiol Biochem 2023; 79:881-890. [PMID: 35239161 PMCID: PMC10635942 DOI: 10.1007/s13105-022-00878-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 01/25/2022] [Indexed: 10/18/2022]
Abstract
Ocoxin is a nutritional supplement that has been shown to exert antioxidant and immunomodulatory responses in patients with chronic hepatitis C. The present work aimed to determine the effects of Ocoxin on activated hepatic stellate cells (HSC), the cell type mainly responsible for collagen deposition in the fibrotic liver. Ocoxin was found to reduce the survival of a cell line of immortalized non-tumoral rat HSC in a dose-response fashion and to diminish collagen type I levels. This latter effect was observed even at doses not affecting cell survival, pointing to an antifibrogenic action for the supplement. The decrease in viability exerted by Ocoxin on HSC correlated with an increase in histone-associated fragments in the cytoplasm and with increased activity of caspase-3, indicating the induction of apoptosis. To determine the molecular mechanisms mediating Ocoxin-induced apoptosis, the activation of members of the MAPK family was analyzed. Incubation of HSC with Ocoxin caused a transient and dramatic enhancement on ERK, JNK, and p38 MAPK phosphorylation levels. Using specific inhibitors for these enzymes, p38 MAPK was identified as a key mediator of the apoptotic effect of Ocoxin on HSC.
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Affiliation(s)
| | - Elena Arriazu
- Department of Biochemistry and Genetics, University of Navarra, 31008, Pamplona, Spain
| | | | - Eduardo Ansorena
- Department of Biochemistry and Genetics, University of Navarra, 31008, Pamplona, Spain
| | - María J Iraburu
- Department of Biochemistry and Genetics, University of Navarra, 31008, Pamplona, Spain.
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11
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Beil J, Perner J, Pfaller L, Gérard MA, Piaia A, Doelemeyer A, Wasserkrug Naor A, Martin L, Piequet A, Dubost V, Chibout SD, Moggs J, Terranova R. Unaltered hepatic wound healing response in male rats with ancestral liver injury. Nat Commun 2023; 14:6353. [PMID: 37816736 PMCID: PMC10564731 DOI: 10.1038/s41467-023-41998-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 09/26/2023] [Indexed: 10/12/2023] Open
Abstract
The possibility that ancestral environmental exposure could result in adaptive inherited effects in mammals has been long debated. Numerous rodent models of transgenerational responses to various environmental factors have been published but due to technical, operational and resource burden, most still await independent confirmation. A previous study reported multigenerational epigenetic adaptation of the hepatic wound healing response upon exposure to the hepatotoxicant carbon tetrachloride (CCl4) in male rats. Here, we comprehensively investigate the transgenerational effects by repeating the original CCl4 multigenerational study with increased power, pedigree tracing, F2 dose-response and suitable randomization schemes. Detailed pathology evaluations do not support adaptive phenotypic suppression of the hepatic wound healing response or a greater fitness of F2 animals with ancestral liver injury exposure. However, transcriptomic analyses identified genes whose expression correlates with ancestral liver injury, although the biological relevance of this apparent transgenerational transmission at the molecular level remains to be determined. This work overall highlights the need for independent evaluation of transgenerational epigenetic inheritance paradigms in mammals.
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Affiliation(s)
- Johanna Beil
- Novartis, Biomedical Research, Basel, Switzerland
| | | | - Lena Pfaller
- Novartis, Biomedical Research, Basel, Switzerland
| | | | | | | | | | - Lori Martin
- Novartis, Biomedical Research, East-Hanover, NJ, USA
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12
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Sharma A, Wang J, Gandhi CR. CD14 is not required for carbon tetrachloride-induced hepatic inflammation and fibrosis with or without lipopolysaccharide challenge. J Cell Physiol 2023; 238:1530-1541. [PMID: 37098757 DOI: 10.1002/jcp.31030] [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: 10/17/2022] [Revised: 04/05/2023] [Accepted: 04/11/2023] [Indexed: 04/27/2023]
Abstract
Binding of lipopolysaccharide (LPS) to CD14 is required for its cellular effects via TLR4. A role of LPS/TLR4-mediated signaling in activated hepatic stellate cells (aHSCs), the major fibrogenic cells, in liver fibrosis has been reported. We investigated effects of LPS on carbon tetrachloride (CCl4)-induced fibrosis in CD14-knockout (KO) mice in vivo, and culture-activated HSCs in vitro. CCl4 (biweekly; 4 weeks)-treated wild type (WT) and CD14-KO mice were challenged with single LPS administration for 24 h. Liver injury, inflammation and fibrosis were determined. Culture-activated HSCs from WT or CD14-KO mice were stimulated with LPS. Parameters of fibrogenic activity (expression of collagen1a1 [Col1a1], α-smooth muscle actin [αSMA] and TGFβ1) and inflammatory cytokines/chemokines were measured. CCl4 treatment caused similar liver injury and fibrosis in WT and CD14-KO mice. LPS increased liver injury and inflammation similarly in CCl4-treated WT and CD14-KO mice, but downregulated Timp1 and upregulated Mmp13. LPS elicited similar NFκB activation and inflammatory response in WT and CD14-KO aHSCs. LPS similarly downregulated Acta2 (encodes αSMA), Pdgfrb, Col1a1 and Mmp13 expression but did not affect Timp1 expression in WT and CD14-KO aHSCs. LPS did not alter Tgfb1 but increased expression of decorin (Dcn) (inhibitor of TGFβ1) expression in WT and CD14-KO aHSCs. The results indicate that the effects of LPS on HSCs are CD14-independent, and CD14 is not required for hepatic fibrosis. LPS-induced down-modulation of fibrogenic markers in aHSCs is also CD14-independent.
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Affiliation(s)
- Akanksha Sharma
- Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Jiang Wang
- Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Chandrashekhar R Gandhi
- Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA
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Lingas EC. Hematological Abnormalities in Cirrhosis: A Narrative Review. Cureus 2023; 15:e39239. [PMID: 37337504 PMCID: PMC10277171 DOI: 10.7759/cureus.39239] [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] [Accepted: 05/18/2023] [Indexed: 06/21/2023] Open
Abstract
Liver cirrhosis remains a major public health issue. Liver fibrosis leading to cirrhosis is the terminal stage of various chronic liver diseases. Inflammatory cytokines are involved in the pathogenesis. Patients with cirrhosis often have hematological abnormalities, such as anemia and thrombocytopenia, which have multifactorial etiologies. Anemia in cirrhosis could be related to bleeding leading to iron deficiency anemia or other nutritional anemia such as vitamin B12 and folate deficiency. The pathophysiology of thrombocytopenia in liver cirrhosis has been postulated to range from splenic sequestration to bone marrow suppression from toxic agents, such as alcohol. It often complicates management due to the risk of bleeding with severely low platelets. This review aimed to highlight pathogenesis of liver cirrhosis, hematological abnormalities in liver cirrhosis, and their clinical significance.
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Wang YK, Ma N, Xu S, Huang JY, Ni QZ, Cao HJ, Zheng QW, Zhu B, Xia J, Zhang FK, Ding XF, Qiu XS, Chen TW, Wang K, Chen W, Li ZG, Cheng SQ, Xie D, Li JJ. PPDPF suppresses the development of hepatocellular carcinoma through TRIM21-mediated ubiquitination of RIPK1. Cell Rep 2023; 42:112340. [PMID: 37027301 DOI: 10.1016/j.celrep.2023.112340] [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: 04/18/2022] [Revised: 11/13/2022] [Accepted: 03/20/2023] [Indexed: 04/08/2023] Open
Abstract
Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) has been reported to play a role in tumorigenesis. However, its function in hepatocellular carcinoma (HCC) remains poorly understood. In this study, we report that PPDPF is significantly downregulated in HCC and the decreased PPDPF expression indicates poor prognosis. In the dimethylnitrosamine (DEN)-induced HCC mouse model, hepatocyte-specific depletion of Ppdpf promotes hepatocarcinogenesis, and reintroduction of PPDPF into liver-specific Ppdpf knockout (LKO) mice inhibits the accelerated HCC development. Mechanistic study shows that PPDPF regulates nuclear factor κB (NF-κB) signaling through modulation of RIPK1 ubiquitination. PPDPF interacts with RIPK1 and facilitates K63-linked ubiquitination of RIPK1 via recruiting the E3 ligase TRIM21, which catalyzes K63-linked ubiquitination of RIPK1 at K140. In addition, liver-specific overexpression of PPDPF activates NF-κB signaling and attenuates apoptosis and compensatory proliferation in mice, which significantly suppresses HCC development. This work identifies PPDPF as a regulator of NF-κB signaling and provides a potential therapeutic candidate for HCC.
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Affiliation(s)
- Yi-Kang Wang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Ning Ma
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Department of Thoracic Surgery, Section of Esophageal Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Sheng Xu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jing-Yi Huang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Qian-Zhi Ni
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200433, China
| | - Hui-Jun Cao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Qian-Wen Zheng
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Bing Zhu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Ji Xia
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Feng-Kun Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xu-Fen Ding
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xiao-Song Qiu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Tian-Wei Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Kang Wang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200433, China
| | - Wei Chen
- Institute of Clinical Medicine Research, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou 310014, China
| | - Zhi-Gang Li
- Department of Thoracic Surgery, Section of Esophageal Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Shu-Qun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200433, China
| | - Dong Xie
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing 100022, China.
| | - Jing-Jing Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing 100022, China.
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15
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Ghufran SM, Sharma S, Ghose S, Biswas S. Divergent effect of Birinapant, and BV6 SMAC mimetic on TNFα induced NF-κB signaling and cell viability in activated hepatic stellate cells. Mol Biol Rep 2023; 50:2107-2117. [PMID: 36542236 DOI: 10.1007/s11033-022-08210-6] [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: 11/08/2021] [Accepted: 12/14/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Tumor necrosis factor-α (TNFα) is a pleiotropic cytokine involved in nuclear factor kappa B (NF-κB) mediated cell survival as well as cell death. High serum TNFα levels correlate with liver fibrosis and enhance hepatic stellate cell (HSC) viability. However, the regulatory role of cellular inhibitor of apoptosis-1/2 (cIAP1/2) during TNFα induced NF-κB signaling in activated HSCs is largely unknown. METHOD AND RESULTS Activated HSCs were treated with cIAP1/2 inhbitiors i.e., SMAC mimetic BV6, and Birinapant in the presence of TNFα and macrophage conditioned media. TNFα cytokine increased cIAP2 expression and enhanced cell viability through the canonical NF-κB signaling in activated HSCs. cIAP2 inhibition via BV6 decreased the TNFα induced canonical NF-κB signaling, and reduced cell viability in activated HSCs. SMAC mimetic, Birinapant alone did not affect the cell viability but treatment of TNFα sensitized HSCs with Birinapant induced cell death. While BV6 mediated cIAP2 ablation was able to decrease the TNFα induced canonical NF-κB signaling, this effect was not observed with Birinapant treatment. Secreted TNFα from M1 polarized macrophages sensitized activated HSCs to BV6 or Birinapant mediated cell death. However, M2 polarized macrophage conditioned medium rescued the activated HSCs from BV6 mediated cytotoxicity. CONCLUSION In this study, we describe the regulatory role of cIAP2 in TNFα induced NF-κB signaling in activated HSCs. Targeting cIAP2 may be a promising approach for liver fibrosis treatment via modulating NF-κB signaling in activated HSCs.
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Affiliation(s)
- Shaikh Maryam Ghufran
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Translational Cancer & Stem Cell Research Laboratory, Amity University Uttar Pradesh (AUUP), Amity University, Research Laboratory 101, J3 Block Sector 125, Noida, 201313, Uttar Pradesh, India
| | - Sachin Sharma
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Translational Cancer & Stem Cell Research Laboratory, Amity University Uttar Pradesh (AUUP), Amity University, Research Laboratory 101, J3 Block Sector 125, Noida, 201313, Uttar Pradesh, India.,Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Sampa Ghose
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Subhrajit Biswas
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Translational Cancer & Stem Cell Research Laboratory, Amity University Uttar Pradesh (AUUP), Amity University, Research Laboratory 101, J3 Block Sector 125, Noida, 201313, Uttar Pradesh, India.
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16
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Optical Biomedical Imaging Reveals Criteria for Violated Liver Regenerative Potential. Cells 2023; 12:cells12030479. [PMID: 36766821 PMCID: PMC9914457 DOI: 10.3390/cells12030479] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/12/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
To reduce the risk of post-hepatectomy liver failure in patients with hepatic pathologies, it is necessary to develop an approach to express the intraoperative assessment of the liver's regenerative potential. Traditional clinical methods do not enable the prediction of the function of the liver remnant. Modern label-free bioimaging, using multiphoton microscopy in combination with second harmonic generation (SHG) and fluorescence lifetime imaging microscopy (FLIM), can both expand the possibilities for diagnosing liver pathologies and for assessing the regenerative potential of the liver. Using multiphoton and SHG microscopy, we assessed the structural state of liver tissue at different stages of induced steatosis and fibrosis before and after 70% partial hepatectomy in rats. Using FLIM, we also performed a detailed analysis of the metabolic state of the hepatocytes. We were able to determine criteria that can reveal a lack of regenerative potential in violated liver, such as the presence of zones with reduced NAD(P)H autofluorescence signals. Furthermore, for a liver with pathology, there was an absence of the jump in the fluorescence lifetime contributions of the bound form of NADH and NADPH the 3rd day after hepatectomy that is characteristic of normal liver regeneration. Such results are associated with decreased intensity of oxidative phosphorylation and of biosynthetic processes in pathological liver, which is the reason for the impaired liver recovery. This modern approach offers an effective tool that can be successfully translated into the clinic for express, intraoperative assessment of the regenerative potential of the pathological liver of a patient.
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17
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Sahu R, Goswami S, Narahari Sastry G, Rawal RK. The Preventive and Therapeutic Potential of the Flavonoids in Liver Cirrhosis: Current and Future Perspectives. Chem Biodivers 2023; 20:e202201029. [PMID: 36703592 DOI: 10.1002/cbdv.202201029] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 01/12/2023] [Indexed: 01/28/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) may vary from moderately mild non-alcohol fatty liver (NAFL) towards the malignant variant known as non-alcoholic steatohepatitis (NASH), which is marked by fatty liver inflammation and may progress to liver cirrhosis (LC), liver cancer, fibrosis, or liver failure. Flavonoids can protect the liver from toxins through their anti-inflammatory, antioxidant, anti-cancer, and antifibrogenic pharmacological activities. Furthermore, flavonoids protect against LC by regulation of hepatic stellate cells (HSCs) trans-differentiation, inhibiting growth factors like TGF-β and platelets-derived growth factor (PDGF), vascular epithelial growth factor (VEGF), viral infections like hepatitis-B, C and D viruses (HBV, HCV & HDV), autoimmune-induced, alcohol-induced, metabolic disorder-induced, causing by apoptosis, and regulating MAPK pathways. These flavonoids may be explored in the future as a therapeutic solution for hepatic diseases.
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Affiliation(s)
- Rakesh Sahu
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India
| | - Sourav Goswami
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India
| | - G Narahari Sastry
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India
| | - Ravindra K Rawal
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India
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18
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Qin L, Liu N, Bao CLM, Yang DZ, Ma GX, Yi WH, Xiao GZ, Cao HL. Mesenchymal stem cells in fibrotic diseases-the two sides of the same coin. Acta Pharmacol Sin 2023; 44:268-287. [PMID: 35896695 PMCID: PMC9326421 DOI: 10.1038/s41401-022-00952-0] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 06/29/2022] [Indexed: 02/06/2023]
Abstract
Fibrosis is caused by extensive deposition of extracellular matrix (ECM) components, which play a crucial role in injury repair. Fibrosis attributes to ~45% of all deaths worldwide. The molecular pathology of different fibrotic diseases varies, and a number of bioactive factors are involved in the pathogenic process. Mesenchymal stem cells (MSCs) are a type of multipotent stem cells that have promising therapeutic effects in the treatment of different diseases. Current updates of fibrotic pathogenesis reveal that residential MSCs may differentiate into myofibroblasts which lead to the fibrosis development. However, preclinical and clinical trials with autologous or allogeneic MSCs infusion demonstrate that MSCs can relieve the fibrotic diseases by modulating inflammation, regenerating damaged tissues, remodeling the ECMs, and modulating the death of stressed cells after implantation. A variety of animal models were developed to study the mechanisms behind different fibrotic tissues and test the preclinical efficacy of MSC therapy in these diseases. Furthermore, MSCs have been used for treating liver cirrhosis and pulmonary fibrosis patients in several clinical trials, leading to satisfactory clinical efficacy without severe adverse events. This review discusses the two opposite roles of residential MSCs and external MSCs in fibrotic diseases, and summarizes the current perspective of therapeutic mechanism of MSCs in fibrosis, through both laboratory study and clinical trials.
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Affiliation(s)
- Lei Qin
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Nian Liu
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Chao-le-meng Bao
- CASTD Regengeek (Shenzhen) Medical Technology Co. Ltd, Shenzhen, 518000 China
| | - Da-zhi Yang
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Gui-xing Ma
- grid.263817.90000 0004 1773 1790Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055 China
| | - Wei-hong Yi
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Guo-zhi Xiao
- grid.263817.90000 0004 1773 1790Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055 China
| | - Hui-ling Cao
- grid.263817.90000 0004 1773 1790Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055 China
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Łotowska JM, Sobaniec-Łotowska ME, Bobrus-Chociej A, Sobaniec P. The Ultrastructure of Hepatic Stellate Cell-Macrophage Intercellular Crosstalk as a New Morphological Insight into Phenomenon of Fibrogenesis in Pediatric Autoimmune Hepatitis. J Clin Med 2023; 12:jcm12031024. [PMID: 36769672 PMCID: PMC9917971 DOI: 10.3390/jcm12031024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/20/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
The aim of the study was the pioneering retrospective ultrastructural evaluation of respective forms of hepatic stellate cells (HSCs) and analysis of their crosstalk with other adjacent nonparenchymal cells (NPCs), especially Kupffer cells/macrophages (KCs/MPs), in pediatric autoimmune hepatitis (AIH). METHODS Ultrastructural assessment of the HSC population and NPCs was performed in transmission electron microscopy (TEM) using pretreatment liver biopsies from 25 children (8 boys and 17 girls) aged 4-17 with clinic-pathologically diagnosed untreated AIH. RESULTS Submicroscopic evaluation allowed easy identification of numerous HSCs in the form of transitory cells, i.e., T-HSCs, accompanied by signs of fibrosis. T-HSCs included cells with features of activation initiation (iHSCs) and activation perpetuation (pHSCs), indicating high HSC activation plasticity. The pHSCs were markedly elongated and mainly showed a distinct loss of lipid cytoplasmic material, expanded and dilated channels of granular endoplasmic reticulum, and linear bundles of microfilaments beneath the cell membrane. They were surrounded by usually mature collagen fibers. Frequently activated KCs/MPs adhered directly to T-HSCs. Between them, tight intercellular junctions were formed by means of point desmosomes. CONCLUSIONS Our qualitative TEM observations indicate a key role of T-HSCs in liver fibrogenesis in pediatric AIH, with the essential involvement of activated KCs/MPs that directly adhere to them. Tight intercellular junctions, being the ultrastructural exponent of the specific cellular mechanisms of the crosstalk between NPCs, can play a vital role in hepatic collagen fibroplasia. A better understanding of HSC population morphology at the ultrastructural level in AIH seems important not only to improve the disease morphological diagnostics but to also provide new insights into therapeutic interventions for the phenomenon of liver fibrogenesis.
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Affiliation(s)
- Joanna Maria Łotowska
- Department of Medical Pathomorphology, Faculty of Medicine with the Division of Dentistry and Division of Medical Education in English, Medical University of Bialystok, 15-269 Bialystok, Poland
- Correspondence: (J.M.Ł.); (P.S.)
| | - Maria Elżbieta Sobaniec-Łotowska
- Department of Medical Pathomorphology, Faculty of Medicine with the Division of Dentistry and Division of Medical Education in English, Medical University of Bialystok, 15-269 Bialystok, Poland
| | - Anna Bobrus-Chociej
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Faculty of Medicine with the Division of Dentistry and Division of Medical Education in English, Medical University of Bialystok, 15-274 Bialystok, Poland
| | - Piotr Sobaniec
- Department of Pediatric Neurology, Faculty of Medicine with the Division of Dentistry and Division of Medical Education in English, Medical University of Bialystok, 15-274 Bialystok, Poland
- Correspondence: (J.M.Ł.); (P.S.)
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20
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Cho SS, Yang JH, Lee JH, Baek JS, Ku SK, Cho IJ, Kim KM, Ki SH. Ferroptosis contribute to hepatic stellate cell activation and liver fibrogenesis. Free Radic Biol Med 2022; 193:620-637. [PMID: 36370962 DOI: 10.1016/j.freeradbiomed.2022.11.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/04/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022]
Abstract
Ferroptosis is a widely known regulator of cell death in connection with the redox state as a consequence of the depletion of glutathione or accumulation of lipid peroxidation. Hepatic stellate cells (HSCs) play a pivotal role in the progression of hepatic fibrosis by increasing the production and secretion of the extracellular matrix. However, the role of ferroptosis in HSC activation and liver fibrogenesis has not been clearly elucidated. The ferroptosis inducer RAS-selective lethal 3 (RSL3) or erastin treatment in HSCs caused cell death. This effect was suppressed only after exposure to ferroptosis inhibitors. We observed induction of ferroptosis by RSL3 treatment in HSCs supported by decreased glutathione peroxidase 4, glutathione deficiency, reactive oxygen species generation, or lipid peroxidation. Interestingly, RSL3 treatment upregulated the expression of plasminogen activator inhibitor-1, a representative fibrogenic marker of HSCs. In addition, treatment with ferroptosis-inducing compounds increased c-JUN phosphorylation and activator protein 1 luciferase activity but did not alter Smad phosphorylation and Smad-binding element luciferase activity. Chronic administration of iron dextran to mice causes ferroptosis of liver in vivo. The expression of fibrosis markers, such as alpha-smooth muscle actin and plasminogen activator inhibitor-1, was increased in the livers of mice with iron accumulation. Hepatic injury accompanying liver fibrosis was observed based on the levels of alanine aminotransferase, aspartate aminotransferase, and hematoxylin and eosin staining. Furthermore, we found that both isolated primary hepatocyte and HSCs undergo ferroptosis. Consistently, cirrhotic liver tissue of patients indicated glutathione peroxidase 4 downregulation in fibrotic region. In conclusion, our results suggest that ferroptosis contribute to HSC activation and the progression of hepatic fibrosis.
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Affiliation(s)
- Sam Seok Cho
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Ji Hye Yang
- College of Korean Medicine, Dongshin University, Naju, Jeollanam-do, 58245, Republic of Korea
| | - Ji Hyun Lee
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Jin Sol Baek
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Sae Kwang Ku
- College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, 38610, Republic of Korea
| | - Il Je Cho
- College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, 38610, Republic of Korea
| | - Kyu Min Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea; Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju, 61452, Republic of Korea.
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.
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Shao J, Ge T, Tang C, Wang G, Pang L, Chen Z. Synergistic anti-inflammatory effect of gut microbiota and lithocholic acid on liver fibrosis. Inflamm Res 2022; 71:1389-1401. [DOI: 10.1007/s00011-022-01629-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 08/17/2022] [Accepted: 08/22/2022] [Indexed: 11/09/2022] Open
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22
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Li J, Yan H, Xiang R, Yang W, Ye J, Yin R, Yang J, Chi Y. ATP Secretion and Metabolism in Regulating Pancreatic Beta Cell Functions and Hepatic Glycolipid Metabolism. Front Physiol 2022; 13:918042. [PMID: 35800345 PMCID: PMC9253475 DOI: 10.3389/fphys.2022.918042] [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: 04/12/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetes (DM), especially type 2 diabetes (T2DM) has become one of the major diseases severely threatening public health worldwide. Islet beta cell dysfunctions and peripheral insulin resistance including liver and muscle metabolic disorder play decisive roles in the pathogenesis of T2DM. Particularly, increased hepatic gluconeogenesis due to insulin deficiency or resistance is the central event in the development of fasting hyperglycemia. To maintain or restore the functions of islet beta cells and suppress hepatic gluconeogenesis is crucial for delaying or even stopping the progression of T2DM and diabetic complications. As the key energy outcome of mitochondrial oxidative phosphorylation, adenosine triphosphate (ATP) plays vital roles in the process of almost all the biological activities including metabolic regulation. Cellular adenosine triphosphate participates intracellular energy transfer in all forms of life. Recently, it had also been revealed that ATP can be released by islet beta cells and hepatocytes, and the released ATP and its degraded products including ADP, AMP and adenosine act as important signaling molecules to regulate islet beta cell functions and hepatic glycolipid metabolism via the activation of P2 receptors (ATP receptors). In this review, the latest findings regarding the roles and mechanisms of intracellular and extracellular ATP in regulating islet functions and hepatic glycolipid metabolism would be briefly summarized and discussed.
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Affiliation(s)
- Jing Li
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Han Yan
- Key Laboratory of Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Rui Xiang
- Key Laboratory of Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Weili Yang
- Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jingjing Ye
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing, China
- Key Laboratory of Trauma and Neural Regeneration (Peking University), National Center for Trauma Medicine, Trauma Medicine Center, Peking University People’s Hospital, Beijing, China
| | - Ruili Yin
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Disease, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Jichun Yang
- Key Laboratory of Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- *Correspondence: Jichun Yang, ; Yujing Chi,
| | - Yujing Chi
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing, China
- *Correspondence: Jichun Yang, ; Yujing Chi,
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23
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Feng X, Cheng Q, Fang L, Liu W, Liu L, Sun C, Lu Z, Li G, Gu R. Corn oligopeptides inhibit Akt/
NF‐κB
signaling pathway and inflammatory factors to ameliorate
CCl
4
‐induced hepatic fibrosis in mice. J Food Biochem 2022; 46:e14162. [DOI: 10.1111/jfbc.14162] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 03/09/2022] [Accepted: 03/11/2022] [Indexed: 01/17/2023]
Affiliation(s)
- Xiao‐Wen Feng
- Beijing Engineering Research Center of Protein and Functional Peptides China National Research Institute of Food and Fermentation Industries Beijing People’s Republic of China
| | - Qing‐Li Cheng
- Beijing Engineering Research Center of Protein and Functional Peptides China National Research Institute of Food and Fermentation Industries Beijing People’s Republic of China
| | - Lei Fang
- Beijing Engineering Research Center of Protein and Functional Peptides China National Research Institute of Food and Fermentation Industries Beijing People’s Republic of China
| | - Wen‐Ying Liu
- Beijing Engineering Research Center of Protein and Functional Peptides China National Research Institute of Food and Fermentation Industries Beijing People’s Republic of China
- Engineering Laboratory for Agro Biomass Recycling & Valorizing, College of Engineering China Agricultural University Beijing People’s Republic of China
| | - Liang‐Wei Liu
- Beijing Engineering Research Center of Protein and Functional Peptides China National Research Institute of Food and Fermentation Industries Beijing People’s Republic of China
- College of Food Science Northeast Agricultural University Harbin People’s Republic of China
| | - Chuan‐Qiang Sun
- Beijing Engineering Research Center of Protein and Functional Peptides China National Research Institute of Food and Fermentation Industries Beijing People’s Republic of China
- College of Food Science Northeast Agricultural University Harbin People’s Republic of China
| | - Zhi‐Hao Lu
- Beijing Engineering Research Center of Protein and Functional Peptides China National Research Institute of Food and Fermentation Industries Beijing People’s Republic of China
| | - Guo‐Ming Li
- Beijing Engineering Research Center of Protein and Functional Peptides China National Research Institute of Food and Fermentation Industries Beijing People’s Republic of China
| | - Rui‐Zeng Gu
- Beijing Engineering Research Center of Protein and Functional Peptides China National Research Institute of Food and Fermentation Industries Beijing People’s Republic of China
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24
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Kamm DR, McCommis KS. Hepatic stellate cells in physiology and pathology. J Physiol 2022; 600:1825-1837. [PMID: 35307840 PMCID: PMC9012702 DOI: 10.1113/jp281061] [Citation(s) in RCA: 133] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 02/04/2022] [Indexed: 11/08/2022] Open
Abstract
Hepatic stellate cells (HSCs) comprise a minor cell population in the liver but serve numerous critical functions in the normal liver and in response to injury. HSCs are primarily known for their activation upon liver injury and for producing the collagen-rich extracellular matrix in liver fibrosis. In the absence of liver injury, HSCs reside in a quiescent state, in which their main function appears to be the storage of retinoids or vitamin A-containing metabolites. Less appreciated functions of HSCs include amplifying the hepatic inflammatory response and expressing growth factors that are critical for liver development and both the initiation and termination of liver regeneration. Recent single-cell RNA sequencing studies have corroborated earlier studies indictaing that HSC activation involves a diverse array of phenotypic alterations and identified unique HSC populations. This review serves to highlight these many functions of HSCs, and to briefly describe the recent genetic tools that will help to thoroughly investigate the role of HSCs in hepatic physiology and pathology.
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Affiliation(s)
- Dakota R. Kamm
- Department of Biochemistry & Molecular Biology Saint Louis University School of Medicine St. Louis MO
| | - Kyle S. McCommis
- Department of Biochemistry & Molecular Biology Saint Louis University School of Medicine St. Louis MO
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25
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Nie X, Yu Q, Li L, Yi M, Wu B, Huang Y, Zhang Y, Han H, Yuan X. Kinsenoside Protects Against Radiation-Induced Liver Fibrosis via Downregulating Connective Tissue Growth Factor Through TGF-β1 Signaling. Front Pharmacol 2022; 13:808576. [PMID: 35126163 PMCID: PMC8814438 DOI: 10.3389/fphar.2022.808576] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/03/2022] [Indexed: 12/25/2022] Open
Abstract
Radiation-induced liver fibrosis (RILF) is a serious complication of the radiotherapy of liver cancer, which lacks effective prevention and treatment measures. Kinsenoside (KD) is a monomeric glycoside isolated from Anoectochilus roxburghii, which has been reported to show protective effect on the early progression of liver fibrosis. However, the role of KD in affecting RILF remains unknown. Here, we found that KD alleviated RILF via downregulating connective tissue growth factor (CTGF) through TGF-β1 signaling. Sprague-Dawley rats were administered with 20 mg/kg KD per day for 8 weeks after a single 30Gy irradiation on the right part of liver, and tumor-bearing nude mice were administered with 30 mg/kg KD per day after a single fraction of 10Gy on the tumor inoculation site. Twenty-four weeks postirradiation, we found that the administration of KD after irradiation resulted in decreased expression of α-SMA and fibronectin in the liver tissue while had no adverse effect on the tumor radiotherapy. Besides, KD inhibited the activation of hepatic stellate cells (HSCs) postirradiation via targeting CTGF as indicated by the transcriptome sequencing. Results of the pathway enrichment and immunohistochemistry suggested that KD reduced the expression of TGF-β1 protein after radiotherapy, and exogenous TGF-β1 induced HSCs to produce α-SMA and other fibrosis-related proteins. The content of activated TGF-β1 in the supernatant decreased after treatment with KD. In addition, KD inhibited the expression of the fibrosis-related proteins by regulating the TGF-β1/Smad/CTGF pathway, resulting in the intervention of liver fibrosis. In conclusion, this study revealed that KD alleviated RILF through the regulation of TGFβ1/Smad/CTGF pathway with no side effects on the tumor therapy. KD, in combination with blocking the TGF-β1 pathway and CTGF molecule or not, may become the innovative and effective treatment for RILF.
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Affiliation(s)
- Xiaoqi Nie
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- Department of Dermatology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Qianqian Yu
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Long Li
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Minxiao Yi
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Bili Wu
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yongbiao Huang
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yonghui Zhang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hu Han
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Hu Han, ; Xianglin Yuan,
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Hu Han, ; Xianglin Yuan,
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26
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Vaspin attenuates steatosis-induced fibrosis via GRP78 receptor by targeting AMPK signaling pathway. J Physiol Biochem 2022; 78:185-197. [PMID: 35001345 DOI: 10.1007/s13105-021-00852-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/13/2021] [Indexed: 12/13/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that is rapidly becoming a public health problem. An imbalance in lipid distribution to the hepatocytes and metabolism causes hepatocyte steatosis. Vaspin is a newly discovered adipokine that has been linked to a variety of metabolic disorders. The effects of vaspin on steatosis and fibrosis pathogenesis and related mechanisms are unclear. Thus, this study investigated the molecular mechanism of vaspin on hepatocyte steatosis and fibrosis. HepG2 cells were treated with 1.2 mM free fatty acid and the intracellular lipid values were measured by flow cytometry and Nile red assay. RT-qPCR was used to assess the effect of vaspin and blocking of the GRP78 receptor on the expression of lipogenesis, oxidation, uptake, and secretion of fatty acid (FA), as well as AMPK activity. In co-cultured HepG2 and LX-2 cell lines, the expression of main proteins of hepatocyte fibrosis was analyzed using Western blot analysis. In the HepG2 cell line, we discovered that vaspin increased oxidation, FA secretion and gene expression, and AMPK activity and decreased lipogenesis and FA uptake and gene expression. Western blot analysis in co-cultured HepG2 and LX-2 cell lines showed that α-SMA and TGF-β1 protein expression decreased. The data demonstrated that vaspin acts as a novel regulator of hepatocyte steatosis through the GRP78 receptor, effectively reducing hepatocyte fibrosis through AMPK activation and decreasing NF-κB gene expression.
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27
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Delgado ME, Cárdenas BI, Farran N, Fernandez M. Metabolic Reprogramming of Liver Fibrosis. Cells 2021; 10:3604. [PMID: 34944111 PMCID: PMC8700241 DOI: 10.3390/cells10123604] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/13/2021] [Accepted: 12/17/2021] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is an excessive and imbalanced deposition of fibrous extracellular matrix (ECM) that is associated with the hepatic wound-healing response. It is also the common mechanism that contributes to the impairment of the liver function that is observed in many chronic liver diseases (CLD). Despite the efforts, no effective therapy against fibrosis exists yet. Worryingly, due to the growing obesity pandemic, fibrosis incidence is on the rise. Here, we aim to summarize the main components and mechanisms involved in the progression of liver fibrosis, with special focus on the metabolic regulation of key effectors of fibrogenesis, hepatic stellate cells (HSCs), and their role in the disease progression. Hepatic cells that undergo metabolic reprogramming require a tightly controlled, fine-tuned cellular response, allowing them to meet their energetic demands without affecting cellular integrity. Here, we aim to discuss the role of ribonucleic acid (RNA)-binding proteins (RBPs), whose dynamic nature being context- and stimuli-dependent make them very suitable for the fibrotic situation. Thus, we will not only summarize the up-to-date literature on the metabolic regulation of HSCs in liver fibrosis, but also on the RBP-dependent post-transcriptional regulation of this metabolic switch that results in such important consequences for the progression of fibrosis and CLD.
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Affiliation(s)
- M. Eugenia Delgado
- IDIBAPS Biomedical Research Institute, University of Barcelona, 08036 Barcelona, Spain; (B.I.C.); (N.F.)
| | | | | | - Mercedes Fernandez
- IDIBAPS Biomedical Research Institute, University of Barcelona, 08036 Barcelona, Spain; (B.I.C.); (N.F.)
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28
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Hernández-Aquino E, Quezada-Ramírez MA, Silva-Olivares A, Ramos-Tovar E, Flores-Beltrán RE, Segovia J, Shibayama M, Muriel P. Curcumin downregulates Smad pathways and reduces hepatic stellate cells activation in experimental fibrosis. Ann Hepatol 2021; 19:497-506. [PMID: 32673649 DOI: 10.1016/j.aohep.2020.05.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 05/06/2020] [Accepted: 05/28/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Curcumin, a polyphenol, is a natural compound that has been widely studied as a hepatoprotector; however, only a few studies have examined its ability to reduce fibrosis in previously established cirrhosis. The objective of this study was to investigate whether curcumin could reduce carbon tetrachloride (CCl4)-induced fibrosis and if so, to determine the action mechanisms involved in the reduction process. MATERIALS AND METHODS CCl4 was administered to male Wistar rats (400 mg/kg, three times a week, i. p.) for 12 weeks; curcumin (100 mg/kg body weight twice per day, p. o.) was administered from week 9-12 of CCl4 treatment. Biochemical markers of hepatic injury and oxidative stress were evaluated. Hematoxylin and eosin, Masson's trichrome stains, transmission electron microscopy; immunohistochemistry, and zymography assays were carried out. Moreover, Smad3 and α-SMA mRNA and protein levels were studied. Western blotting by TGF-β, CTGF, Col-I, MMP-13, NF-κB, IL-1, IL-10, Smad7, pSmad3, and pJNK proteins was developed. RESULTS AND CONCLUSIONS Curcumin reduced liver damage, oxidative stress, fibrosis, and restored normal activity of MMP-9 and MMP-2. Besides, curcumin restored NF-κB, IL-1, IL-10, TGF-β, CTGF, Col-I, MMP-13, and Smad7 protein levels. On the other hand, curcumin decreased JNK and Smad3 phosphorylation. Furthermore, curcumin treatment decreased α-SMA and Smad3 protein and mRNA levels. Curcumin normalized GSH, and NF-κB, JNK-Smad3, and TGF-β-Smad3 pathways, leading to a decrement in activated hepatic stellate cells, thereby producing its antifibrotic effects.
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Affiliation(s)
- Erika Hernández-Aquino
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional, Mexico City, Mexico
| | | | | | | | - Rosa E Flores-Beltrán
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional, Mexico City, Mexico
| | - José Segovia
- Department of Physiology, Biophysics and Neurosciences, Cinvestav-IPN, Mexico City, Mexico
| | - Mineko Shibayama
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Mexico City, Mexico
| | - Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional, Mexico City, Mexico.
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29
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Sultana H, Komai M, Shirakawa H. The Role of Vitamin K in Cholestatic Liver Disease. Nutrients 2021; 13:nu13082515. [PMID: 34444675 PMCID: PMC8400302 DOI: 10.3390/nu13082515] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/14/2021] [Accepted: 07/21/2021] [Indexed: 12/13/2022] Open
Abstract
Vitamin K (VK) is a ligand of the pregnane X receptor (PXR), which plays a critical role in the detoxification of xenobiotics and metabolism of bile acids. VK1 may reduce the risk of death in patients with chronic liver failure. VK deficiency is associated with intrahepatic cholestasis, and is already being used as a drug for cholestasis-induced liver fibrosis in China. In Japan, to treat osteoporosis in patients with primary biliary cholangitis, VK2 formulations are prescribed, along with vitamin D3. Animal studies have revealed that after bile duct ligation-induced cholestasis, PXR knockout mice manifested more hepatic damage than wild-type mice. Ligand-mediated activation of PXR improves biochemical parameters. Rifampicin is a well-known human PXR ligand that has been used to treat intractable pruritus in severe cholestasis. In addition to its anti-cholestatic properties, PXR has anti-fibrotic and anti-inflammatory effects. However, because of the scarcity of animal studies, the mechanism of the effect of VK on cholestasis-related liver disease has not yet been revealed. Moreover, the application of VK in cholestasis-related diseases is controversial. Considering this background, the present review focuses on the effect of VK in cholestasis-related diseases, emphasizing its function as a modulator of PXR.
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Affiliation(s)
- Halima Sultana
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (H.S.); (M.K.)
| | - Michio Komai
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (H.S.); (M.K.)
| | - Hitoshi Shirakawa
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (H.S.); (M.K.)
- International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan
- Correspondence: ; Tel.: +81-22-757-4402
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30
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Yu G, Mu H, Zhou H, Fang F, Cui Y, Wu Q, Xiong Q, Li H. MicroRNA-361 suppresses the biological processes of hepatic stellate cells in HBV-relative hepatic fibrosis by NF-kappaB p65. Cells Dev 2021; 167:203711. [PMID: 34216805 DOI: 10.1016/j.cdev.2021.203711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 10/22/2020] [Accepted: 06/17/2021] [Indexed: 11/15/2022]
Abstract
BACKGROUND This research study explores the effect of miR-361 on the activation of immortalized human and mice hepatic stallate cells (HSCs). METHODS 10 liver specimens from healthy volunteers and 20 HBV-relevant HCC tissues from patients. The expressions of miR-361 in HCC patients, HBx transgenic mice, HCC cell lines expressing HBx, and human and mouse HSCs were detected. The influences of miR-361 on the biological processes of HSCs were explored. The target of miR-361 and the effects of p65 on miR-361 were also verified and analyzed. RESULTS Microarray analysis and quantitative real-time PCR (Q-PCR) indicated that miR-361 was decreased in HBV-relevant HCC tissues, HBx transgenic mice, HBx-transfected HepG2 cells, human and mice HSCs. Bio-informatics prediction and dual-luciferase reporter assay (DLRA) suggested that nuclear factor kappa B subunit p65 gene was a target of miR-361. Furthermore, this study showed that p65 expression was upregulated in the HBV-relevant HCC tissues, HBx transgenic mice, HBx-transfected HepG2 cells. MiR-361 upregulation also caused a reduction in p65 expression in both human and mice HSCs. In addition, p65 overexpression counteracted the effect of miR-361 in human and mice HSCs' biological processes. These findings reveal a latent mechanism underlying p65 modulation by miR-361 which is capable of initiating HSC growth and migration. CONCLUSION miR-361 is potentially functioning as a potent marker for HBV-relevant HCC development or liver fibrosis (LF) progression.
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Affiliation(s)
- Ge Yu
- Department of Hepatobiliary Cancer, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin 300202, China
| | - Han Mu
- Department of Hepatobiliary Cancer, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin 300202, China
| | - Hongyuan Zhou
- Department of Hepatobiliary Cancer, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin 300202, China
| | - Feng Fang
- Department of Hepatobiliary Cancer, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin 300202, China
| | - Yunlong Cui
- Department of Hepatobiliary Cancer, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin 300202, China
| | - Qiang Wu
- Department of Hepatobiliary Cancer, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin 300202, China
| | - Qingqing Xiong
- Department of Hepatobiliary Cancer, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin 300202, China.
| | - Huikai Li
- Department of Hepatobiliary Cancer, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin 300202, China.
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31
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Yang J, Xu C, Wu M, Wu Y, Jia X, Zhou C, Zhang X, Ge S, Li Z, Zhang L. MicroRNA-124 inhibits hepatic stellate cells inflammatory cytokines secretion by targeting IQGAP1 through NF-κB pathway. Int Immunopharmacol 2021; 95:107520. [PMID: 33743313 DOI: 10.1016/j.intimp.2021.107520] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/17/2021] [Accepted: 02/17/2021] [Indexed: 01/01/2023]
Abstract
Liver fibrosis is a health concern that leads to organ failure mediated via production of inflammatory cytokines and fibrotic biomarkers. To date, there was no direct approved antifibrotic therapy, and current treatment was mainly the removal of the causative factor. Recent studies demonstrated that aberrant expression of miR-124 was involved in the progression of various liver diseases including hepatocellular carcinoma (HCC). However, whether miR-124 could function as a transcriptional regulator in the inflammatory cytokines secretion of liver fibrosis remains unclear. In this study, we demonstrated that the expression of miR-124 was downregulated in liver fibrosis tissues and TNF-α-induced LX-2 cells, concomitant with the upregulated expression of IQGAP1, suggesting that miR-124 and IQGAP1 might be associated with the development of inflammation in liver fibrosis. Therefore, we demonstrated that the overexpression of miR-124 and knockdown of IQGAP1 could lead to the downregulation of TNF-α, IL-1β and IL-6. While knockdown of miR-124 or overexpression of IQGAP1 showed reversed results. Moreover, dual luciferase reporter assays demonstrated that miR-124 specifically targeted the 3'-UTR of IQGAP1, and thus inhibited the expression of IQGAP1. Mechanistically, we found that the expression changes of miR-124 and IQGAP1 could be involved in inhibition or activation of NF-κB signaling pathway in response to TNF-α. In conclusion, these results indicated that miR-124 plays a crucial role in TNF-α-induced LX-2 cells via regulating NF-κB signaling pathway.
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Affiliation(s)
- Junfa Yang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Changqing Xu
- The Third People's Hospital of Hefei (Hefei Third Clinical College of Anhui Medical University), Hefei, Anhui Province, China
| | - Maomao Wu
- Department of Pharmacy, Anhui Chest Hospital, Hefei, Anhui Province, China
| | - Ying Wu
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Xiaodi Jia
- Fujian Normal University, Fuzhou 350007, China
| | - Chang Zhou
- School of Basic Medical Science, Anhui Medical University, Hefei 230032, China
| | - Xianzheng Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Shenglin Ge
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
| | - Zeng Li
- School of Pharmacy, Anhui Medical University, Hefei 230032, China.
| | - Lingling Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China.
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Fallowfield JA, Jimenez-Ramos M, Robertson A. Emerging synthetic drugs for the treatment of liver cirrhosis. Expert Opin Emerg Drugs 2021; 26:149-163. [PMID: 33856246 DOI: 10.1080/14728214.2021.1918099] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: The number of deaths and prevalent cases of cirrhosis are increasing worldwide, but there are no licensed antifibrotic or pro-regenerative medicines and liver transplantation is a limited resource. Cirrhosis is characterized by extreme liver fibrosis, organ dysfunction, and complications related to portal hypertension. Advances in our understanding of liver fibrosis progression and regression following successful etiological therapy betray vulnerabilities in common and disease-specific mechanisms that could be targeted pharmacologically.Area covered: This review summarizes the cellular and molecular pathogenesis of cirrhosis as a preface to discussion of the current drug development landscape. The dominant indication for global pharma R&D pipelines is cirrhosis related to nonalcoholic steatohepatitis (NASH). We searched Clinicaltrials.gov, GlobalData, Pharmaprojects and PubMed for pertinent information on emerging synthetic drugs for cirrhosis, with a focus on compounds listed in phase 2 and phase 3 trials.Expert opinion: Although cirrhosis can regress following successful etiological treatment, there are no specific antifibrotic or pro-regenerative drugs approved for this condition. Obstacles to drug development in cirrhosis include intrinsic biological factors, a heterogeneous patient population, and lack of acceptable surrogate endpoints. Nevertheless, several synthetic drugs are being evaluated in clinical trials and the NASH field is rapidly embracing a drug combination approach.
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Hepatic Stellate Cell Activation and Inactivation in NASH-Fibrosis-Roles as Putative Treatment Targets? Biomedicines 2021; 9:biomedicines9040365. [PMID: 33807461 PMCID: PMC8066583 DOI: 10.3390/biomedicines9040365] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic fibrosis is the primary predictor of mortality in patients with non-alcoholic steatohepatitis (NASH). In this process, the activated hepatic stellate cells (HSCs) constitute the principal cells responsible for the deposition of a fibrous extracellular matrix, thereby driving the hepatic scarring. HSC activation, migration, and proliferation are controlled by a complex signaling network involving growth factors, lipotoxicity, inflammation, and cellular stress. Conversely, the clearance of activated HSCs is a prerequisite for the resolution of the extracellular fibrosis. Hence, pathways regulating the fate of the HSCs may represent attractive therapeutic targets for the treatment and prevention of NASH-associated hepatic fibrosis. However, the development of anti-fibrotic drugs for NASH patients has not yet resulted in clinically approved therapeutics, underscoring the complex biology and challenges involved when targeting the intricate cellular signaling mechanisms. This narrative review investigated the mechanisms of activation and inactivation of HSCs with a focus on NASH-associated hepatic fibrosis. Presenting an updated overview, this review highlights key cellular pathways with potential value for the development of future treatment modalities.
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Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol 2021; 18:151-166. [PMID: 33128017 DOI: 10.1038/s41575-020-00372-7] [Citation(s) in RCA: 1100] [Impact Index Per Article: 275.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2020] [Indexed: 01/18/2023]
Abstract
Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate the fibrous scar. The primary source of these myofibroblasts are the resident hepatic stellate cells. Clinical and experimental liver fibrosis regresses when the causative agent is removed, which is associated with the elimination of these activated myofibroblasts and resorption of the fibrous scar. Understanding the mechanisms of liver fibrosis regression could identify new therapeutic targets to treat liver fibrosis. This Review summarizes studies of the molecular mechanisms underlying the reversibility of liver fibrosis, including apoptosis and the inactivation of hepatic stellate cells, the crosstalk between the liver and the systems that orchestrate the recruitment of bone marrow-derived macrophages (and other inflammatory cells) driving fibrosis resolution, and the interactions between various cell types that lead to the intracellular signalling that induces fibrosis or its regression. We also discuss strategies to target hepatic myofibroblasts (for example, via apoptosis or inactivation) and the myeloid cells that degrade the matrix (for example, via their recruitment to fibrotic liver) to facilitate fibrosis resolution and liver regeneration.
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Affiliation(s)
- Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA.
| | - David Brenner
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
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Wu Z, Huang S, Zheng X, Gu S, Xu Q, Gong Y, Zhang J, Fu B, Tang L. Regulatory long non-coding RNAs of hepatic stellate cells in liver fibrosis (Review). Exp Ther Med 2021; 21:351. [PMID: 33732324 PMCID: PMC7903415 DOI: 10.3892/etm.2021.9782] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 04/29/2020] [Indexed: 12/11/2022] Open
Abstract
Liver fibrosis (LF) is a continuous wound healing process caused by numerous chronic hepatic diseases and poses a major threat to human health. Activation of hepatic stellate cells (HSCs) is a critical event in the development of hepatic fibrosis. Long non-coding RNAs (lncRNAs) that are involved in HSC activation, participate in the development of LF and are likely to be therapeutic targets for LF. In the present review, the cellular signaling pathways of LF with respect to HSCs were discussed. In particular, this present review highlighted the current knowledge on the role of lncRNAs in activating or inhibiting LF, revealing lncRNAs that are likely to be biomarkers or therapeutic targets for LF. Additional studies should be performed to elucidate the potential of lncRNAs in the diagnosis and prognosis of LF and to provide novel therapeutic approaches for the reversion of LF.
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Affiliation(s)
- Zhengjie Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Shunmei Huang
- Department of Geriatrics, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Xiaoqin Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Silan Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Qiaomai Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Yiwen Gong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Jiaying Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Bin Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Lingling Tang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
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Cytoplasmic vacuolation with endoplasmic reticulum stress directs sorafenib induced non-apoptotic cell death in hepatic stellate cells. Sci Rep 2021; 11:3089. [PMID: 33542321 PMCID: PMC7862314 DOI: 10.1038/s41598-021-82381-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 01/19/2021] [Indexed: 02/06/2023] Open
Abstract
The activated hepatic stellate cells (HSCs) are the major cells that secrete the ECM proteins and drive the pathogenesis of fibrosis in chronic liver disease. Targeting of HSCs by modulating their activation and proliferation has emerged as a promising approach in the development of anti-fibrotic therapy. Sorafenib, a multi-kinase inhibitor has shown anti-fibrotic properties by inhibiting the survival and proliferation of HSCs. In present study we investigated sorafenib induced cytoplasmic vacuolation mediated decreased cell viability of HSCs in dose and time dependent manner. In this circumstance, sorafenib induces ROS and ER stress in HSCs without involvement of autophagic signals. The protein synthesis inhibitor cycloheximide treatment significantly decreased the sorafenib-induced cytoplasmic vacuolation with increasing cell viability. Antioxidant human serum albumin influences the viability of HSCs by reducing sorafenib induced vacuolation and cell death. However, neither caspase inhibitor Z-VAD-FMK nor autophagy inhibitor chloroquine could rescue the HSCs from sorafenib-induced cytoplasmic vacuolation and cell death. Using TEM and ER organelle tracker, we conclude that the cytoplasmic vacuoles are due to ER dilation. Sorafenib treatment induces calreticulin and GPR78, and activates IRE1α-XBP1s axis of UPR pathway, which eventually trigger the non-apoptotic cell death in HSCs. This study provides a notable mechanistic insight into the ER stress directed non-apoptotic cell death with future directions for the development of efficient anti-fibrotic therapeutic strategies.
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Worrell JC, Leslie J, Smith GR, Zaki MYW, Paish HL, Knox A, James ML, Cartwright TN, O'Reilly S, Kania G, Distler O, Distler JHW, Herrick AL, Jeziorska M, Borthwick LA, Fisher AJ, Mann J, Mann DA, Oakley F. cRel expression regulates distinct transcriptional and functional profiles driving fibroblast matrix production in systemic sclerosis. Rheumatology (Oxford) 2021; 59:3939-3951. [PMID: 32725139 DOI: 10.1093/rheumatology/keaa272] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 04/24/2020] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES NF-κB regulates genes that control inflammation, cell proliferation, differentiation and survival. Dysregulated NF-κB signalling alters normal skin physiology and deletion of cRel limits bleomycin-induced skin fibrosis. This study investigates the role of cRel in modulating fibroblast phenotype in the context of SSc. METHODS Fibrosis was assessed histologically in mice challenged with bleomycin to induce lung or skin fibrosis. RNA sequencing and pathway analysis was performed on wild type and Rel-/- murine lung and dermal fibroblasts. Functional assays examined fibroblast proliferation, migration and matrix production. cRel overexpression was investigated in human dermal fibroblasts. cRel immunostaining was performed on lung and skin tissue sections from SSc patients and non-fibrotic controls. RESULTS cRel expression was elevated in murine lung and skin fibrosis models. Rel-/- mice were protected from developing pulmonary fibrosis. Soluble collagen production was significantly decreased in fibroblasts lacking cRel while proliferation and migration of these cells was significantly increased. cRel regulates genes involved in extracellular structure and matrix organization. Positive cRel staining was observed in fibroblasts in human SSc skin and lung tissue. Overexpression of constitutively active cRel in human dermal fibroblasts increased expression of matrix genes. An NF-κB gene signature was identified in diffuse SSc skin and nuclear cRel expression was elevated in SSc skin fibroblasts. CONCLUSION cRel regulates a pro-fibrogenic transcriptional programme in fibroblasts that may contribute to disease pathology. Targeting cRel signalling in fibroblasts of SSc patients could provide a novel therapeutic avenue to limit scar formation in this disease.
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Affiliation(s)
- Julie C Worrell
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne
| | - Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne
| | - Graham R Smith
- Bioinformatics Support Unit, Newcastle University, Newcastle upon Tyne, UK
| | - Marco Y W Zaki
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne.,Biochemistry Department, Faculty of Pharmacy, Minia University, Egypt
| | - Hannah L Paish
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne
| | - Amber Knox
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne
| | - Michelle L James
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne
| | - Tyrell N Cartwright
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne
| | - Steven O'Reilly
- Department of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK
| | - Gabriela Kania
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
| | - Oliver Distler
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
| | - Jörg H W Distler
- Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Ariane L Herrick
- Centre for Musculoskeletal Research, The University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester
| | - Maria Jeziorska
- Division of Cardiovascular Sciences, University of Manchester, Manchester
| | - Lee A Borthwick
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne
| | - Andrew J Fisher
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne.,Institute of Transplantation, The Freeman Hospital, High Heaton, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Jelena Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne
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Emerging physiological and pathological roles of MeCP2 in non-neurological systems. Arch Biochem Biophys 2021; 700:108768. [PMID: 33485848 DOI: 10.1016/j.abb.2021.108768] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 01/08/2021] [Accepted: 01/14/2021] [Indexed: 02/08/2023]
Abstract
Numerous neurological and non-neurological disorders are associated with dysfunction of epigenetic modulators, and methyl CpG binding protein 2 (MeCP2) is one of such proteins. Initially identified as a transcriptional repressor, MeCP2 specifically binds to methylated DNA, and mutations of MeCP2 have been shown to cause Rett syndrome (RTT), a severe neurological disorder. Recently, accumulating evidence suggests that ubiquitously expressed MeCP2 also plays a central role in non-neurological disorders including cardiac dysfunction, liver injury, respiratory disorders, urological dysfunction, adipose tissue metabolism disorders, movement abnormality and inflammatory responses in a DNA methylation dependent or independent manner. Despite significant progresses in our understanding of MeCP2 over the last few decades, there is still a considerable knowledge gap to translate the in vitro and in vivo experimental findings into therapeutic interventions. In this review, we provide a synopsis of the role of MeCP2 in the pathophysiology of non-neurological disorders, MeCP2-based research directions and therapeutic strategies for non-neurological disorders are also discussed.
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Zhang X, Zhang X, Huang W, Ge X. The role of heat shock proteins in the regulation of fibrotic diseases. Biomed Pharmacother 2020; 135:111067. [PMID: 33383375 DOI: 10.1016/j.biopha.2020.111067] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 11/08/2020] [Accepted: 11/20/2020] [Indexed: 12/29/2022] Open
Abstract
Heat shock proteins (HSPs) are key players to restore cell homeostasis and act as chaperones by assisting the folding and assembly of newly synthesized proteins and preventing protein aggregation. Recently, evidence has been accumulating that HSPs have been proven to have other functions except for the classical molecular chaperoning in that they play an important role in a wider range of fibrotic diseases via modulating cytokine induction and inflammation response, including lung fibrosis, liver fibrosis, and idiopathic pulmonary fibrosis. The recruitment of inflammatory cells, a large number of secretion of pro-fibrotic cytokines such as transforming growth factor-β1 (TGF-β1) and increased apoptosis, oxidative stress, and proteasomal system degradation are all events occurring during fibrogenesis, which might be associated with HSPs. However, their role on fibrotic process is not yet fully understood. In this review, we discuss new discoveries regarding the involvement of HSPs in the regulation of organ and tissue fibrosis, and note recent findings suggesting that HSPs may be a promising therapeutic target for improving the current frustrating outcome of fibrotic disorders.
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Affiliation(s)
- Xiaoling Zhang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, 226019, PR China.
| | - Xiaoyan Zhang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China
| | - Wenmin Huang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China
| | - Xiaoqun Ge
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001, PR China; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.
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40
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Sun H, Feng J, Tang L. Function of TREM1 and TREM2 in Liver-Related Diseases. Cells 2020; 9:2626. [PMID: 33297569 PMCID: PMC7762355 DOI: 10.3390/cells9122626] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/01/2020] [Accepted: 12/03/2020] [Indexed: 02/07/2023] Open
Abstract
TREM1 and TREM2 are members of the triggering receptors expressed on myeloid cells (TREM) family. Both TREM1 and TREM2 are immunoglobulin superfamily receptors. Their main function is to identify foreign antigens and toxic substances, thereby adjusting the inflammatory response. In the liver, TREM1 and TREM2 are expressed on non-parenchymal cells, such as liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, and cells which infiltrate the liver in response to injury including monocyte-derived macrophages and neutrophils. The function of TREM1 and TREM2 in inflammatory response depends on Toll-like receptor 4. TREM1 mainly augments inflammation during acute inflammation, while TREM2 mainly inhibits chronic inflammation to protect the liver from pathological changes. Chronic inflammation often induces metabolic abnormalities, fibrosis, and tumorigenesis. The above physiological changes lead to liver-related diseases, such as liver injury, nonalcoholic steatohepatitis, hepatic fibrosis, and hepatocellular carcinoma. Here, we review the function of TREM1 and TREM2 in different liver diseases based on inflammation, providing a more comprehensive perspective for the treatment of liver-related diseases.
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Affiliation(s)
- Huifang Sun
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China;
| | - Jianguo Feng
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Liling Tang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China;
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41
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Leslie J, Macia MG, Luli S, Worrell JC, Reilly WJ, Paish HL, Knox A, Barksby BS, Gee LM, Zaki MYW, Collins AL, Burgoyne RA, Cameron R, Bragg C, Xu X, Chung GW, Brown CDA, Blanchard AD, Nanthakumar CB, Karsdal M, Robinson SM, Manas DM, Sen G, French J, White SA, Murphy S, Trost M, Zakrzewski JL, Klein U, Schwabe RF, Mederacke I, Nixon C, Bird T, Teuwen LA, Schoonjans L, Carmeliet P, Mann J, Fisher AJ, Sheerin NS, Borthwick LA, Mann DA, Oakley F. c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis. Nat Metab 2020; 2:1350-1367. [PMID: 33168981 PMCID: PMC7116435 DOI: 10.1038/s42255-020-00306-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 09/30/2020] [Indexed: 02/07/2023]
Abstract
Fibrosis is a common pathological feature of chronic disease. Deletion of the NF-κB subunit c-Rel limits fibrosis in multiple organs, although the mechanistic nature of this protection is unresolved. Using cell-specific gene-targeting manipulations in mice undergoing liver damage, we elucidate a critical role for c-Rel in controlling metabolic changes required for inflammatory and fibrogenic activities of hepatocytes and macrophages and identify Pfkfb3 as the key downstream metabolic mediator of this response. Independent deletions of Rel in hepatocytes or macrophages suppressed liver fibrosis induced by carbon tetrachloride, while combined deletion had an additive anti-fibrogenic effect. In transforming growth factor-β1-induced hepatocytes, c-Rel regulates expression of a pro-fibrogenic secretome comprising inflammatory molecules and connective tissue growth factor, the latter promoting collagen secretion from HMs. Macrophages lacking c-Rel fail to polarize to M1 or M2 states, explaining reduced fibrosis in RelΔLysM mice. Pharmacological inhibition of c-Rel attenuated multi-organ fibrosis in both murine and human fibrosis. In conclusion, activation of c-Rel/Pfkfb3 in damaged tissue instigates a paracrine signalling network among epithelial, myeloid and mesenchymal cells to stimulate fibrogenesis. Targeting the c-Rel-Pfkfb3 axis has potential for therapeutic applications in fibrotic disease.
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Affiliation(s)
- Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
| | - Marina García Macia
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Saimir Luli
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Julie C Worrell
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - William J Reilly
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Hannah L Paish
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Amber Knox
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ben S Barksby
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Lucy M Gee
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Marco Y W Zaki
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Amy L Collins
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Rachel A Burgoyne
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Rainie Cameron
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Charlotte Bragg
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Xin Xu
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Git W Chung
- Newcells Biotech, The Biosphere, Newcastle Helix, Newcastle upon Tyne, UK
| | - Colin D A Brown
- Newcells Biotech, The Biosphere, Newcastle Helix, Newcastle upon Tyne, UK
| | - Andrew D Blanchard
- Fibrosis Discovery Performance Unit, Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, UK
| | - Carmel B Nanthakumar
- Fibrosis Discovery Performance Unit, Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, UK
| | - Morten Karsdal
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - Stuart M Robinson
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Derek M Manas
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Gourab Sen
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Jeremy French
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Steven A White
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Sandra Murphy
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Matthias Trost
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Johannes L Zakrzewski
- Center for Discovery and Innovation and John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA
| | - Ulf Klein
- Division of Haematology & Immunology, Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | | | - Ingmar Mederacke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Colin Nixon
- Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK
| | - Tom Bird
- Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
- MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Laure-Anne Teuwen
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Luc Schoonjans
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Jelena Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Andrew J Fisher
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Institute of Transplantation, The Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Neil S Sheerin
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Lee A Borthwick
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
- Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK.
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42
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Li Y, Zhou A, Cui X, Zhang Y, Xie J. 6'"-p-Coumaroylspinosin protects PC12 neuronal cells from acrylamide-induced oxidative stress and apoptosis. J Food Biochem 2020; 44:e13321. [PMID: 32592426 DOI: 10.1111/jfbc.13321] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 05/20/2020] [Accepted: 05/21/2020] [Indexed: 11/29/2022]
Abstract
6'"-p-coumaroylspinosin (P-CS) is a flavonoid isolated from Ziziphi Spinosae Semen (ZSS), whereas, the antioxidative activity has not been reported. Oxidative stress is believed to be one of the main causes of neurodegenerative disorders. In this study, the antioxidative effect of P-CS on PC12 cells was determined. The cells were treated with acrylamide (AA) in the absence or presence of P-CS, and cell apoptosis was analyzed. Interestingly, P-CS pretreatment of the cells could significantly prevent AA-induced cell death, glutathione (GSH) contents decrease, and reactive oxygen species (ROS) overproduction. Further investigation of the molecular mechanism underlying the effect of P-CS on cell apoptosis revealed that P-CS was able to suppress the expression of Bax and Bim induced by AA and inhibit the JNKs pathway. Our findings support a role of P-CS in preventing neuronal cell apoptosis induced by AA, suggesting its therapeutic potential for the treatment of neurodegenerative disorders as a medicinal supplement. PRACTICAL APPLICATIONS: Oxidative stress is believed to cause damage in subcellular organelles, nucleic acids, and alteration in protein aggregation as well as disruption of the signaling cascades associated with aging and apoptosis. A small molecule, non-poisonous natural antioxidant is needed to protect the brain from oxidative stress. Compared with western medicine, natural products carry less risk of adverse effects and are not too expensive, especially for the third-world countries. Furthermore, ZSS could be used to produce or prepare antioxidants, such as P-CS, which has been reported significant anti-oxidative activity in this study.
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Affiliation(s)
- Yaxin Li
- College of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, China.,Tianjin Key Laboratory of Food Biotechnology, Tianjin, China
| | - Aimin Zhou
- Department of Chemistry and Center for Gene Regulation in Health and Diseases, Cleveland State University, Cleveland, OH, USA
| | - Xusheng Cui
- Shijiazhuang Yiling pharmaceutical Co. Ltd, Hebei, China
| | - Yanqing Zhang
- College of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, China.,Tianjin Key Laboratory of Food Biotechnology, Tianjin, China
| | - Junbo Xie
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Shi MJ, Yan XL, Dong BS, Yang WN, Su SB, Zhang H. A network pharmacology approach to investigating the mechanism of Tanshinone IIA for the treatment of liver fibrosis. JOURNAL OF ETHNOPHARMACOLOGY 2020; 253:112689. [PMID: 32101775 DOI: 10.1016/j.jep.2020.112689] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/30/2020] [Accepted: 02/19/2020] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL REVELVANCE Tanshinone IIA (TIIA) is a major component extracted from the traditional herbal medicine salvia miltiorrhiza (Danshen), which activates blood circulation and treats chronic hepatitis and liver fibrosis. However, the underlying molecular mechanism of TIIA against hepatic fibrosis is still largely unknown. AIM OF THE STUDY The present study aimed to evaluate the antifibrotic effects of TIIA in liver fibrosis and investigate its underlying mechanism through network pharmacology-based prediction and experimental verification. MATERIALS AND METHODS In this study, a "TIIA-targets-liver fibrosis" network was constructed by combining the TIIA-specific and hepatic fibrosis-specific targets with protein-protein interactions (PPIS), and network pharmacology was applied to identify the potential targets and mechanisms of TIIA in the treatment of hepatic fibrosis. The antifibrotic effect of TIIA was investigated in CCl4-induced liver fibrosis in rats in vivo and in the human HSC line LX2 in vitro. RESULTS We identified 75 potential targets of TIIA and 1382 targets of liver fibrosis. Subsequently, the 29 target proteins that overlapped between the potential TIIA targets and the liver fibrosis targets indicated that TIIA has potential antifibrotic effects through regulating multiple targets, including c-Jun, c-Myc, CCND1, MMP9 and P65. Pathway and functional enrichment analysis of these putative targets showed that TIIA could regulate the MAPK, PI3K/Akt and Wnt signaling pathways. Consistently, in vivo and in vitro experiments indicated that TIIA attenuated CCl4-induced liver injury and fibrosis and inhibited hepatic stellate cell (HSC) proliferation and activation; these findings were concomitant with the decreased expression of α-smooth muscle actin (α-SMA) and human α2 (I) collagen (COL1A2). Moreover, TIIA remarkably downregulated the expression of c-Jun, c-Myc, MMP9, PI3K and P38 proteins, which were upregulated in CCl4-induced hepatic fibrosis in vivo. TIIA significantly downregulated the expression of c-Jun, p-c-Jun, c-Myc, CCND1, MMP9, P65, P-P65, PI3K and P38 proteins, which were upregulated during HSC activation in vitro. CONCLUSION Our study demonstrated that TIIA could significantly improve liver function, decrease liver injury, alleviate ECM accumulation, and attenuate HSC proliferation and activation, thus exerting an antifibrotic effect. The possible molecular mechanism involved MAPK, Wnt and PI3K/Akt signaling pathways via inhibiting c-Jun, p-c-Jun, c-Myc, CCND1, MMP9, P65, P-P65, PI3K and P38. Overall, our results suggest that TIIA could alleviate liver fibrosis through multiple targets and multiple signaling pathways and provide deep insight into the pharmacological mechanisms of TIIA in the treatment of hepatic fibrosis.
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Affiliation(s)
- Miao-Juan Shi
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiu-Li Yan
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ben-Sheng Dong
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Wen-Na Yang
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Hui Zhang
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Gandhi CR. Pro- and Anti-fibrogenic Functions of Gram-Negative Bacterial Lipopolysaccharide in the Liver. Front Med (Lausanne) 2020; 7:130. [PMID: 32373617 PMCID: PMC7186417 DOI: 10.3389/fmed.2020.00130] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 03/24/2020] [Indexed: 12/14/2022] Open
Abstract
Extensive research performed over several decades has identified cells participating in the initiation and progression of fibrosis, and the numerous underlying inter- and intra-cellular signaling pathways. However, liver fibrosis continues to be a major clinical challenge as the precise targets of treatment are still elusive. Activation of physiologically quiescent perisinusoidal hepatic stellate cells (HSCs) to a myofibroblastic proliferating, contractile and fibrogenic phenotype is a critical event in the pathogenesis of chronic liver disease. Thus, elucidation of the mechanisms of the reversal to quiescence or inhibition of activated HSCs, and/or their elimination via apoptosis has been the focus of intense investigation. Lipopolysaccharide (LPS), a gut-resident Gram-negative bacterial endotoxin, is a powerful pro-inflammatory molecule implicated in hepatic injury, inflammation and fibrosis. In both acute and chronic liver injury, portal venous levels of LPS are elevated due to increased intestinal permeability. LPS, via CD14 and Toll-like receptor 4 (TLR4) and its adapter molecules, stimulates macrophages, neutrophils and several other cell types to produce inflammatory mediators as well as factors that can activate HSCs and stimulate their fibrogenic activity. LPS also stimulates synthesis of pro- and anti-inflammatory cytokines/chemokines, growth mediators and molecules of immune regulation by HSCs. However, LPS was found to arrest proliferation of activated HSCs and to convert them into non-fibrogenic phenotype. Interestingly, LPS can elicit responses in HSCs independent of CD14 and TLR4. Identifying and/or developing non-inflammatory but anti-fibrogenic mimetics of LPS could be relevant for treating liver fibrosis.
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Affiliation(s)
- Chandrashekhar R Gandhi
- Divisions of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Cincinnati VA Medical Center, Cincinnati, OH, United States
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Xia Z, Ding L, Zheng J, Xu Y, Jin W, Sheng X, Wu J. Alginate Suppresses Liver Fibrosis Through the Inhibition of Nuclear Factor-κB Signaling. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:1295-1305. [PMID: 32280199 PMCID: PMC7127827 DOI: 10.2147/dddt.s233665] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 01/08/2020] [Indexed: 01/19/2023]
Abstract
Purpose Liver fibrosis (or liver scarring) is a causative factor for hepatitis, cirrhosis and hepatocellular carcinoma (HCC). Alginate (Agn) isolated from brown algae is known to slow the proliferation of fibroblasts, through the mechanisms of these effects remain undefined. This study explored the benefits of Agn on hepatic health and its associated mechanism(s) of action in hepatic stellate cells (HSC-T6s). Materials and Methods To assess the effects of Agn, HSC-T6s were treated with PDGF and cell proliferation, colony formation, cell migration, cell invasiveness and apoptosis were assessed. Rat models of liver fibrosis were produced through 12-week injections of intraperitoneal (IP) carbon tetrachloride (CCl4). Rats were Agn-treated from weeks 8 to 12, and liver damage was assessed through Masson’s and H & E staining. Gene expression profiles were assayed via RT-PCR, Western blot and commercial ELISA kits. Results Agn reduced the proliferation of HSC-T6s and increased apoptotic rates through the downregulation of the Bcl-2:Bax ratio. Agn also inhibited the invasion and migration of HSC-T6s, prevented ECM deposition, and reduced the occurrence of liver fibrosis in rat models. Agn also prevented IκBα and p65 phosphorylation. Conclusion Agn prevents liver fibrosis through its attenuation of HSC activation and division through the suppression of NF-κB in in vitro and animal models. This highlights how the clinical use of Agn can prevent hepatic fibrosis.
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Affiliation(s)
- Ziqiang Xia
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China
| | - Li Ding
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China
| | - Juzeng Zheng
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China
| | - Yilun Xu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China
| | - Wenyi Jin
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China
| | - Xiong Sheng
- Department of Infectious Diseases, The First Affiliated Hospital of Jiaxing College, Jiaxing 314000, People's Republic of China.,Department of Infectious Diseases, The First Hospital of Jiaxing, Jiaxing 314000, People's Republic of China
| | - Jinming Wu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China
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Atluri K, Brouillette MJ, Seol D, Khorsand B, Sander E, Salem AK, Fredericks D, Petersen E, Smith S, Fowler TP, Martin JA. Sulfasalazine Resolves Joint Stiffness in a Rabbit Model of Arthrofibrosis. J Orthop Res 2020; 38:629-638. [PMID: 31692083 DOI: 10.1002/jor.24499] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 10/06/2019] [Indexed: 02/04/2023]
Abstract
Joint stiffness due to fibrosis/capsule contracture is a seriously disabling complication of articular injury that surgical interventions often fail to completely resolve. Fibrosis/contracture is associated with the abnormal persistence of myofibroblasts, which over-produce and contract collagen matrices. We hypothesized that intra-articular therapy with drugs targeting myofibroblast survival (sulfasalazine), or collagen production (β-aminopropionitrile and cis-hydroxyproline), would reduce joint stiffness in a rabbit model of fibrosis/contracture. Drugs were encapsulated in poly[lactic-co-glycolic] acid pellets and implanted in joints after fibrosis/contracture induction. Capsule α-smooth muscle actin (α-SMA) expression and intimal thickness were evaluated by immunohistochemistry and histomorphometry, respectively. Joint stiffness was quantified by flexion-extension testing. Drawer tests were employed to determine if the drugs induced cruciate ligament laxity. Joint capsule fibroblasts were tested in vitro for contractile activity and α-SMA expression. Stiffness in immobilized joints treated with blank pellets (control) was significantly higher than in non-immobilized, untreated joints (normal) (p = 0.0008), and higher than in immobilized joints treated with sulfasalazine (p = 0.0065). None of the drugs caused significant cruciate ligament laxity. Intimal thickness was significantly lower than control in the normal and sulfasalazine-treated groups (p = 0.010 and 0.025, respectively). Contractile activity in the cells from controls was significantly increased versus normal (p = 0.001). Sulfasalazine and β-aminopropionitrile significantly inhibited this effect (p = 0.005 and 0.0006, respectively). α-SMA expression was significantly higher in control versus normal (p = 0.0021) and versus sulfasalazine (p = 0.0007). These findings support the conclusion that sulfasalazine reduced stiffness by clearing myofibroblasts from fibrotic joints. Statement of clinical significance: The results provide proof-of-concept that established joint stiffness can be resolved non-surgically. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:629-638, 2020.
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Affiliation(s)
- Keerthi Atluri
- Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, Iowa, 52242
| | - Marc J Brouillette
- Department of Orthopedics and Rehabilitation, University of Iowa, Iowa City, Iowa, 52242
| | - Dongrim Seol
- Department of Orthopedics and Rehabilitation, University of Iowa, Iowa City, Iowa, 52242
| | - Behnoush Khorsand
- Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, Iowa, 52242
| | - Edward Sander
- Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa, 52242
| | - Aliasger K Salem
- Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, Iowa, 52242
| | - Douglas Fredericks
- Department of Orthopedics and Rehabilitation, University of Iowa, Iowa City, Iowa, 52242
| | - Emily Petersen
- Department of Orthopedics and Rehabilitation, University of Iowa, Iowa City, Iowa, 52242
| | - Sonja Smith
- Department of Orthopedics and Rehabilitation, University of Iowa, Iowa City, Iowa, 52242
| | - Timothy P Fowler
- Department of Orthopedics and Rehabilitation, University of Iowa, Iowa City, Iowa, 52242
| | - James A Martin
- Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, Iowa, 52242.,Department of Orthopedics and Rehabilitation, University of Iowa, Iowa City, Iowa, 52242.,Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa, 52242
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Intercellular crosstalk of hepatic stellate cells in liver fibrosis: New insights into therapy. Pharmacol Res 2020; 155:104720. [PMID: 32092405 DOI: 10.1016/j.phrs.2020.104720] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 01/08/2020] [Accepted: 02/20/2020] [Indexed: 02/08/2023]
Abstract
Liver fibrosis is a dynamic wound-healing process characterized by the net accumulation of extracellular matrix. There is no efficient antifibrotic therapy other than liver transplantation to date. Activated hepatic stellate cells (HSCs) are the major cellular source of matrix-producing myofibroblasts, playing a central role in the initiation and progression of liver fibrosis. Paracrine signals from resident and inflammatory cells such as hepatocytes, liver sinusoidal endothelial cells, hepatic macrophages, natural killer/natural killer T cells, biliary epithelial cells, hepatic progenitor cells, and platelets can directly or indirectly regulate HSC differentiation and activation. Intercellular crosstalk between HSCs and those "responded" cells has been a critical event involved in HSC activation and fibrogenesis. This review summarizes recent advancement regarding intercellular communication between HSCs and other "responded cells" during liver fibrosis and experimental models of intercellular crosstalk systems, and provides novel ideas for potential antifibrotic therapeutic strategy.
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Dou L, Shi X, He X, Gao Y. Macrophage Phenotype and Function in Liver Disorder. Front Immunol 2020; 10:3112. [PMID: 32047496 PMCID: PMC6997484 DOI: 10.3389/fimmu.2019.03112] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 12/20/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatic macrophages are a remarkably heterogeneous population consisting of self-renewing tissue-resident phagocytes, termed Kupffer cells (KCs), and recruited macrophages derived from peritoneal cavity as well as the bone marrow. KCs are located in the liver sinusoid where they scavenge the microbe from the portal vein to maintain liver homeostasis. Liver injury may trigger hepatic recruitment of peritoneal macrophages and monocyte-derived macrophages. Studies describing macrophage accumulation have shown that hepatic macrophages are involved in the initiation and progression of various liver diseases. They act as tolerogenic antigen-presenting cells to inhibit T-cell activation by producing distinct sets of cytokines, chemokines, and mediators to maintain or resolve inflammation. Furthermore, by releasing regenerative growth factors, matrix metalloproteinase arginase, they promote tissue repair. Recent experiments found that KCs and recruited macrophages may play different roles in the development of liver disease. Given that hepatic macrophages are considerably plastic populations, their phenotypes and functions are likely switching along disease progression. In this review, we summarize current knowledge about the role of tissue-resident macrophages and recruited macrophages in pathogenesis of alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), viral hepatitis, and hepatocellular carcinoma (HCC).
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Affiliation(s)
- Lang Dou
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaomin Shi
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoshun He
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yifang Gao
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Zhou Z, Qi J, Zhao J, Lim CW, Kim J, Kim B. Dual TBK1/IKKɛ inhibitor amlexanox attenuates the severity of hepatotoxin-induced liver fibrosis and biliary fibrosis in mice. J Cell Mol Med 2020; 24:1383-1398. [PMID: 31821710 PMCID: PMC6991653 DOI: 10.1111/jcmm.14817] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/23/2019] [Accepted: 10/26/2019] [Indexed: 12/31/2022] Open
Abstract
Although numerous studies have suggested that canonical IκB kinases (IKK) play a key role in the progression of liver fibrosis, the role of non-canonical IKKε and TANK-binding kinase 1 (TBK1) on the development and progression of liver fibrosis remains unclear. To demonstrate such issue, repeated injection of CCl4 was used to induce hepatotoxin-mediated chronic liver injury and biliary fibrosis was induced by 0.1% diethoxycarbonyl-1, 4-dihydrocollidine diet feeding for 4 weeks. Mice were orally administered with amlexanox (25, 50, and 100 mg/kg) during experimental period. Significantly increased levels of TBK1 and IKKε were observed in fibrotic livers or hepatic stellate cells (HSCs) isolated from fibrotic livers. Interestingly, amlexanox treatment significantly inhibited the phosphorylation of TBK1 and IKKε accompanied by reduced liver injury as confirmed by histopathologic analysis, decreased serum biochemical levels and fibro-inflammatory responses. Additionally, treatment of amlexanox promoted the fibrosis resolution. In accordance with these findings, amlexanox treatment suppressed HSC activation and its related fibrogenic responses by partially inhibiting signal transducer and activator of transcription 3. Furthermore, amlexanox decreased the activation and inflammatory responses in Kupffer cells. Collectively, we found that inhibition of the TBK1 and IKKε by amlexanox is a promising therapeutic strategy to cure liver fibrosis.
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Affiliation(s)
- Zixiong Zhou
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program)College of Veterinary MedicineJeonbuk National UniversityIksanKorea
| | - Jing Qi
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program)College of Veterinary MedicineJeonbuk National UniversityIksanKorea
| | - Jing Zhao
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program)College of Veterinary MedicineJeonbuk National UniversityIksanKorea
| | - Chae Woong Lim
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program)College of Veterinary MedicineJeonbuk National UniversityIksanKorea
| | - Jong‐Won Kim
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program)College of Veterinary MedicineJeonbuk National UniversityIksanKorea
| | - Bumseok Kim
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program)College of Veterinary MedicineJeonbuk National UniversityIksanKorea
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Hemistepsin A alleviates liver fibrosis by inducing apoptosis of activated hepatic stellate cells via inhibition of nuclear factor-κB and Akt. Food Chem Toxicol 2019; 135:111044. [PMID: 31830547 DOI: 10.1016/j.fct.2019.111044] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 11/22/2019] [Accepted: 12/05/2019] [Indexed: 01/18/2023]
Abstract
Hemistepsin A (HsA), isolated from Hemistepta lyrata (Bunge) Bunge, has the ability to ameliorate hepatitis in mice. However, the effects of H. lyrata and HsA on other types of liver disease have not been explored. In this report, we investigated the effects of H. lyrata and HsA on liver fibrosis and the underlying molecular mechanisms in activated hepatic stellate cells (HSCs). Based on cell viability-guided isolation, we found HsA was the major natural product responsible for H. lyrata-mediated cytotoxicity in LX-2 cells. HsA significantly decreased the viability of LX-2 cells and primary activated HSCs, increased the binding of Annexin V, and altered the expression of apoptosis-related proteins, suggesting that HsA induces apoptosis in activated HSCs. HsA reduced the phosphorylation of IKKε and the transactivation of nuclear factor-κB (NF-κB). Moreover, HsA decreased the phosphorylation of Akt and its downstream signaling molecules. Transfection experiments suggested that inhibition of NF-κB or Akt is essential for HsA-induced apoptosis of HSCs. In a CCl4-induced liver fibrosis model, HsA administration significantly decreased ALT and AST activities. Furthermore, HsA attenuated CCl4-mediated collagen deposits and profibrogenic genes expression in hepatic tissue. Thus, HsA may serve as a natural product for managing liver fibrosis through inhibition of NF-κB/Akt-dependent signaling.
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