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Du F, Li J, Zhong X, Zhang Z, Zhao Y. Endothelial-to-mesenchymal transition in the tumor microenvironment: Roles of transforming growth factor-β and matrix metalloproteins. Heliyon 2024; 10:e40118. [PMID: 39568849 PMCID: PMC11577214 DOI: 10.1016/j.heliyon.2024.e40118] [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: 08/28/2023] [Revised: 10/26/2024] [Accepted: 11/03/2024] [Indexed: 11/22/2024] Open
Abstract
Cancer is a leading cause of global morbidity and mortality. Tumor cells grow in a complex microenvironment, comprising immune cells, stromal cells, and vascular cells, collaborating to support tumor growth and facilitate metastasis. Transforming growth factor-beta (TGF-β) is a multipotent factor that can not only affect fibrosis promotion but also assume distinct roles in the early and late stages of the tumor. Matrix metalloproteinases (MMPs) primarily function to degrade the extracellular matrix, a pivotal cellular player in tumor progression. Moreover, endothelial-to-mesenchymal transition (EndMT), similar to epithelial-to-mesenchymal transition, is associated with cancer progression by promoting angiogenesis, disrupting the endothelial barrier, and leading to cancer-associated fibroblasts. Recent studies have underscored the pivotal roles of TGF-β and MMPs in EndMT. This review delves into the contributions of TGF-β and MMPs, as well as their regulatory mechanisms, within the tumor microenvironment. This collective understanding offers fresh insights into the potential for combined targeted therapies in the fight against cancer.
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Affiliation(s)
- Fei Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
- Department of Pharmacy, Meishan TianFu New Area People's Hospital, Meishan, Sichuan, China
| | - Jing Li
- Department of Oncology and Hematology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Xiaolin Zhong
- Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Zhuo Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
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Yoladi FB, Palabiyik-Yucelik SS, Bahador Zirh E, Halici Z, Baydar T. Effects of idebenone and coenzyme Q10 on NLRP3/caspase-1/IL-1β pathway regulation on ethanol-induced hepatotoxicity in rats. Drug Chem Toxicol 2024; 47:1205-1217. [PMID: 38804209 DOI: 10.1080/01480545.2024.2351191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 04/29/2024] [Indexed: 05/29/2024]
Abstract
Chronic and excessive alcohol consumption leads to liver toxicity. There is a need to investigate effective therapeutic strategies to alleviate alcohol-induced liver injury, which remains the leading cause of liver-related morbidity and mortality worldwide. Therefore here, we looked into and evaluated how ethanol-induced hepatotoxicity was affected by coenzyme Q10 (CoQ10) and its analog, idebenone (IDE), on the NLRP3/caspase-1/IL-1 pathway. Hepatotoxicity induced in rats through the oral administration of gradually increasing dosages of ethanol (from 2 to 6 g/kg/day) over 30 days and the effect of CoQ10 (10 or 20 mg/kg) and IDE (50 or 100 mg/kg) were evaluated. Serum hepatotoxicity markers (ALT, AST, GGT, ALP, and TBIL), tissue oxidative stress markers and the mRNA expressions of IL-1β, IL-18, TGF-β, NF-κB, NLRP3, and caspase-1 were evaluated. Masson's trichrome staining was also used to visualize fibrosis in the liver tissue. The results indicated that ethanol exposure led to hepatotoxicity as well as considerable NLRP3/caspase-1/IL-1β pathway activation. Moreover, CoQ10 or IDE treatment reduced measured parameters in a dosage-dependent manner. Thus, by inhibiting the NLRP3/caspase-1/IL-1 pathway, CoQ10 and IDE can prevent the hepatotoxicity caused by ethanol, although CoQ10 is more effective than IDE. This study will provide insight into new therapeutic avenues that take advantage of the anti-inflammatory and antioxidant properties of CoQ10 and IDE in ethanol-induced liver diseases.
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Affiliation(s)
- Fatma Betül Yoladi
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Atatürk University, Erzurum, Turkey
- Department of Toxicology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
| | - Saziye Sezin Palabiyik-Yucelik
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Atatürk University, Erzurum, Turkey
- Clinical Research, Development and Design Application and Research Center, Atatürk University, Erzurum, Turkey
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ondokuz Mayıs University, Samsun, Turkey
| | - Elham Bahador Zirh
- Department of Histology and Embryology, Faculty of Medicine, TOBB University of Economics and Technology, Ankara, Turkey
| | - Zekai Halici
- Clinical Research, Development and Design Application and Research Center, Atatürk University, Erzurum, Turkey
- Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Terken Baydar
- Department of Toxicology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
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Akkız H, Gieseler RK, Canbay A. Liver Fibrosis: From Basic Science towards Clinical Progress, Focusing on the Central Role of Hepatic Stellate Cells. Int J Mol Sci 2024; 25:7873. [PMID: 39063116 PMCID: PMC11277292 DOI: 10.3390/ijms25147873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 06/28/2024] [Accepted: 06/29/2024] [Indexed: 07/28/2024] Open
Abstract
The burden of chronic liver disease is globally increasing at an alarming rate. Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such as cirrhosis, liver cancer, and mortality. LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; and produce proinflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. In addition, the accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. The main source of myofibroblasts is resident HSCs. Activated HSCs migrate to the site of active fibrogenesis to initiate the formation of a fibrous scar. Single-cell technologies revealed that quiescent HSCs are highly homogenous, while activated HSCs/myofibroblasts are much more heterogeneous. The complex process of inflammation results from the response of various hepatic cells to hepatocellular death and inflammatory signals related to intrahepatic injury pathways or extrahepatic mediators. Inflammatory processes modulate fibrogenesis by activating HSCs and, in turn, drive immune mechanisms via cytokines and chemokines. Increasing evidence also suggests that cellular stress responses contribute to fibrogenesis. Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. However, despite numerous clinical studies on plausible drug candidates, an approved antifibrotic therapy still remains elusive. This state-of-the-art review presents cellular and molecular mechanisms involved in hepatic fibrogenesis and its resolution, as well as comprehensively discusses the drivers linking liver injury to chronic liver inflammation and LF.
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Affiliation(s)
- Hikmet Akkız
- Department of Gastroenterology and Hepatology, University of Bahçeşehir, Beşiktaş, Istanbul 34353, Turkey
| | - Robert K. Gieseler
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
| | - Ali Canbay
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
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Xiao Y, Vazquez-Padron RI, Martinez L, Singer HA, Woltmann D, Salman LH. Role of platelet factor 4 in arteriovenous fistula maturation failure: What do we know so far? J Vasc Access 2024; 25:390-406. [PMID: 35751379 PMCID: PMC9974241 DOI: 10.1177/11297298221085458] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The rate of arteriovenous fistula (AVF) maturation failure remains unacceptably high despite continuous efforts on technique improvement and careful pre-surgery planning. In fact, half of all newly created AVFs are unable to be used for hemodialysis (HD) without a salvage procedure. While vascular stenosis in the venous limb of the access is the culprit, the underlying factors leading to vascular narrowing and AVF maturation failure are yet to be determined. We have recently demonstrated that AVF non-maturation is associated with post-operative medial fibrosis and fibrotic stenosis, and post-operative intimal hyperplasia (IH) exacerbates the situation. Multiple pathological processes and signaling pathways are underlying the stenotic remodeling of the AVF. Our group has recently indicated that a pro-inflammatory cytokine platelet factor 4 (PF4/CXCL4) is upregulated in veins that fail to mature after AVF creation. Platelet factor 4 is a fibrosis marker and can be detected in vascular stenosis tissue, suggesting that it may contribute to AVF maturation failure through stimulation of fibrosis and development of fibrotic stenosis. Here, we present an overview of the how PF4-mediated fibrosis determines AVF maturation failure.
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Affiliation(s)
- Yuxuan Xiao
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Roberto I Vazquez-Padron
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Laisel Martinez
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Harold A Singer
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Daniel Woltmann
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Loay H Salman
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
- Division of Nephrology and Hypertension, Albany Medical College, Albany, NY, USA
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Frangogiannis NG. TGF-β as a therapeutic target in the infarcted and failing heart: cellular mechanisms, challenges, and opportunities. Expert Opin Ther Targets 2024; 28:45-56. [PMID: 38329809 DOI: 10.1080/14728222.2024.2316735] [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: 10/20/2023] [Accepted: 02/06/2024] [Indexed: 02/10/2024]
Abstract
INTRODUCTION Myocardial fibrosis accompanies most cardiac conditions and can be reparative or maladaptive. Transforming Growth Factor (TGF)-β is a potent fibrogenic mediator, involved in repair, remodeling, and fibrosis of the injured heart. AREAS COVERED This review manuscript discusses the role of TGF-β in heart failure focusing on cellular mechanisms and therapeutic implications. TGF-β is activated in infarcted, remodeling and failing hearts. In addition to its fibrogenic actions, TGF-β has a broad range of effects on cardiomyocytes, immune, and vascular cells that may have both protective and detrimental consequences. TGF-β-mediated effects on macrophages promote anti-inflammatory transition, whereas actions on fibroblasts mediate reparative scar formation and effects on pericytes are involved in maturation of infarct neovessels. On the other hand, TGF-β actions on cardiomyocytes promote adverse remodeling, and prolonged activation of TGF-β signaling in fibroblasts stimulates progression of fibrosis and heart failure. EXPERT OPINION Understanding of the cell-specific actions of TGF-β is necessary to design therapeutic strategies in patients with myocardial disease. Moreover, to implement therapeutic interventions in the heterogeneous population of heart failure patients, mechanism-driven classification of both HFrEF and HFpEF patients is needed. Heart failure patients with prolonged or overactive fibrogenic TGF-β responses may benefit from cautious TGF-β inhibition.
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Affiliation(s)
- Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Department of Medicine and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
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Mohamed MR, Haybaeck J, Wu H, Su H, Bartneck M, Lin C, Boekschoten MV, Boor P, Goeppert B, Rupp C, Strnad P, Davis RJ, Cubero FJ, Trautwein C. JNKs protect from cholestatic liver disease progression by modulating Apelin signalling. JHEP Rep 2023; 5:100854. [PMID: 37791376 PMCID: PMC10543210 DOI: 10.1016/j.jhepr.2023.100854] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 07/03/2023] [Accepted: 07/07/2023] [Indexed: 10/05/2023] Open
Abstract
Background & Aims Cholestatic liver injury is associated with c-Jun N-terminal kinases (JNK) activation in distinct cell types. Its hepatocyte-specific function during cholestasis, however, has not yet been established. Therefore, in our present study, we investigated the role of JNK1/2 during cholestasis and dissected its hepatocyte-specific function. Methods A cohort of patients with primary biliary cholangitis (n = 29) and primary sclerosing cholangitis (n = 37) was examined. Wild-type, hepatocyte-specific knockout mice for Jnk2 (Jnk2Δhepa) or Jnk1 and Jnk2 (Jnk1Δhepa/2Δhepa) were generated. Mice were subjected to bile duct ligation (BDL) or carbon tetrachloride (CCl4) treatment. Finally, Apelin signalling was blocked using a specific inhibitor. As an interventional approach, Jnk1/2 were silenced in wild-type mice using lipid nanoparticles for small interfering RNA delivery. Results JNK activation was increased in liver specimens from patients with chronic cholestasis (primary biliary cholangitis and primary sclerosing cholangitis) and in livers of Mdr2-/- and BDL-treated animals. In Jnk1Δhepa/2Δhepa animals, serum transaminases increased after BDL, and liver histology demonstrated enhanced cell death, compensatory proliferation, hepatic fibrogenesis, and inflammation. Furthermore, microarray analysis revealed that hepatocytic Jnk1/2 ablation induces JNK-target genes involved in oxidative stress and Apelin signalling after BDL. Consequently, blocking Apelin signalling attenuated BDL-induced liver injury and fibrosis in Jnk1Δhepa/2Δhepa mice. Finally, we established an interventional small interfering RNA approach of selective Jnk1/2 targeting in hepatocytes in vivo, further demonstrating the essential protective role of Jnk1/2 during cholestasis. Conclusions Jnk1 and Jnk2 work together to protect hepatocytes from cholestatic liver disease by controlling Apelin signalling. Dual modification of JNK signalling in hepatocytes is feasible, and enhancing its expression might be an attractive therapeutic approach for cholestatic liver disease. Impact and Implications The cell-specific function of Jnk genes during cholestasis has not been explicitly explored. In this study, we showed that combined Jnk1/2, but not Jnk2 deficiency, in hepatocytes exacerbates liver damage and fibrosis by enhancing Apelin signalling, which contributes to cholestasis progression. Combined cell-specific Jnk targeting may be a new molecular strategy for treating cholestatic liver disease.
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Affiliation(s)
| | - Johannes Haybaeck
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria
- Diagnostic and Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
- Department of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Hanghang Wu
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
| | - Huan Su
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - Matthias Bartneck
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - Cheng Lin
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - Mark V. Boekschoten
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Peter Boor
- Institute of Pathology and Department of Nephrology, University Hospital, RWTH Aachen, Aachen, Germany
| | - Benjamin Goeppert
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian Rupp
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - Roger J. Davis
- Howard Hughes Medical Institute and University of Massachusetts Medical School, Worcester, MA, USA
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
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Park HJ, Choi J, Kim H, Yang DY, An TH, Lee EW, Han BS, Lee SC, Kim WK, Bae KH, Oh KJ. Cellular heterogeneity and plasticity during NAFLD progression. Front Mol Biosci 2023; 10:1221669. [PMID: 37635938 PMCID: PMC10450943 DOI: 10.3389/fmolb.2023.1221669] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 07/18/2023] [Indexed: 08/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease that can progress to nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis, and hepatocellular carcinoma (HCC). NAFLD ranges from simple steatosis (or nonalcoholic fatty liver [NAFL]) to NASH as a progressive form of NAFL, which is characterized by steatosis, lobular inflammation, and hepatocellular ballooning with or without fibrosis. Because of the complex pathophysiological mechanism and the heterogeneity of NAFLD, including its wide spectrum of clinical and histological characteristics, no specific therapeutic drugs have been approved for NAFLD. The heterogeneity of NAFLD is closely associated with cellular plasticity, which describes the ability of cells to acquire new identities or change their phenotypes in response to environmental stimuli. The liver consists of parenchymal cells including hepatocytes and cholangiocytes and nonparenchymal cells including Kupffer cells, hepatic stellate cells, and endothelial cells, all of which have specialized functions. This heterogeneous cell population has cellular plasticity to adapt to environmental changes. During NAFLD progression, these cells can exert diverse and complex responses at multiple levels following exposure to a variety of stimuli, including fatty acids, inflammation, and oxidative stress. Therefore, this review provides insights into NAFLD heterogeneity by addressing the cellular plasticity and metabolic adaptation of hepatocytes, cholangiocytes, hepatic stellate cells, and Kupffer cells during NAFLD progression.
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Affiliation(s)
- Hyun-Ju Park
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Juyong Choi
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Hyunmi Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Da-Yeon Yang
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Tae Hyeon An
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Eun-Woo Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Baek-Soo Han
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
- Biodefense Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Sang Chul Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Won Kon Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kwang-Hee Bae
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kyoung-Jin Oh
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
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Jiang B, Zhou Y, Liu Y, He S, Liao B, Peng T, Yao L, Qi L. Research Progress on the Role and Mechanism of IL-37 in Liver Diseases. Semin Liver Dis 2023; 43:336-350. [PMID: 37582401 PMCID: PMC10620037 DOI: 10.1055/a-2153-8836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/17/2023]
Abstract
Cytokines are important components of the immune system that can predict or influence the development of liver diseases. IL-37, a new member of the IL-1 cytokine family, exerts potent anti-inflammatory and immunosuppressive effects inside and outside cells. IL-37 expression differs before and after liver lesions, suggesting that it is associated with liver disease; however, its mechanism of action remains unclear. This article mainly reviews the biological characteristics of IL-37, which inhibits hepatitis, liver injury, and liver fibrosis by inhibiting inflammation, and inhibits the development of hepatocellular carcinoma (HCC) by regulating the immune microenvironment. Based on additional evidence, combining IL-37 with liver disease markers for diagnosis and treatment can achieve more significant effects, suggesting that IL-37 can be developed into a powerful tool for the clinical adjuvant treatment of liver diseases, especially HCC.
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Affiliation(s)
- Baoyi Jiang
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Yulin Zhou
- Department of Clinical Laboratory, Shunde New Rongqi Hospital, Foshan, China
| | - Yanting Liu
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Siqi He
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Baojian Liao
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Tieli Peng
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Leyi Yao
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Ling Qi
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
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Azamov B, Lee KM, Hur J, Muradillaeva S, Shim WS, Lee C, Song P. Oxoglaucine Suppresses Hepatic Fibrosis by Inhibiting TGFβ-Induced Smad2 Phosphorylation and ROS Generation. Molecules 2023; 28:4971. [PMID: 37446633 DOI: 10.3390/molecules28134971] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/15/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Hepatic fibrosis is the first stage of liver disease, and can progress to a chronic status, such as cirrhosis or hepatocellular carcinoma. Excessive production of extracellular matrix (ECM) components plays an important role in the development of fibrosis. Mechanistically, transforming growth factor beta (TGFβ)-induced phosphorylation of Smad is thought to be a key signaling pathway in the development of liver fibrosis. Although the natural isoquinoline alkaloid oxoglaucine (1,2,9,10-tetramethoxy-7H-dibenzo(de,g)quinolin-7-one) exerts numerous beneficial effects, including anti-cancer, anti-inflammatory, and anti-osteoarthritic effects in diverse cell types, the effects of oxoglaucine on liver fibrosis and fibrogenic gene expression have not been fully elucidated. The aim of this study is to evaluate the signaling pathway and antifibrotic activity of isoquinoline alkaloid oxoglaucine in TFGβ-induced hepatic fibrosis in vitro. Using Hepa1c1c7 cells and primary hepatocytes, we demonstrated that oxoglaucine treatment resulted in inhibition of the expression of fibrosis markers such as collagen, fibronectin, and alpha-SMA. Subsequent experiments showed that oxoglaucine suppressed TGFβ-induced phosphorylation of Smad2 and reactive oxygen species (ROS) generation, without altering cell proliferation. We further determined that the increase in Smad7 by oxoglaucine treatment is responsible for the inhibition of Smad2 phosphorylation and the anti-fibrogenic effects. These findings indicate that oxoglaucine plays a crucial role in suppression of fibrosis in hepatocytes, thereby making it a potential drug candidate for treatment of liver fibrosis.
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Affiliation(s)
- Bakhovuddin Azamov
- Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Kwang-Min Lee
- Department of Life Science and Environmental Biochemistry, Life and Industry Convergence Research Institute, Pusan National University, Miryang 50463, Republic of Korea
| | - Jin Hur
- Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Shakhnoza Muradillaeva
- Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Wan-Seog Shim
- Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Chanhee Lee
- Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Parkyong Song
- Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
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Wiering L, Subramanian P, Hammerich L. Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease. Cell Mol Gastroenterol Hepatol 2023; 15:1277-1292. [PMID: 36828280 PMCID: PMC10148161 DOI: 10.1016/j.jcmgh.2023.02.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 02/15/2023] [Accepted: 02/15/2023] [Indexed: 02/26/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a fast growing, chronic liver disease affecting ∼25% of the global population. Nonalcoholic fatty liver disease severity ranges from the less severe simple hepatic steatosis to the more advanced nonalcoholic steatohepatitis (NASH). The presence of NASH predisposes individuals to liver fibrosis, which can further progress to cirrhosis and hepatocellular carcinoma. This makes hepatic fibrosis an important indicator of clinical outcomes in patients with NASH. Hepatic stellate cell activation dictates fibrosis development during NASH. Here, we discuss recent advances in the analysis of the profibrogenic pathways and mediators of hepatic stellate cell activation and inactivation, which ultimately determine the course of disease in nonalcoholic fatty liver disease/NASH.
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Affiliation(s)
- Leke Wiering
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Berlin, Germany
| | - Pallavi Subramanian
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Linda Hammerich
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
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11
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Wang K, Wen D, Xu X, Zhao R, Jiang F, Yuan S, Zhang Y, Gao Y, Li Q. Extracellular matrix stiffness-The central cue for skin fibrosis. Front Mol Biosci 2023; 10:1132353. [PMID: 36968277 PMCID: PMC10031116 DOI: 10.3389/fmolb.2023.1132353] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 02/20/2023] [Indexed: 03/29/2023] Open
Abstract
Skin fibrosis is a physiopathological process featuring the excessive deposition of extracellular matrix (ECM), which is the main architecture that provides structural support and constitutes the microenvironment for various cellular behaviors. Recently, increasing interest has been drawn to the relationship between the mechanical properties of the ECM and the initiation and modulation of skin fibrosis, with the engagement of a complex network of signaling pathways, the activation of mechanosensitive proteins, and changes in immunoregulation and metabolism. Simultaneous with the progression of skin fibrosis, the stiffness of ECM increases, which in turn perturbs mechanical and humoral homeostasis to drive cell fate toward an outcome that maintains and enhances the fibrosis process, thus forming a pro-fibrotic "positive feedback loop". In this review, we highlighted the central role of the ECM and its dynamic changes at both the molecular and cellular levels in skin fibrosis. We paid special attention to signaling pathways regulated by mechanical cues in ECM remodeling. We also systematically summarized antifibrotic interventions targeting the ECM, hopefully enlightening new strategies for fibrotic diseases.
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Affiliation(s)
- Kang Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Burn and Plastic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Dongsheng Wen
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuewen Xu
- Department of Burn and Plastic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Rui Zhao
- West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Feipeng Jiang
- West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Shengqin Yuan
- School of Public Administration, Sichuan University, Chengdu, Sichuan, China
| | - Yifan Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Yifan Zhang, ; Ya Gao, ; Qingfeng Li,
| | - Ya Gao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Yifan Zhang, ; Ya Gao, ; Qingfeng Li,
| | - Qingfeng Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Yifan Zhang, ; Ya Gao, ; Qingfeng Li,
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Babaahmadi-Rezaei H, Mohamed R, Dayati P, Mehr RN, Seif F, Sharifat N, Khedri A, Kamato D, Little PJ. Endothelin-1 dependent expression of GAG genes involves NOX and p38 mediated Smad linker region phosphorylation. Clin Exp Pharmacol Physiol 2022; 49:710-718. [PMID: 35527471 PMCID: PMC9322435 DOI: 10.1111/1440-1681.13650] [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: 09/06/2021] [Revised: 03/03/2022] [Accepted: 04/04/2022] [Indexed: 11/29/2022]
Abstract
Endothelin-1 (ET-1) is implicated in the development of atherosclerosis and mediates glycosaminoglycan (GAG) chain hyperelongation on proteoglycans. Our aim was to identify the ET-1-mediated signalling pathway involving NADPH oxidase (NOX), p38 MAP kinsae and Smad2 linker region phosphorylation (phospho-Smad2L) regulate GAG synthesizing enzymes mRNA expression (C4ST-1 and ChSy1) involved in GAG chains hyperelongation in human vascular smooth muscle cells (VSMCs). Signalling intermediates were detected and quantified by Western blotting and the mRNA levels of GAG synthesizing enzymes were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). ET-1 treatment of human VSMCs resulted in an increase in phospho-Smad2L level. The TGF-β receptor antagonist, SB431542 and the mixed ETA and ETB receptor antagonist bosentan, inhibited ET-1-mediated phospho-Smad2L level. In the presence of apocynin and diphenyleneiodonium chloride (DPI) (NOX inhibitors) and SB239063 (p38 inhibitor) ET-1-mediated phospho-Smad2L levels were inhibited. The gene expression levels of GAG synthesizing enzymes post-ET-1 treatment were increased compared to untreated controls (P<0.01). The ET-mediated the mRNA levels of these enzymes were blocked by the bosentan, SB431542, SB239063, DPI, apocynin and antioxidant N-acetyl-L-cysteine (NAC). ET-1-mediated signalling to GAG synthesizing enzymes gene expression occurs via transactivation-dependent pathway involving NOX, p38 MAP kinsae and Smad2 linker region phosphorylation. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Hossein Babaahmadi-Rezaei
- Hyperlipidemia Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Rafat Mohamed
- The University of Queensland, , Pharmacy Australia Centre of Excellence, 20 Cornwall St, Woolloongabba, QLD, Australia
| | - Parisa Dayati
- Hyperlipidemia Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Reyhaneh Niayesh Mehr
- Hyperlipidemia Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Faezeh Seif
- Hyperlipidemia Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Narges Sharifat
- Hyperlipidemia Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Azam Khedri
- Hyperlipidemia Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Dannii Kamato
- The University of Queensland, , Pharmacy Australia Centre of Excellence, 20 Cornwall St, Woolloongabba, QLD, Australia
| | - Peter J Little
- The University of Queensland, , Pharmacy Australia Centre of Excellence, 20 Cornwall St, Woolloongabba, QLD, Australia.,Department of Pharmacy, Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou, China
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Xu XY, Geng Y, Xu HX, Ren Y, Liu DY, Mao Y. Antrodia camphorata-Derived Antrodin C Inhibits Liver Fibrosis by Blocking TGF-Beta and PDGF Signaling Pathways. Front Mol Biosci 2022; 9:835508. [PMID: 35242813 PMCID: PMC8886226 DOI: 10.3389/fmolb.2022.835508] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/18/2022] [Indexed: 12/16/2022] Open
Abstract
Hepatic stellate cells (HSCs) play an essential role in the development of liver fibrosis. Antrodia camphorata (A. camphorata) is a medicinal fungus with hepatoprotective effect. This study investigated whether Antrodin C, an A. camphorata-fermented metabolite, could exert a protective role on liver fibrosis both in vitro and in vivo. The anti-fibrotic effect of Antrodin C was investigated in CFSC-8B cell (hepatic stellate cell) stimulated by transforming growth factor-β1 (TGF-β1) or platelet-derived growth factor-BB (PDGF-BB) in vitro and in CCl4 induced liver fibrosis in mice. Antrodin C (50 μM) inhibited TGF-β1 or PDGF-BB stimulated CFSC-8B cell activation, migration and extracellular matrix (ECM) accumulation (all p < 0.05). Antrodin C (3, 6 mg/kg/d) oral administration reduced the degree of liver fibrosis induced by CCl4 in mice. Antrodin C down-regulated the expression of α-smooth muscle actin (α-SMA) and collagen I in fibrotic livers. Furthermore, Antrodin C ameliorated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation in serum (all p < 0.05). Mechanistically, Antrodin C executes its anti-fibrotic activity through negatively modulate TGF-β1 downstream SMAD Family Member 2 (Smad2), AKT Serine/Threonine Kinase 1 (AKT), extracellular signal-regulated kinase (ERK), and P38 MAP Kinase (P38), as well as PDGF-BB downstream AKT and ERK signaling pathways. Antrodin C ameliorates the activation, migration, ECM production in HSCs and CCl4-induced liver fibrosis in mice, suggesting that Antrodin C could serve as a protective molecule against liver fibrosis.
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Affiliation(s)
- Xin-Yi Xu
- Institute of Cancer, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Yan Geng
- School of Life Science and Health Engineering, Jiangnan University, Wuxi, China
- *Correspondence: Yan Geng, ; Yong Mao,
| | - Hao-Xiang Xu
- Department of Urology, Affiliated Wuxi No. 2 Hospital of Nanjing Medical University, Wuxi, China
| | - Yilin Ren
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Deng-Yang Liu
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Yong Mao
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
- *Correspondence: Yan Geng, ; Yong Mao,
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Abstract
Transforming growth factor-β (TGFβ) isoforms are upregulated and activated in myocardial diseases and have an important role in cardiac repair and remodelling, regulating the phenotype and function of cardiomyocytes, fibroblasts, immune cells and vascular cells. Cardiac injury triggers the generation of bioactive TGFβ from latent stores, through mechanisms involving proteases, integrins and specialized extracellular matrix (ECM) proteins. Activated TGFβ signals through the SMAD intracellular effectors or through non-SMAD cascades. In the infarcted heart, the anti-inflammatory and fibroblast-activating actions of TGFβ have an important role in repair; however, excessive or prolonged TGFβ signalling accentuates adverse remodelling, contributing to cardiac dysfunction. Cardiac pressure overload also activates TGFβ cascades, which initially can have a protective role, promoting an ECM-preserving phenotype in fibroblasts and preventing the generation of injurious, pro-inflammatory ECM fragments. However, prolonged and overactive TGFβ signalling in pressure-overloaded cardiomyocytes and fibroblasts can promote cardiac fibrosis and dysfunction. In the atria, TGFβ-mediated fibrosis can contribute to the pathogenic substrate for atrial fibrillation. Overactive or dysregulated TGFβ responses have also been implicated in cardiac ageing and in the pathogenesis of diabetic, genetic and inflammatory cardiomyopathies. This Review summarizes the current evidence on the role of TGFβ signalling in myocardial diseases, focusing on cellular targets and molecular mechanisms, and discussing challenges and opportunities for therapeutic translation.
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Affiliation(s)
- Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, USA.
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Wu X, Shu L, Zhang Z, Li J, Zong J, Cheong LY, Ye D, Lam KSL, Song E, Wang C, Xu A, Hoo RLC. Adipocyte Fatty Acid Binding Protein Promotes the Onset and Progression of Liver Fibrosis via Mediating the Crosstalk between Liver Sinusoidal Endothelial Cells and Hepatic Stellate Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2003721. [PMID: 34105268 PMCID: PMC8188197 DOI: 10.1002/advs.202003721] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 02/10/2021] [Indexed: 05/16/2023]
Abstract
Development of liver fibrosis results in drastic changes in the liver microenvironment, which in turn accelerates disease progression. Although the pathological function of various hepatic cells in fibrogenesis is identified, the crosstalk between them remains obscure. The present study demonstrates that hepatic expression of adipocyte fatty acid binding protein (A-FABP) is induced especially in the liver sinusoidal endothelial cells (LSECs) in mice after bile duct ligation (BDL). Genetic ablation and pharmacological inhibition of A-FABP attenuate BDL- or carbon tetrachloride-induced liver fibrosis in mice associating with reduced collagen accumulation, LSEC capillarization, and hepatic stellate cell (HSC) activation. Mechanistically, elevated A-FABP promotes LSEC capillarization by activating Hedgehog signaling, thus impairs the gatekeeper function of LSEC on HSC activation. LSEC-derived A-FABP also acts on HSCs in paracrine manner to potentiate the transactivation of transforming growth factor β1 (TGFβ1) by activating c-Jun N-terminal kinase (JNK)/c-Jun signaling. Elevated TGFβ1 subsequently exaggerates liver fibrosis. These findings uncover a novel pathological mechanism of liver fibrosis in which LSEC-derived A-FABP is a key regulator modulating the onset and progression of the disease. Targeting A-FABP may represent a potential approach against liver fibrosis.
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Affiliation(s)
- Xiaoping Wu
- State Key Laboratory of Pharmaceutical BiotechnologyLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
- Department of Pharmacology and PharmacyLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
| | - Lingling Shu
- State Key Laboratory of Pharmaceutical BiotechnologyLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
- Department of MedicineLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Zixuan Zhang
- State Key Laboratory of Pharmaceutical BiotechnologyLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
- Department of Pharmacology and PharmacyLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
| | - Jingjing Li
- Department of Pharmacology and PharmacyLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
| | - Jiuyu Zong
- State Key Laboratory of Pharmaceutical BiotechnologyLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
- Department of Pharmacology and PharmacyLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
| | - Lai Yee Cheong
- State Key Laboratory of Pharmaceutical BiotechnologyLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
- Department of MedicineLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
| | - Dewei Ye
- Joint Laboratory of Guangdong and Hong Kong on Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhou510000China
| | - Karen S. L. Lam
- State Key Laboratory of Pharmaceutical BiotechnologyLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
- Department of MedicineLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
| | - Erfei Song
- Department of Metabolic and Bariatric SurgeryThe First Affiliated Hospital of Jinan UniversityGuangzhouGuangdong510630China
| | - Cunchuan Wang
- Department of Metabolic and Bariatric SurgeryThe First Affiliated Hospital of Jinan UniversityGuangzhouGuangdong510630China
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical BiotechnologyLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
- Department of Pharmacology and PharmacyLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
- Department of MedicineLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
| | - Ruby L. C. Hoo
- State Key Laboratory of Pharmaceutical BiotechnologyLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
- Department of Pharmacology and PharmacyLKS Faculty of Medicinethe University of Hong KongHong Kong999077China
- HKU‐Shenzhen Institute of Research and Innovation (HKU‐SIRI)Shenzhen518057China
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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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Phan THG, Paliogiannis P, Nasrallah GK, Giordo R, Eid AH, Fois AG, Zinellu A, Mangoni AA, Pintus G. Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis. Cell Mol Life Sci 2021; 78:2031-2057. [PMID: 33201251 PMCID: PMC7669490 DOI: 10.1007/s00018-020-03693-7] [Citation(s) in RCA: 216] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 10/08/2020] [Accepted: 10/28/2020] [Indexed: 12/17/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonia, is a progressive, irreversible, and typically lethal disease characterized by an abnormal fibrotic response involving vast areas of the lungs. Given the poor knowledge of the mechanisms underpinning IPF onset and progression, a better understanding of the cellular processes and molecular pathways involved is essential for the development of effective therapies, currently lacking. Besides a number of established IPF-associated risk factors, such as cigarette smoking, environmental factors, comorbidities, and viral infections, several other processes have been linked with this devastating disease. Apoptosis, senescence, epithelial-mesenchymal transition, endothelial-mesenchymal transition, and epithelial cell migration have been shown to play a key role in IPF-associated tissue remodeling. Moreover, molecules, such as chemokines, cytokines, growth factors, adenosine, glycosaminoglycans, non-coding RNAs, and cellular processes including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, hypoxia, and alternative polyadenylation have been linked with IPF development. Importantly, strategies targeting these processes have been investigated to modulate abnormal cellular phenotypes and maintain tissue homeostasis in the lung. This review provides an update regarding the emerging cellular and molecular mechanisms involved in the onset and progression of IPF.
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Affiliation(s)
- Thị Hằng Giang Phan
- Department of Immunology and Pathophysiology, University of Medicine and Pharmacy, Hue University, Hue City, Vietnam
| | - Panagiotis Paliogiannis
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, 07100, Sassari, Italy
| | - Gheyath K Nasrallah
- Department of Biomedical Sciences, College of Health Sciences Member of QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.
- Biomedical Research Center Qatar University, P.O Box 2713, Doha, Qatar.
| | - Roberta Giordo
- Department of Medical Laboratory Sciences, College of Health Sciences, and Sharjah Institute for Medical Research, University of Sharjah, University City Rd, Sharjah, 27272, United Arab Emirates
| | - Ali Hussein Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, PO Box 2713, Doha, Qatar
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, PO Box 11-0236, Beirut, Lebanon
| | - Alessandro Giuseppe Fois
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, 07100, Sassari, Italy
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, 07100, Sassari, Italy
| | - Arduino Aleksander Mangoni
- Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, Australia.
| | - Gianfranco Pintus
- Department of Medical Laboratory Sciences, College of Health Sciences, and Sharjah Institute for Medical Research, University of Sharjah, University City Rd, Sharjah, 27272, United Arab Emirates.
- Department of Biomedical Sciences, University of Sassari, 07100, Sassari, Italy.
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Cicuéndez B, Ruiz-Garrido I, Mora A, Sabio G. Stress kinases in the development of liver steatosis and hepatocellular carcinoma. Mol Metab 2021; 50:101190. [PMID: 33588102 PMCID: PMC8324677 DOI: 10.1016/j.molmet.2021.101190] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/31/2020] [Accepted: 02/09/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an important component of metabolic syndrome and one of the most prevalent liver diseases worldwide. This disorder is closely linked to hepatic insulin resistance, lipotoxicity, and inflammation. Although the mechanisms that cause steatosis and chronic liver injury in NAFLD remain unclear, a key component of this process is the activation of stress-activated kinases (SAPKs), including p38 and JNK in the liver and immune system. This review summarizes findings which indicate that the dysregulation of stress kinases plays a fundamental role in the development of steatosis and are important players in inducing liver fibrosis. To avoid the development of steatohepatitis and liver cancer, SAPK activity must be tightly regulated not only in the hepatocytes but also in other tissues, including cells of the immune system. Possible cellular mechanisms of SAPK actions are discussed.
Hepatic JNK triggers steatosis and insulin resistance, decreasing lipid oxidation and ketogenesis in HFD-fed mice. Decreased liver expression of p38α/β in HFD increases lipogenesis. Hepatic p38γ/δ drive insulin resistance and inhibit autophagy, which may lead to steatosis. Macrophage p38α/β promote cytokine production and M1 polarization, leading to lipid accumulation in hepatocytes. Myeloid p38γ/δ contribute to cytokine production and neutrophil migration, protecting against steatosis, diabetes and NAFLD. JNK1 and p38γ induce HCC while p38α blocks it. However, deletion of hepatic JNK1/2 induces cholangiocarcinoma. SAPK are potential therapeutic target for metabolic disorders, steatohepatitis and liver cancer.
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Affiliation(s)
- Beatriz Cicuéndez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Irene Ruiz-Garrido
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Alfonso Mora
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
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Aishwarya V, Solaipriya S, Sivaramakrishnan V. Role of ellagic acid for the prevention and treatment of liver diseases. Phytother Res 2020; 35:2925-2944. [PMID: 33368795 DOI: 10.1002/ptr.7001] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 11/29/2020] [Accepted: 12/13/2020] [Indexed: 12/21/2022]
Abstract
Globally, one of the alarming problems is the prevalence and burden of liver diseases, which accounts for 2 million cases per year. Chronic liver aetiologies such as hepatitis infections, alcoholic or non-alcoholic liver disease, environmental agents, and drug-induced toxicity are invariably responsible for liver fibrosis progression to finally hepatocellular carcinoma. Current treatment options are unable to overwhelm and cure liver diseases. Emerging findings suggest researchers' interest in using evidence-based complementary medicine such as ellagic acid with extensive pharmacological properties. They include antioxidant, anti-inflammatory, anti-hyperlipidaemic, anti-viral, anti-angiogenic, and anticancer activity. The molecular functions elicited by ellagic acid include scavenging of free radicals, regulation of lipid metabolism, the prohibition of fibrogenesis response-mediating proteins, inhibits hepatic stellate cells and myofibroblasts, restrains hepatic viral replication, facilitates suppression of growth factors, regulates transcription factors, proinflammatory cytokines, augments the liver immune response, fosters apoptosis and inhibits cell proliferation in tumorigenic cells. This review will most notably focus on preclinical and clinical information based on currently available evidence to warrant ellagic acid's prospective role in preventing liver diseases.
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Affiliation(s)
- Venkatasubramanian Aishwarya
- Department of Genetic Engineering, College of Engineering and Technology, SRM Institute of Science and Technology, Chennai, India
| | - Solairaja Solaipriya
- Department of Biotechnology, College of Engineering and Technology, SRM Institute of Science and Technology, Chennai, India
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Hori Y, Ikeura T, Yamaguchi T, Yoshida K, Matsuzaki K, Ishida M, Satoi S, Okazaki K. Role of phosphorylated Smad3 signal components in intraductal papillary mucinous neoplasm of pancreas. Hepatobiliary Pancreat Dis Int 2020; 19:581-589. [PMID: 32532597 DOI: 10.1016/j.hbpd.2020.05.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 05/26/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Malignant intraductal papillary mucinous neoplasm (IPMN) has poor prognosis. The carcinogenesis of IPMN is not clear. The aim of this study was to clarify transitions in phosphorylated Smad3 signaling during IPMN carcinogenesis. METHODS By using immunohistochemistry, we examined the expression of pSmad3C and pSmad3L from 51 IPMN surgical specimens resected at our institution between 2010 and 2013. We also examined the expression of Ki-67, c-Myc and p-JNK. RESULTS The median immunostaining index of pSmad3C was 79.2% in low-grade dysplasia, 74.9% in high-grade dysplasia, and 42.0% in invasive carcinoma (P < 0.01), whereas that of pSmad3L was 3.4%, 4.3%, and 42.4%, respectively (P < 0.01). There was a negative relationship between the expression of pSmad3C and c-Myc (P < 0.001, r = -0.615) and a positive relationship between the expression of pSmad3L and c-Myc (P < 0.001, r = 0.696). Negative relationship between the expression of pSmad3C and Ki-67 (P < 0.01, r = -0.610) and positive relationship between the expression of pSmad3L and Ki-67 (P < 0.01, r = 0.731) were confirmed. p-JNK-positive cells were frequently observed among pSmad3L-positive cancer cells. The median of pSmad3L/pSmad3C ratio in the non-recurrence group and the recurrence group were 0.58 (range, 0.05-0.93), 3.83 (range, 0.85-5.96), respectively (P = 0.02). The median immunostaining index of c-Myc in the non-recurrence group and the recurrence group were 2.91 (range, 0-36.9) and 82.1 (range, 46.2-97.1), respectively (P = 0.02). The median immunostaining index of Ki-67 in the non-recurrence group and the recurrence group were 12.9 (range 5.7-30.8) and 90.9 (range 52.9-98.5), respectively (P = 0.02). CONCLUSIONS pSmad3L was upregulated in malignant IPMN. pSmad3L/pSmad3C ratio may be a useful prognostic factor in IPMN.
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Affiliation(s)
- Yuichi Hori
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 5731191, Japan
| | - Tsukasa Ikeura
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 5731191, Japan
| | - Takashi Yamaguchi
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 5731191, Japan
| | - Katsunori Yoshida
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 5731191, Japan
| | - Koichi Matsuzaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 5731191, Japan
| | - Mitsuaki Ishida
- Department of Pathology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 5731191, Japan
| | - Sohei Satoi
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 5731191, Japan
| | - Kazuichi Okazaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 5731191, Japan.
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21
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Chen Y, Yuan B, Chen G, Zhang L, Zhuang Y, Niu H, Zeng Z. Circular RNA RSF1 promotes inflammatory and fibrotic phenotypes of irradiated hepatic stellate cell by modulating miR-146a-5p. J Cell Physiol 2020; 235:8270-8282. [PMID: 31960423 DOI: 10.1002/jcp.29483] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 01/07/2020] [Indexed: 02/06/2023]
Abstract
The role of circular RNA (circRNA) in radiation-induced liver disease (RILD) remains largely unknown. In this study, Ras-related C3 botulinum toxin substrate 1 (RAC1) was elevated in irradiated human hepatic stellate cell (HSC) line LX2, the important effector cell mediating RILD. Overexpression of RAC1 promotes cell proliferation, proinflammatory cytokines production, and α-smooth muscle actin expression, which were blocked by microRNA (miR)-146a-5p mimics. CircRNA RSF1 (circRSF1) was upregulated in irradiated LX2 cells and predicted to harbor binding site for miR-146a-5p. Biotinylated-RNA pull down and dual-luciferase reporter detection confirmed the direct interaction of circRSF1 and miR-146a-5p. Enforced expression of circRSF1 increased RAC1 expression by acting as miR-146a-5p sponge to inhibit miR-146a-5p activity, and thus enhanced the cell viability, and promoted inflammatory and fibrotic phenotype of irradiated LX2 cells. These findings indicate a functional regulatory axis composing of circRSF1, miR-146a-5p, and RAC1 in irradiated HSC, which may provide attractive therapeutic targets for RILD.
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Affiliation(s)
- Yuhan Chen
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Baoying Yuan
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Genwen Chen
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Li Zhang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuan Zhuang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hao Niu
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhaochong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
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22
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Liu Q, Mao H, Nie J, Chen W, Yang Q, Dong X, Yu X. Transforming Growth Factor β1 Induces Epithelial–mesenchymal Transition by Activating the Jnk–SMAD3 Pathway in Rat Peritoneal Mesothelial Cells. Perit Dial Int 2020. [DOI: 10.1177/089686080802803s18] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
⋄ Background Peritoneal fibrosis is a serious complication in long-term peritoneal dialysis (PD) patients. Epithelial-mesenchymal transition (EMT) plays an important role in peritoneal fibrosis, and TGFβ1 is the crucial inducer of EMT. Phosphorylation of Smad proteins is required for TGFβ1-induced EMT. It was reported that C-Jun N-terminal kinase (JNK) was involved in the TGFβ1/Smad signaling pathway and might regulate the activation of Smad proteins. However, whether JNK is activated by TGFβ1 in rat peritoneal mesothelial cells (RPMCs) and the role taken by JNK signaling in EMT induced by TGFβ1 remains undetermined. In the present study, we investigated the role of JNK-Smad pathway in EMT induced by TGFβ1 in RPMCs. ⋄ Methods We harvested RPMCs from the peritoneum of male Sprague-Dawley rats and then cultured the cells in Dulbecco modified Eagle medium / F12 medium with 15% (volume:volume) fetal bovine serum. The cells were pretreated with SP600125, a specific inhibitor of JNK, for 4 hours before incubation with TGFβ1. The protein expression levels of phosphorylated JNK, Smad2, and Smad3 were detected by Western blotting. The messenger RNA levels and protein expression of α-smooth muscle actin (α-SMA), E-cadherin, and collagen I were determined with reverse transcriptase polymerase chain reaction and Western blotting respectively. ⋄ Results Expression of α-SMA and collagen I were significantly increased and expression of E-cadherin decreased with TGFβ1 in RPMCs. Transforming growth factor β1 can stimulate phosphorylated JNK expression from 5 minutes, with the peak at 10 minutes, and phosphorylated Smad2 and Smad3 expression from 10 minutes, with the peak at 30 minutes. The addition of SP600125, which blocked activation of JNK, effectively inhibited TGFβ1-induced phosphorylation of Smad3, but not Smad2. Also, our results showed that SP600125 effectively suppressed TGFβ1-induced high expression of α-SMA and collagen I, and prevented TGFβ1-induced downregulation of E-cadherin expression in RPMCs. ⋄ Conclusions This study demonstrated that JNK signaling may play an important role in EMT induced by TGFβ1 in RPMCs through activation of Smad3, suggesting that JNK inhibitor may prove to be a novel therapeutic agent for peritoneal fibrosis.
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Affiliation(s)
- Qinghua Liu
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Haiping Mao
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Jing Nie
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Wei Chen
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Qiongqiong Yang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Xiuqing Dong
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Xueqing Yu
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China
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23
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Sweeney M, Corden B, Cook SA. Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle? EMBO Mol Med 2020; 12:e10865. [PMID: 32955172 PMCID: PMC7539225 DOI: 10.15252/emmm.201910865] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 07/30/2020] [Accepted: 08/14/2020] [Indexed: 12/11/2022] Open
Abstract
Cardiac fibrosis is central to the pathology of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). Irrespective of the underlying profibrotic condition (e.g. ageing, diabetes, hypertension), maladaptive cardiac fibrosis is defined by the transformation of resident fibroblasts to matrix-secreting myofibroblasts. Numerous profibrotic factors have been identified at the molecular level (e.g. TGFβ, IL11, AngII), which activate gene expression programs for myofibroblast activation. A number of existing HF therapies indirectly target fibrotic pathways; however, despite multiple clinical trials in HFpEF, a specific clinically effective antifibrotic therapy remains elusive. Therapeutic inhibition of TGFβ, the master-regulator of fibrosis, has unfortunately proven toxic and ineffective in clinical trials to date, and new approaches are needed. In this review, we discuss the pathophysiology and clinical implications of interstitial fibrosis in HFpEF. We provide an overview of trials targeting fibrosis in HFpEF to date and discuss the promise of potential new therapeutic approaches and targets in the context of underlying molecular mechanisms.
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Affiliation(s)
- Mark Sweeney
- MRC‐London Institute of Medical SciencesHammersmith Hospital CampusLondonUK
- Wellcome Trust 4i/NIHR Clinical Research FellowImperial CollegeLondonUK
| | - Ben Corden
- MRC‐London Institute of Medical SciencesHammersmith Hospital CampusLondonUK
- National Heart Research Institute SingaporeNational Heart Centre SingaporeSingaporeSingapore
- Cardiovascular and Metabolic Disorders ProgramDuke‐National University of Singapore Medical SchoolSingaporeSingapore
- National Heart and Lung InstituteImperial College LondonLondonUK
| | - Stuart A Cook
- MRC‐London Institute of Medical SciencesHammersmith Hospital CampusLondonUK
- National Heart Research Institute SingaporeNational Heart Centre SingaporeSingaporeSingapore
- Cardiovascular and Metabolic Disorders ProgramDuke‐National University of Singapore Medical SchoolSingaporeSingapore
- National Heart and Lung InstituteImperial College LondonLondonUK
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24
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SMAD-oncoprotein interplay: Potential determining factors in targeted therapies. Biochem Pharmacol 2020; 180:114155. [DOI: 10.1016/j.bcp.2020.114155] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/11/2020] [Accepted: 07/13/2020] [Indexed: 12/12/2022]
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25
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Peng F, Tian Y, Ma J, Xu Z, Wang S, Tang M, Lei J, Gong G, Jiang Y. CAT1 silencing inhibits TGF-β1-induced mouse hepatic stellate cell activation in vitro and hepatic fibrosis in vivo. Cytokine 2020; 136:155288. [PMID: 32980687 DOI: 10.1016/j.cyto.2020.155288] [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: 02/19/2020] [Revised: 09/03/2020] [Accepted: 09/04/2020] [Indexed: 12/31/2022]
Abstract
Hepatic fibrosis is characterized by abnormal accumulation of extracellular matrix (ECM). Hepatic stellate cells (HSCs) are the primary cells that produce ECM in response to hepatic injury, and transforming growth factor-beta (TGF-β) has been regarded as the central stimulus responsible for HSC-mediated ECM production. In the present study, we attempted to identify a critical factor in HSC activation and the underlying mechanism. By analyzing online microarray expression profiles, we found that the expression of high-affinity cationic amino acid transporter 1 (CAT1) was upregulated in hepatic fibrosis models and activated HSCs. We isolated and identified mouse HSCs (MHSCs) and found that in these cells, CAT1 was most highly upregulated by TGF-β1 stimulation in both time- and dose-dependent manners. In vitro, CAT1 overexpression further enhanced, while CAT1 silencing inhibited, the effect of TGF-β1 in promoting MHSC activation. In vivo, CAT1 silencing significantly improved the hepatic fibrosis induced by both CCl4 and non-alcoholic fatty liver disease (NAFLD). In summary, CAT1 was significantly upregulated in TGF-β1-activated MHSCs and mice with hepatic fibrosis. CAT1 silencing inhibited TGF-β1-induced MHSC activation in vitro and fibrogenic changes in vivo. CAT1 is a promising target for hepatic fibrosis treatment that requites further investigation in human cells and clinical practice.
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Affiliation(s)
- Feng Peng
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yi Tian
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Jing Ma
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Zhenyu Xu
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Sujuan Wang
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Min Tang
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Jianhua Lei
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Guozhong Gong
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yongfang Jiang
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China.
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26
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Wang L, Liao Y, Yang R, Yu Z, Zhang L, Zhu Z, Wu X, Shen J, Liu J, Xu L, Wu Z, Sun X. Sja-miR-71a in Schistosome egg-derived extracellular vesicles suppresses liver fibrosis caused by schistosomiasis via targeting semaphorin 4D. J Extracell Vesicles 2020; 9:1785738. [PMID: 32944173 PMCID: PMC7480424 DOI: 10.1080/20013078.2020.1785738] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Schistosomiasis is characterized by liver fibrosis, and studies have indicated that Schistosoma japonicum (S. japonicum) eggs can limit the progression of liver fibrosis. However, the detailed molecular mechanisms are yet unclear. Extracellular vesicles (EVs) contain a selection of miRNAs for long-distance exchange of information and act as an important pathway for host-parasite communication. This study aimed to explore the potential role of S. japonicum egg-derived EVs and its key miRNA in liver fibrosis. Herein, we found that S. japonicum egg-derived EVs can inhibit the activation of hepatic stellate cells, which is mediated via the high expression of Sja-miR-71a. Sja-miR-71a in EVs attenuates the pathological progression and liver fibrosis in S. japonicum infection. Sja-miR-71a inhibiting TGF-β1/SMAD and interleukin (IL)-13/STAT6 pathways via directly targeting semaphorin 4D (Sema4D). In addition, Sja-miR-71a can also suppress liver fibrosis by regulating Th1/Th2/Th17 and Treg balance. This study contributes to further understanding of the molecular mechanisms underlying Schistosoma-host interactions, and Sema4D may be a potential target for schistosomiasis liver fibrosis treatment.
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Affiliation(s)
- Lifu Wang
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Yao Liao
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Ruibing Yang
- Medical Department of Xizang Minzu University, Xianyang, China
| | - Zilong Yu
- Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Lichao Zhang
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Zifeng Zhu
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Xiaoying Wu
- The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jia Shen
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Jiahua Liu
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Lian Xu
- Nantong University, Nantong, China
| | - Zhongdao Wu
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Xi Sun
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
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27
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Frangogiannis N. Transforming growth factor-β in tissue fibrosis. J Exp Med 2020; 217:e20190103. [PMID: 32997468 PMCID: PMC7062524 DOI: 10.1084/jem.20190103] [Citation(s) in RCA: 713] [Impact Index Per Article: 142.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 12/24/2019] [Indexed: 12/21/2022] Open
Abstract
TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β–driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.
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Affiliation(s)
- Nikolaos Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY
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28
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Kamato D, Do BH, Osman N, Ross BP, Mohamed R, Xu S, Little PJ. Smad linker region phosphorylation is a signalling pathway in its own right and not only a modulator of canonical TGF-β signalling. Cell Mol Life Sci 2020; 77:243-251. [PMID: 31407020 PMCID: PMC11104920 DOI: 10.1007/s00018-019-03266-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 07/16/2019] [Accepted: 08/05/2019] [Indexed: 01/01/2023]
Abstract
Transforming growth factor (TGF)-β signalling pathways are intensively investigated because of their diverse association with physiological and pathophysiological states. Smad transcription factors are the key mediators of TGF-β signalling. Smads can be directly phosphorylated in the carboxy terminal by the TGF-β receptor or in the linker region via multiple intermediate serine/threonine kinases. Growth factors in addition to hormones and TGF-β can activate many of the same kinases which can phosphorylate the Smad linker region. Historically, Smad linker region phosphorylation was shown to prevent nuclear translocation of Smads and inhibit TGF-β signalling pathways; however, it was subsequently shown that Smad linker region phosphorylation can be a driver of gene expression. This review will cover the signalling pathways of Smad linker region phosphorylation that drive the expression of genes involved in pathology and pathophysiology. The role of Smad signalling in cell biology is expanding rapidly beyond its role in TGF-β signalling and many signalling paradigms need to be re-evaluated in terms of Smad involvement.
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Affiliation(s)
- Danielle Kamato
- Pharmacy Australia Centre of Excellence, School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, QLD, 4102, Australia.
- Department of Pharmacy, Xinhua College of Sun Yat-Sen University, Tianhe District, Guangzhou, 510520, China.
| | - Bich Hang Do
- Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City, 700000, Vietnam
| | - Narin Osman
- School of Medical Sciences, RMIT University, Bundoora, VIC, 3083, Australia
- Department of Immunology, Monash University, Melbourne, VIC, 3004, Australia
| | - Benjamin P Ross
- Pharmacy Australia Centre of Excellence, School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, QLD, 4102, Australia
| | - Raafat Mohamed
- Pharmacy Australia Centre of Excellence, School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, QLD, 4102, Australia
- Department of Basic Sciences, College of Dentistry, University of Mosul, Mosul, Iraq
| | - Suowen Xu
- Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Peter J Little
- Pharmacy Australia Centre of Excellence, School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, QLD, 4102, Australia
- Department of Pharmacy, Xinhua College of Sun Yat-Sen University, Tianhe District, Guangzhou, 510520, China
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29
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Zhou J, Lan Q, Li W, Yang L, You J, Zhang YM, Ni W. Tripartite motif protein 52 (TRIM52) promoted fibrosis in LX-2 cells through PPM1A-mediated Smad2/3 pathway. Cell Biol Int 2020; 44:108-116. [PMID: 31329338 DOI: 10.1002/cbin.11206] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 07/16/2019] [Indexed: 01/24/2023]
Abstract
To investigate the roles of tripartite motif containing 52 (TRIM52) in human hepatic fibrosis in vitro, human hepatic stellate cell line LX-2 cells were transfected with hepatitis B virus (HBV) replicon to establish HBV-induced fibrosis in LX-2 cells, and then treated with small interfering RNA-mediated knockdown of TRIM52 (siTRIM52). LX-2 cells without HBV replicon transfection were treated with lentiviruses-mediated overexpression of TRIM52 and phosphatase magnesium dependent 1A (PPM1A). Fibrosis response of LX-2 cells were assessed by the production of hydroxyproline (Hyp) and collagen I/III, as well as protein levels of α-smooth muscle actin (α-SMA). PPM1A and phosphorylated (p)-Smad2/3 were measured to assess the mechanism. The correlation between TRIM52 and PPM1A was determined using co-immunoprecipitation, and whether and how TRIM52 regulated the degradation of PPM1A were determined by ubiquitination assay. Our data confirmed HBV-induced fibrogenesis of LX-2 cells, as evidenced by significant increase in Hyp and collagen I/III and α-SMA, which was associated with reduction of PPM1A and elevation of transforming growth factor-β (TGF-β), p-Smad2/3, and p-Smad3L. However, those changes induced by HBV were significantly attenuated with additional siTRIM52 treatment. Similar to HBV, overexpression of TRIM52 exerted promoted effect in the fibrosis of LX-2 cells. Interestingly, TRIM52 induced the fibrogenesis of LX-2 cells and the activation of TGF-β/Smad pathway were significantly reversed by PPM1A overexpression. Furthermore, our data confirmed TRIM52 as a deubiquitinase that influenced the accumulation of PPM1A protein, and subsequently regulated the fibrogenesis of LX-2 cells. TRIM52 was a fibrosis promoter in hepatic fibrosis in vitro, likely through PPM1A-mediated TGF-β/Smad pathway.
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Affiliation(s)
- Ju Zhou
- Department of Infectious Disease, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, P. R. China
| | - Qing Lan
- Department of Infectious Disease, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, P. R. China
| | - Wu Li
- Department of Infectious Disease, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, P. R. China
| | - Lin Yang
- Department of Traditional Chinese Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, P. R. China
| | - Jing You
- Department of Infectious Disease, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, P. R. China
| | - Yan-Mei Zhang
- Department of Infectious Disease, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, P. R. China
| | - Wei Ni
- Department of Traditional Chinese Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, P. R. China
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30
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Wu C, Chen W, Ding H, Li D, Wen G, Zhang C, Lu W, Chen M, Yang Y. Salvianolic acid B exerts anti-liver fibrosis effects via inhibition of MAPK-mediated phospho-Smad2/3 at linker regions in vivo and in vitro. Life Sci 2019; 239:116881. [PMID: 31678285 DOI: 10.1016/j.lfs.2019.116881] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/13/2019] [Accepted: 09/16/2019] [Indexed: 12/17/2022]
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31
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Penke LR, Peters-Golden M. Molecular determinants of mesenchymal cell activation in fibroproliferative diseases. Cell Mol Life Sci 2019; 76:4179-4201. [PMID: 31563998 PMCID: PMC6858579 DOI: 10.1007/s00018-019-03212-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 06/01/2019] [Accepted: 06/26/2019] [Indexed: 02/06/2023]
Abstract
Uncontrolled scarring, or fibrosis, can interfere with the normal function of virtually all tissues of the body, ultimately leading to organ failure and death. Fibrotic diseases represent a major cause of death in industrialized countries. Unfortunately, no curative treatments for these conditions are yet available, highlighting the critical need for a better fundamental understanding of molecular mechanisms that may be therapeutically tractable. The ultimate indispensable effector cells responsible for deposition of extracellular matrix proteins that comprise scars are mesenchymal cells, namely fibroblasts and myofibroblasts. In this review, we focus on the biology of these cells and the molecular mechanisms that regulate their pertinent functions. We discuss key pro-fibrotic mediators, signaling pathways, and transcription factors that dictate their activation and persistence. Because of their possible clinical and therapeutic relevance, we also consider potential brakes on mesenchymal cell activation and cellular processes that may facilitate myofibroblast clearance from fibrotic tissue-topics that have in general been understudied.
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Affiliation(s)
- Loka R Penke
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, 6301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109-5642, USA
| | - Marc Peters-Golden
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, 6301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109-5642, USA.
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Lysyl oxidases: linking structures and immunity in the tumor microenvironment. Cancer Immunol Immunother 2019; 69:223-235. [PMID: 31650200 PMCID: PMC7000489 DOI: 10.1007/s00262-019-02404-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 09/24/2019] [Indexed: 02/08/2023]
Abstract
The lysyl oxidases (LOXs) are a family of enzymes deputed to cross-link collagen and elastin, shaping the structure and strength of the extracellular matrix (ECM). However, many novel “non-canonical” functions, alternative substrates, and regulatory mechanisms have been described and are being continuously elucidated. The activity of LOXs, therefore, appears to be integrated into a complex network of signals regulating many cell functions, including survival/proliferation/differentiation. Among these signaling pathways, TGF-β and PI3K/Akt/mTOR, in particular, cross-talk extensively with each other and with LOXs also initiating complex feedback loops which modulate the activity of LOXs and direct the remodeling of the ECM. A growing body of evidence indicates that LOXs are not only important in the homeostasis of the normal structure of the ECM, but are also implicated in the establishment and maturation of the tumor microenvironment. LOXs’ association with advanced and metastatic cancer is well established; however, there is enough evidence to support a significant role of LOXs in the transformation of normal epithelial cells, in the accelerated tumor development and the induction of invasion of the premalignant epithelium. A better understanding of LOXs and their interactions with the different elements of the tumor immune microenvironment will prove invaluable in the design of novel anti-tumor strategies.
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Ramos-Tovar E, Muriel P. Free radicals, antioxidants, nuclear factor-E2-related factor-2 and liver damage. J Appl Toxicol 2019; 40:151-168. [PMID: 31389060 DOI: 10.1002/jat.3880] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 07/03/2019] [Accepted: 07/04/2019] [Indexed: 12/11/2022]
Abstract
Oxidative/nitrosative stress is proposed to be a critical factor in various diseases, including liver pathologies. Antioxidants derived from medicinal plants have been studied extensively and are relevant to many illnesses, including liver diseases. Several hepatic disorders, such as viral hepatitis and alcoholic or nonalcoholic steatohepatitis, involve free radicals/oxidative stress as agents that cause or at least exacerbate liver injury, which can result in chronic liver diseases, such as liver fibrosis, cirrhosis and end-stage hepatocellular carcinoma. In this scenario, nuclear factor-E2-related factor-2 (Nrf2) appears to be an essential factor to counteract or attenuate oxidative or nitrosative stress in hepatic cells. In fact, a growing body of evidence indicates that Nrf2 plays complex and multicellular roles in hepatic inflammation, fibrosis, hepatocarcinogenesis and regeneration via the induction of its target genes. Inflammation is the most common feature of chronic liver diseases, triggering fibrosis, cirrhosis and hepatocellular carcinoma. Increasing evidence indicates that Nrf2 counteracts the proinflammatory process by modulating the recruitment of inflammatory cells and inducing the endogenous antioxidant response of the cell. In this review, the interactions between antioxidant and inflammatory molecular pathways are analyzed.
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Affiliation(s)
- Erika Ramos-Tovar
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico
| | - Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico
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Wang L, Yang G, Yuan L, Yang Y, Zhao H, Ho CT, Li S. Green Tea Catechins Effectively Altered Hepatic Fibrogenesis in Rats by Inhibiting ERK and Smad1/2 Phosphorylation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:5437-5445. [PMID: 30424599 DOI: 10.1021/acs.jafc.8b05179] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Polyphenols derived from green tea have been reported to have a wide range of profound functions. Tea catechins, including epicatechin, epigallocatechin (EGC), epicatechin-3- O-gallate (ECG), and epigallocatechin-3- O-gallate (EGCG), are considered as the major bioactive polyphenols in tea. The present study was designed to elucidate the potential antifibrogenic role of three abundant tea catechins (ECG, EGC, and EGCG) in a CCl4-induced fibrotic rat and their underlying molecular mechanisms. Tea catechins, especially groups of ECG, EGC, and EGCG, effectively induced several beneficial alterations of liver injury markers, oxidative status, and liver histology. Furthermore, catechins ameliorated liver fibrosis, as evidenced by the reduced expression of desmin, α-smooth muscle actin, transforming growth factor β (TGF-β), and downstream ERK1/2 and Smad1/2 phosphorylation. The most significant inhibitory effect on those proteins was observed in ECG (300 mg/kg) and EGCG (300 mg/kg) groups. In addition, catechins conferred their protective role by downregulating the proinflammation cytokines TGF-β, tumor necrosis factor α, and interleukin 17. It is postulated that tea catechins, particularly ECG and EGCG, are potential therapeutic candidates in antifibrotic therapy.
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Affiliation(s)
- Liwen Wang
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
- Tianjin Key Laboratory of Food and Biotechnology, School of Biotechnology and Food Science , Tianjin University of Commerce , Tianjin 300134 , People's Republic of China
| | - Guliang Yang
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
| | - Li Yuan
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
| | - Yiwen Yang
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
| | - Hui Zhao
- Tianjin Key Laboratory of Food and Biotechnology, School of Biotechnology and Food Science , Tianjin University of Commerce , Tianjin 300134 , People's Republic of China
| | - Chi-Tang Ho
- Department of Food Science , Rutgers, The State University of New Jersey , New Brunswick , New Jersey 08901 , United States
| | - Shiming Li
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
- Department of Food Science , Rutgers, The State University of New Jersey , New Brunswick , New Jersey 08901 , United States
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Lin TA, Ke BJ, Cheng CS, Wang JJ, Wei BL, Lee CL. Red Quinoa Bran Extracts Protects against Carbon Tetrachloride-Induced Liver Injury and Fibrosis in Mice via Activation of Antioxidative Enzyme Systems and Blocking TGF-β1 Pathway. Nutrients 2019; 11:nu11020395. [PMID: 30781895 PMCID: PMC6412755 DOI: 10.3390/nu11020395] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/07/2019] [Accepted: 02/08/2019] [Indexed: 12/31/2022] Open
Abstract
The late stages of liver fibrosis are considered to be irreversible. Red quinoa (Chenopodium formosanum Koidz), a traditional food for Taiwanese aborigines, was gradually developed as a novel supplemental food due to high dietary fibre and polyphenolic compounds. Its bran was usually regarded as the agricultural waste, but it contained a high concentration of rutin known as an antioxidant and anti-inflammatory agent. This study is to explore the effect of red quinoa bran extracts on the prevention of carbon tetrachloride (CCl4)-induced liver fibrosis. BALB/c mice were intraperitoneally injected CCl4 to induce liver fibrosis and treated with red quinoa whole seed powder, bran ethanol extracts, bran water extracts, and rutin. In the results, red quinoa powder provided more protection than rutin against CCl4-induced oxidative stress, pro-inflammatory factor expression and fibrosis development. However, the bran ethanol extract with high rutin content provided the most liver protection and anti-fibrosis effect via blocking the tumor necrosis factor alpha (TNF-α)/interleukin 6 (IL-6) pathway and transforming growth factor beta 1 (TGF-β1) pathway.
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Affiliation(s)
- Ting-An Lin
- Department of Life Science, National Taitung University, Taitung 950, Taiwan.
| | - Bo-Jun Ke
- Department of Life Science, National Taitung University, Taitung 950, Taiwan.
| | | | - Jyh-Jye Wang
- Department of Nutrition and Health Science, Fooyin University, Kaohsiung 831, Taiwan.
| | - Bai-Luh Wei
- Department of Life Science, National Taitung University, Taitung 950, Taiwan.
| | - Chun-Lin Lee
- Department of Life Science, National Taitung University, Taitung 950, Taiwan.
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Ramos-Tovar E, Buendia-Montaño LD, Galindo-Gómez S, Hernández-Aquino E, Tsutsumi V, Muriel P. Stevia prevents experimental cirrhosis by reducing hepatic myofibroblasts and modulating molecular profibrotic pathways. Hepatol Res 2019; 49:212-223. [PMID: 30338893 DOI: 10.1111/hepr.13275] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 09/17/2018] [Accepted: 10/10/2018] [Indexed: 12/21/2022]
Abstract
AIM The aims of the present study were to investigate the capacity of stevia leaves to prevent experimental cirrhosis induced by chronic administration of carbon tetrachloride (CCl4 ) in rats and to explore the action mechanism involved. METHODS Liver cirrhosis was established by CCl4 treatment (400 mg/kg i.p. three times a week for 12 weeks); stevia powder was administered (100 mg/kg by gavage daily) during the CCl4 treatment. Serum markers of liver damage and hydroxyproline were evaluated and histopathological analyses were carried out. The profibrotic pathways were analyzed by western blot and immunohistochemistry. RESULTS We found for the first time that stevia cotreatment prevented the elevation of serum markers of necrosis and cholestasis and the occurrence of liver fibrosis. It is worth noting that stevia downregulated several profibrogenic pathways, including the reduction of hepatic myofibroblasts and decreased matrix metalloproteinase (MMP)2 and MMP13 expression, thereby blocking the liberation of transforming growth factor-β from the extracellular matrix. Notably, stevia reduced the phosphorylation of pSmad3L, the most profibrogenic and mitogenic Smad, by inhibiting the activation of c-Jun N-terminal kinase and extracellular signal-regulated kinase. Interestingly, Smad7, an important antifibrotic molecule, was upregulated by stevia treatment in cirrhotic rats. These multitarget mechanisms led to the prevention of experimental cirrhosis. CONCLUSIONS Because stevia possesses a reasonable safety profile, our results indicate that it could be useful in the clinical setting to treat chronic liver diseases.
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Affiliation(s)
- Erika Ramos-Tovar
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico
| | - Laura D Buendia-Montaño
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico
| | - Silvia Galindo-Gómez
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Mexico City, Mexico
| | - Erika Hernández-Aquino
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico
| | - Víctor Tsutsumi
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Mexico City, Mexico
| | - Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico
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Jiang Y, Zhao Y, He F, Wang H. Artificial MicroRNA-Mediated Tgfbr2 and Pdgfrb Co-Silencing Ameliorates Carbon Tetrachloride-Induced Hepatic Fibrosis in Mice. Hum Gene Ther 2018; 30:179-196. [PMID: 30024280 DOI: 10.1089/hum.2018.047] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic stellate cells (HSCs) are the primary cell type responsible for liver fibrogenesis. Transforming growth factor beta 1 (TGF-β1) and platelet-derived growth factor (PDGF) are key profibrotic cytokines that regulate HSC activation and proliferation with functional convergence. Dual RNA interference against their receptors may achieve therapeutic effects. A novel RNAi strategy based on HSC-specific GFAP promoter-driven and lentiviral-expressed artificial microRNAs (amiRNAs) was devised that consists of an microRNA-30a backbone and effective shRNAs against mouse Pdgfrβ and Tgfbr2. Then, its antifibrotic efficacy was tested in primary and cultured HSCs and in mice affected with carbon tetrachloride-induced hepatic fibrosis. The study shows that amiRNA-mediated Pdgfrβ and Tgfbr2 co-silencing inhibits HSC activation and proliferation. After recombinant lentiviral particles were delivered into the liver via tail-vein injection, therapeutic amiRNAs were preferentially expressed in HSCs and efficiently co-knocked down in situ Tgfbr2 and Pdgfrβ expression, which correlates with downregulated expression of target or effector genes of their signaling, which include Pai-1, P70S6K, and D-cyclins. amiRNA-based HSC-specific co-silencing of Tgfbr2 and Pdgfrβ significantly suppressed hepatic expression of fibrotic markers α-Sma and Col1a1, extracellular matrix regulators Mmps and Timp1, and phenotypically ameliorated liver fibrosis, as indicated by reductions in serum alanine aminotransferase activity, collagen deposition, and α-Sma-positive staining. The findings provide proof of concept for the use of amiRNA-mediated co-silencing of two profibrogenic pathways in liver fibrosis treatment and highlight the therapeutic potential of concatenated amiRNAs for gene therapy.
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Affiliation(s)
- Yan Jiang
- 1 The Fifth People's Hospital of Shanghai, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Yuanyuan Zhao
- 1 The Fifth People's Hospital of Shanghai, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Fuchu He
- 1 The Fifth People's Hospital of Shanghai, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, P.R. China.,2 State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, P.R. China
| | - Haijian Wang
- 1 The Fifth People's Hospital of Shanghai, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, P.R. China
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Kamato D, Burch M, Zhou Y, Mohamed R, Stow JL, Osman N, Zheng W, Little PJ. Individual Smad2 linker region phosphorylation sites determine the expression of proteoglycan and glycosaminoglycan synthesizing genes. Cell Signal 2018; 53:365-373. [PMID: 30423352 DOI: 10.1016/j.cellsig.2018.11.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 11/09/2018] [Accepted: 11/09/2018] [Indexed: 01/04/2023]
Abstract
Growth factors such as thrombin and transforming growth factor (TGF)-β facilitate glycosaminoglycan (GAG) chain hyperelongation on proteoglycans, a phenomenon that increases lipoprotein binding in the vessel wall and the development of atherosclerosis. TGF-β signals via canonical carboxy terminal phosphorylation of R-Smads and also non-canonical linker region phosphorylation of R-Smads. The G protein coupled receptor agonist, thrombin, can transactivate the TGF-β receptor leading to both canonical and non-canonical Smad signalling. Linker region phosphorylation drives the expression of genes for the synthesis of the proteoglycan, biglycan. Proteoglycan synthesis involves core protein synthesis, the initiation of GAG chains and the subsequent elongation of GAG chains. We have explored the relationship between the thrombin stimulated phosphorylation of individual serine and threonine sites in the linker region of Smad2 and the expression of GAG initiation xylosyltransferase-1 (XT-1) and GAG elongation chondroitin 4-sulfotransferase-1 (C4ST-1) and chondroitin synthase-1 (CHSY-1) genes. Thrombin stimulated the phosphorylation of all four target residues (Thr220, Ser245, Ser250 and Ser255 residues) with a similar temporal pattern - phosphorylation was maximal at 15 min (the earliest time point studied) and the level of the phospho-proteins declined thereafter over the following 4 h. Jnk, p38 and PI3K, selectively mediated the phosphorylation of the Thr220 residue whereas the serine residues were variously phosphorylated by multiple kinases. Thrombin stimulated the expression of all three genes - XT-1, C4ST-1 and CHSY-1. The three pathways mediating Thr220 phosphorylation were also involved in the expression of XT-1. The target pathways (excluding Jnk) were involved in the expression of the GAG elongation genes (C4ST-1 and CHSY-1). These findings support the contention that individual Smad linker region phosphorylation sites are linked to the expression of genes for the initiation and elongation of GAG chains on proteoglycans. The context of this work is that a specific inhibitor of GAG elongation represents a potential therapeutic agent for preventing GAG elongation and lipid binding and the results indicate that the specificity of the pathways is such that it might be therapeutically feasible to specifically target GAG elongation without interfering with other physiological processes with which proteoglycans are involved.
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Affiliation(s)
- Danielle Kamato
- School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD 4102, Australia; Department of Pharmacy, Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou 510520, China.
| | - Micah Burch
- Department of Cardiovascular Medicine, Brigham and Harvard Medical School, Boston, MA 02115, USA
| | - Ying Zhou
- School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD 4102, Australia
| | - Raafat Mohamed
- School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD 4102, Australia
| | - Jennifer L Stow
- Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, 4067, Australia
| | - Narin Osman
- School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD 4102, Australia; School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia; Department of Immunology and Pathology, Monash University, Melbourne, VIC 3004, Australia
| | - Wenhua Zheng
- School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD 4102, Australia; Faculty of Health Sciences, University of Macau, Taipa, China
| | - Peter J Little
- School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD 4102, Australia; Department of Pharmacy, Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou 510520, China
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Impaired mammary tumor formation and metastasis by the point mutation of a Smad3 linker phosphorylation site. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3664-3671. [DOI: 10.1016/j.bbadis.2018.08.031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 08/08/2018] [Accepted: 08/23/2018] [Indexed: 02/06/2023]
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Wu C, Kan H, Hu M, Liu X, Boye A, Jiang Y, Wu J, Wang J, Yang X, Yang Y. Compound Astragalus and Salvia miltiorrhiza extract inhibits hepatocarcinogenesis via modulating TGF-β/TβR and Imp7/8. Exp Ther Med 2018; 16:1052-1060. [PMID: 30112050 PMCID: PMC6090435 DOI: 10.3892/etm.2018.6292] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 05/11/2018] [Indexed: 12/15/2022] Open
Abstract
Compound Astragalus and Salvia miltiorrhiza extract (CASE) is a Chinese herbal formula consisting of astragalosides, astragalus polysaccharide and salvianolic acids extracted from Astragalus membranaceus and Salvia miltiorhiza. Previous studies by our group have demonstrated that CASE effectively suppresses diethylinitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats via modulating transforming growth factor β/Mothers against decapentaplegic (TGFβ/Smad) signaling. To further elucidate the mechanism of CASE, the effects of CASE on TGF-β1, the serine/threonine kinase receptors of TGF-β [TGF-β receptor type-I (TβRI) and TβRII] and karyopherins [Importin 7 (Imp7) and Imp8], which are crucial for TGF-β/Smad signaling in fibro-hepatocarcinogenesis, were assessed in the present study using in vivo (DEN-induced HCC in rats) and in vitro [TGF-β1-stimulated rat myofibroblasts (MFBs) and HepG2 cells] models of fibro-hepatocarcinogenesis. Hematoxylin and eosin staining revealed that CASE may suppress inflammatory reactions and fibrosis in HCC as well as increasing the differentiation of HCC cells. Positive TGF-β1 staining was increased in HCC nodule areas and in adjacent normal liver tissues in DEN-treated rats, while TβRI staining was increased only in normal adjacent liver tissues. The elevated expression of TGF-β1, TβRI and TβRII was suppressed by CASE. CASE treatment also reduced glutathione S-transferase P 1 and Imp7/8 protein expression in fibro-hepatocarcinogenesis. In vitro experiments confirmed that CASE was able to decrease the expression of TβRI and TβRII in TGF-β1-stimulated MFBs and HepG2 cells. These results indicate that the anti-HCC effect of CASE may be achieved by mediating TGF-β/TβR and Imp7/8 protein expression, suggesting that CASE has multiple targets in HCC treatment.
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Affiliation(s)
- Chao Wu
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Hongwei Kan
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Min Hu
- Department of Pathology, Anhui University of Chinese Traditional Medicine, Hefei, Anhui 230038, P.R. China
| | - Xin Liu
- Therapeutics Research Centre, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia
| | - Alex Boye
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yufeng Jiang
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Jiajun Wu
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Jiyu Wang
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Xiaochuan Yang
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yan Yang
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
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Yoshida K, Matsuzaki K, Murata M, Yamaguchi T, Suwa K, Okazaki K. Clinico-Pathological Importance of TGF-β/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis. Cancers (Basel) 2018; 10:cancers10060183. [PMID: 29874844 PMCID: PMC6025395 DOI: 10.3390/cancers10060183] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 05/19/2018] [Accepted: 06/01/2018] [Indexed: 12/20/2022] Open
Abstract
Chronic viral hepatitis is a global public health problem, with approximately 570 million persons chronically infected. Hepatitis B and C viruses increase the risk of morbidity and mortality from liver cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic complications that develop. Hepatitis virus infection induces transforming growth factor (TGF)-β, which influences microenvironments within the infected liver. TGF-β promotes liver fibrosis by up-regulating extracellular matrix production by hepatic stellate cells. TGF-β is also up-regulated in patients with HCC, in whom it contributes importantly to bringing about a favorable microenvironment for tumor growth. Thus, TGF-β is thought to be a major factor regulating liver fibrosis and carcinogenesis. Since TGF-β carries out regulatory signaling by influencing the phosphorylation of Smads, we have generated several kinds of phospho-specific antibodies to Smad2/3. Using these, we have identified three types of phospohorylated forms: COOH-terminally phosphorylated Smad2/3 (pSmad2C and pSmad3C), linker phosphorylated Smad2/3 (pSmad2L and pSmad3L), and dually phosphorylated Smad3 (pSmad2L/C and pSmad3L/C). TGF-β-mediated pSmad2/3C signaling terminates cell proliferation; on the other hand, cytokine-induced pSmad3L signaling accelerates cell proliferation and promotes fibrogenesis. This review addresses TGF-β/Smad signal transduction in chronic liver injuries and carcinogenic processes. We also discuss the reversibility of Smad signaling after antiviral therapy.
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Affiliation(s)
- Katsunori Yoshida
- Department of Gastroenterology and Hepatology, Kansai Medical University 2-5-1, Shin-Machi, Hirakata, Osaka 573-1010, Japan.
| | - Koichi Matsuzaki
- Department of Gastroenterology and Hepatology, Kansai Medical University 2-5-1, Shin-Machi, Hirakata, Osaka 573-1010, Japan.
| | - Miki Murata
- Department of Gastroenterology and Hepatology, Kansai Medical University 2-5-1, Shin-Machi, Hirakata, Osaka 573-1010, Japan.
| | - Takashi Yamaguchi
- Department of Gastroenterology and Hepatology, Kansai Medical University 2-5-1, Shin-Machi, Hirakata, Osaka 573-1010, Japan.
| | - Kanehiko Suwa
- Department of Gastroenterology and Hepatology, Kansai Medical University 2-5-1, Shin-Machi, Hirakata, Osaka 573-1010, Japan.
| | - Kazuichi Okazaki
- Department of Gastroenterology and Hepatology, Kansai Medical University 2-5-1, Shin-Machi, Hirakata, Osaka 573-1010, Japan.
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G protein coupled receptors can transduce signals through carboxy terminal and linker region phosphorylation of Smad transcription factors. Life Sci 2018; 199:10-15. [DOI: 10.1016/j.lfs.2018.03.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 02/23/2018] [Accepted: 03/02/2018] [Indexed: 11/22/2022]
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Chen Y, Wu Z, Yuan B, Dong Y, Zhang L, Zeng Z. MicroRNA-146a-5p attenuates irradiation-induced and LPS-induced hepatic stellate cell activation and hepatocyte apoptosis through inhibition of TLR4 pathway. Cell Death Dis 2018; 9:22. [PMID: 29348414 PMCID: PMC5833436 DOI: 10.1038/s41419-017-0038-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 10/05/2017] [Accepted: 10/06/2017] [Indexed: 12/14/2022]
Abstract
Elevated toll-like receptor 4 (TLR4) expression is associated with a high risk of radiation-induced liver disease (RILD). MicroRNA (miR)-146a-5p is a key regulator of lipopolysaccharide (LPS)/TLR4 signaling, but its role in modulation of RILD remains unclear. Here, we found that irradiation and LPS stimulation induced TLR4 and miR-146a-5p expression in the human hepatic stellate cell (HSC) line LX2. Ectopic expression of miR-146a-5p in LX2 inhibited irradiation-induced and LPS-induced pro-inflammatory cytokine secretion and cell proliferation, and promoted cell apoptosis by down-regulating the expression levels of TLR4, interleukin-1 receptor associated kinase 1 (IRAK1), tumor necrosis factor receptor associated factor 6 (TRAF6) and phosphorylation of nuclear factor-kappa B. In addition, the culture medium from the irradiated and LPS-stimulated HSCs transfected with miR-146a-5p significantly attenuated apoptosis in irradiated hepatocytes. Overexpression of miR-146a-5p reduced α-smooth muscle actin production in irradiated and LPS-stimulated LX2 cells, which was associated with inhibition of TRAF6-mediated JNK and Smad2 phosphorylation. Knockdown of TRAF6 or IRAK1 mimicked the effects of miR-146a-5p on HSC function. Furthermore, miR-146a-5p treatment alleviated irradiation-induced and endotoxin-induced hepatic inflammatory response and fibrogenesis in mice through inhibition of the TLR4 signaling pathway. Collectively, this study reveals the anti-pro-inflammatory and anti-fibrotic effects of miR-146a-5p on liver injury, and suggests a potential application of miR-146a-5p in the therapeutic prevention of RILD.
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Affiliation(s)
- Yuhan Chen
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, 200032, Shanghai, China
| | - Zhifeng Wu
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, 200032, Shanghai, China
| | - Baoying Yuan
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, 200032, Shanghai, China
| | - Yinying Dong
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, 200032, Shanghai, China
| | - Li Zhang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, 200032, Shanghai, China
| | - Zhaochong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, 200032, Shanghai, China.
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44
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TGF-β-Induced Endothelial-Mesenchymal Transition in Fibrotic Diseases. Int J Mol Sci 2017; 18:ijms18102157. [PMID: 29039786 PMCID: PMC5666838 DOI: 10.3390/ijms18102157] [Citation(s) in RCA: 273] [Impact Index Per Article: 34.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 10/06/2017] [Accepted: 10/13/2017] [Indexed: 12/22/2022] Open
Abstract
Fibrotic diseases are characterized by net accumulation of extracellular matrix proteins in affected organs leading to their dysfunction and ultimate failure. Myofibroblasts have been identified as the cells responsible for the progression of the fibrotic process, and they originate from several sources, including quiescent tissue fibroblasts, circulating CD34⁺ fibrocytes and the phenotypic conversion of various cell types into activated myofibroblasts. Several studies have demonstrated that endothelial cells can transdifferentiate into mesenchymal cells through a process termed endothelial- mesenchymal transition (EndMT) and that this can give rise to activated myofibroblasts involved in the development of fibrotic diseases. Transforming growth factor β (TGF-β) has a central role in fibrogenesis by modulating the fibroblast phenotype and function, inducing myofibroblast transdifferentiation and promoting matrix accumulation. In addition, TGF-β by inducing EndMT may further contribute to the development of fibrosis. Despite extensive investigation of the pathogenesis of fibrotic diseases, no effective treatment strategies are available. Delineation of the mechanisms responsible for initiation and progression of fibrotic diseases is crucial for the development of therapeutic strategies for the treatment of the disease. In this review, we summarize the role of the TGF-β signaling pathway and EndMT in the development of fibrotic diseases and discuss their therapeutic potential.
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45
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Cheng JC, Tseng CP, Liao MH, Peng CY, Yu JS, Chuang PH, Huang JT, Chen JJW. Activation of hepatic stellate cells by the ubiquitin C-terminal hydrolase 1 protein secreted from hepatitis C virus-infected hepatocytes. Sci Rep 2017; 7:4448. [PMID: 28667290 PMCID: PMC5493679 DOI: 10.1038/s41598-017-04259-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 05/11/2017] [Indexed: 12/17/2022] Open
Abstract
Hepatitis C virus (HCV) infection of hepatocytes promotes liver fibrosis by activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix in liver tissue. Whether or not host factors released from the HCV-infected hepatocytes play role in HSCs activation is unclear. In this study, HSCs were activated by the conditioned medium derived from HCV replicon cells. Secretomic profiling of HCV replicon cells and the parental Huh7 cells revealed ubiquitin carboxy-terminal hydrolase L1 (UCHL1) as a novel secreted protein from HCV-infected hepatocytes. UCHL1 expression in hepatocytes was induced by HCV infection. UCHL1 was expressed in the liver and found in the plasma of patients with chronic hepatitis C. Molecular analysis by use of the anti-UCHL1 neutralization antibody and purified UCHL1 protein showed that secreted UCHL1 protein was bound to the cell surface of HSCs and activated JNK signaling leading to overexpression of alpha-smooth muscle actin and the activation of HSCs. These results provide further for understanding the underlying mechanism in HCV-mediated hepatic fibrogenesis.
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Affiliation(s)
- Ju-Chien Cheng
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, 40402, Taiwan.
| | - Ching-Ping Tseng
- Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, 33302, Taiwan.,Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, 33302, Taiwan.,Molecular Medicine Research Center, Chang Gung University, Taoyuan, 33302, Taiwan.,Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan, 33302, Taiwan
| | - Mei-Huei Liao
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, 40402, Taiwan.,Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40402, Taiwan
| | - Cheng-Yuan Peng
- Department of Internal Medicine, China Medical University Hospital, Taichung, 40402, Taiwan
| | - Jau-Song Yu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, 33302, Taiwan.,Molecular Medicine Research Center, Chang Gung University, Taoyuan, 33302, Taiwan.,Liver Research Center, Chang Gung Memorial Hospital, Linkou, 33302, Taiwan
| | - Po-Heng Chuang
- Department of Internal Medicine, China Medical University Hospital, Taichung, 40402, Taiwan
| | - Jing-Tang Huang
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, 40402, Taiwan
| | - Jeremy J W Chen
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40402, Taiwan
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46
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Lopez ON, Bohanon FJ, Wang X, Ye N, Corsello T, Rojas-Khalil Y, Chen H, Chen H, Zhou J, Radhakrishnan RS. STAT3 Inhibition Suppresses Hepatic Stellate Cell Fibrogenesis: HJC0123, a Potential Therapeutic Agent for Liver Fibrosis. RSC Adv 2016; 6:100652-100663. [PMID: 28546859 PMCID: PMC5440088 DOI: 10.1039/c6ra17459k] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Hepatic Stellate Cells (HSCs) are the major source of the excessive extracellular matrix (ECM) production that replaces liver parenchyma with fibrous tissue during liver fibrosis. The signal transducer and activator of transcription 3 (STAT3) promotes HCSs survival, proliferation, and activation contributing to fibrogenesis. We have previously used a fragment-based drug design approach and have discovered a novel STAT3 inhibitor, HJC0123. Here, we explored the biological effects of HJC0123 on the fibrogenic properties of HSCs. HJC0123 treatment resulted in the inhibition of HSCs proliferation at submicromolar concentrations. HJC0123 reduced the phosphorylation, nuclear translocation, and transcriptional activity of STAT3. It decreased the expression of STAT3-regulated proteins, induced cell cycle arrest, promoted apoptosis and downregulated SOCS3. HJC0123 treatment inhibited HSCs activation and downregulated ECM protein fibronectin and type I collagen expression. In addition, HJC0123 increased IL-6 production and decreased TGF-β induced Smad2/3 phosphorylation. These results demonstrate that HJC0123 represents a novel STAT3 inhibitor that suppresses the fibrogenic properties of HSCs, suggesting its therapeutic potential in liver fibrosis.
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Affiliation(s)
- Omar Nunez Lopez
- Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, USA, 77555
| | - Fredrick J. Bohanon
- Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, USA, 77555
| | - Xiaofu Wang
- Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, USA, 77555
| | - Na Ye
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, USA, 77555
| | - Tiziana Corsello
- Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, USA, 77555
| | - Yesenia Rojas-Khalil
- Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, USA, 77555
| | - Haijun Chen
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, USA, 77555
| | - Haiying Chen
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, USA, 77555
| | - Jia Zhou
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, USA, 77555
- Department of Pediatrics, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, USA, 77555
| | - Ravi S. Radhakrishnan
- Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, USA, 77555
- Department of Pediatrics, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, USA, 77555
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47
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Amygdalin inhibits HSC-T6 cell proliferation and fibrosis through the regulation of TGF-β/CTGF. Mol Cell Toxicol 2016. [DOI: 10.1007/s13273-016-0031-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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48
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JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships. Microbiol Mol Biol Rev 2016; 80:793-835. [PMID: 27466283 DOI: 10.1128/mmbr.00043-14] [Citation(s) in RCA: 378] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.
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49
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MicroRNA-146a-5p Negatively Regulates Pro-Inflammatory Cytokine Secretion and Cell Activation in Lipopolysaccharide Stimulated Human Hepatic Stellate Cells through Inhibition of Toll-Like Receptor 4 Signaling Pathways. Int J Mol Sci 2016; 17:ijms17071076. [PMID: 27399683 PMCID: PMC4964452 DOI: 10.3390/ijms17071076] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 06/20/2016] [Accepted: 06/28/2016] [Indexed: 12/13/2022] Open
Abstract
Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this study, we found that TLR4 and α-smooth muscle actin (α-SMA) were up-regulated and miR-146a-5p was down-regulated in human hepatic stellate cell (HSC) line LX2 after LPS stimulation. Overexpression of miR-146a-5p inhibited LPS induced pro-inflammatory cytokines secretion through down-regulating the expression levels of TLR-4, IL-1 receptor-associated kinase 1 (IRAK1), TNF receptor associated factor-6 (TRAF6) and phosphorylation of nuclear factor-kappa B (NF-κB). Knockdown of IRAK1 and TRAF6 also suppressed pro-inflammatory cytokine production by inhibiting NF-κB phosphorylation. In addition, miR-146a-5p mimic blocked LPS induced TRAF6 dependent c-Jun N-terminal kinase (JNK) and Smad2 activation as well as α-SMA production. Taken together, these results suggest that miR-146a-5p suppresses pro-inflammatory cytokine secretion and cell activation of HSC through inhibition of TLR4/NF-κB and TLR4/TRAF6/JNK pathway.
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50
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Alonso-Merino E, Martín Orozco R, Ruíz-Llorente L, Martínez-Iglesias OA, Velasco-Martín JP, Montero-Pedrazuela A, Fanjul-Rodríguez L, Contreras-Jurado C, Regadera J, Aranda A. Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses. Proc Natl Acad Sci U S A 2016; 113:E3451-60. [PMID: 27247403 PMCID: PMC4914168 DOI: 10.1073/pnas.1506113113] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
TGF-β, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-β/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMAD-binding elements in response to TGF-β, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases.
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Affiliation(s)
- Elvira Alonso-Merino
- Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 20829 Madrid, Spain
| | - Rosa Martín Orozco
- Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 20829 Madrid, Spain
| | - Lidia Ruíz-Llorente
- Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 20829 Madrid, Spain
| | - Olaia A Martínez-Iglesias
- Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 20829 Madrid, Spain
| | - Juan Pedro Velasco-Martín
- Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, 20829 Madrid, Spain
| | - Ana Montero-Pedrazuela
- Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 20829 Madrid, Spain
| | - Luisa Fanjul-Rodríguez
- Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 20829 Madrid, Spain
| | - Constanza Contreras-Jurado
- Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 20829 Madrid, Spain
| | - Javier Regadera
- Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, 20829 Madrid, Spain
| | - Ana Aranda
- Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 20829 Madrid, Spain;
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