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Liu X, Wang X, Xu L, Fan J, Yuan Q, Zhang F, Liu J, Qiu X, Li Y, Xia C, Liu H. Targeting delivery of a novel TGF-β type I receptor-mimicking peptide to activated hepatic stellate cells for liver fibrosis therapy via inhibiting the TGF-β1/Smad and p38 MAPK signaling pathways. Eur J Pharmacol 2024; 977:176708. [PMID: 38843945 DOI: 10.1016/j.ejphar.2024.176708] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 06/01/2024] [Accepted: 06/03/2024] [Indexed: 06/23/2024]
Abstract
Excessive transforming growth factor β1 (TGF-β1) secreted by activated hepatic stellate cells (aHSCs) aggravates liver fibrosis via over-activation of TGF-β1-mediated signaling pathways in a TGF-β type I receptor (TβRI) dependent manner. TβRI with the C-terminal valine truncated (RIPΔ), as a novel TβRI-mimicking peptide, is an appealing anti-fibrotic candidate by competitive binding of TGF-β1 to block TGF-β1 signal transduction. Platelet-derived growth factor receptor β (PDGFβR) is highly expressed on the surface of aHSCs in liver fibrosis. Herein, we designed a novel RIPΔ variant Z-RIPΔ (PDGFβR-specific affibody ZPDGFβR fused to the N-terminus of RIPΔ) for liver fibrosis therapy, and expect to improve the anti-liver fibrosis efficacy by specifically inhibiting the TGF-β1 activity in aHSCs. Target peptide Z-RIPΔ was prepared in Escherichia coli by SUMO fusion system. Moreover, Z-RIPΔ specifically bound to TGF-β1-activated aHSCs, inhibited cell proliferation and migration, and reduced the expression of fibrosis markers (α-SMA and FN) and TGF-β1 pathway-related effectors (p-Smad2/3 and p-p38) in vitro. Furthermore, Z-RIPΔ specifically targeted the fibrotic liver, alleviated the liver histopathology, mitigated the fibrosis responses, and blocked TGF-β1-mediated Smad and p38 MAPK cascades. More importantly, Z-RIPΔ exhibited a higher fibrotic liver-targeting capacity and stronger anti-fibrotic effects than its parent RIPΔ. Besides, Z-RIPΔ showed no obvious toxicity effects in treating both an in vitro cell model and an in vivo mouse model of liver fibrosis. In conclusion, Z-RIPΔ represents a promising targeted candidate for liver fibrosis therapy.
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Affiliation(s)
- Xiaohui Liu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157011, PR China
| | - Xiaohua Wang
- Laboratory of Pathogenic Microbiology and Immunology, Mudanjiang Medical University, Mudanjiang, 157011, PR China; Department of Cell Biology, Mudanjiang Medical University, Mudanjiang, 157011, PR China
| | - Liming Xu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157011, PR China
| | - Junjie Fan
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157011, PR China
| | - Qi Yuan
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157011, PR China
| | - Fan Zhang
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157011, PR China
| | - Jieting Liu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157011, PR China
| | - Xiaowen Qiu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157011, PR China
| | - Yanqiu Li
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157011, PR China
| | - Caiyun Xia
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157011, PR China
| | - Haifeng Liu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157011, PR China; Laboratory of Pathogenic Microbiology and Immunology, Mudanjiang Medical University, Mudanjiang, 157011, PR China.
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Guo Y, Tian G, Chen X, Hou Y, Zhang X, Xue X, Zhao L, Wu Y. GL-V9 ameliorates liver fibrosis by inhibiting TGF-β/smad pathway. Exp Cell Res 2023; 425:113521. [PMID: 36841325 DOI: 10.1016/j.yexcr.2023.113521] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 02/12/2023] [Accepted: 02/13/2023] [Indexed: 02/27/2023]
Abstract
Liver fibrosis is a wound-healing response that arises from various aetiologies. Flavonoid compounds have been proved of their anti-liver fibrosis effects. This study aimed to elucidate the protective effect and mechanism of flavonoid compound GL-V9 on CCl4-induced and DDC-induced liver fibrosis. Treatment with GL-V9 alleviated hepatic injury and exhibited a dramatic protection effect of liver fibrosis. Further experiments found that GL-V9 treatment inhibited extracellular matrix (ECM) expression. Activation of hepatic stellate cells (HSCs) is a central driver of fibrosis. GL-V9 could inhibit the activation of HSCs through directly binding to TGFβRI, subsequently inhibit TGF-β/Smad pathway. In conclusion, this study proved that GL-V9 executed a protective effect on liver fibrosis by inhibiting TGF-β/Smad pathway.
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Affiliation(s)
- Yabing Guo
- Pharmaceutical Animal Experimental Center of China Pharmaceutical University, Nanjing, 211198, China
| | - Geng Tian
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Xin Chen
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Yingjian Hou
- Center of Cellular and Molecular Biology, China Pharmaceutical University, Nanjing, 211198, China
| | - Xinyu Zhang
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Xin Xue
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Li Zhao
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
| | - Yun Wu
- Yancheng Third People's Hospital, Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng, 224001, China.
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Lyu SY, Xiao W, Cui GZ, Yu C, Liu H, Lyu M, Kuang QY, Xiao EH, Luo YH. Role and mechanism of DNA methylation and its inhibitors in hepatic fibrosis. Front Genet 2023; 14:1124330. [PMID: 37056286 PMCID: PMC10086238 DOI: 10.3389/fgene.2023.1124330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
Liver fibrosis is a repair response to injury caused by various chronic stimuli that continually act on the liver. Among them, the activation of hepatic stellate cells (HSCs) and their transformation into a myofibroblast phenotype is a key event leading to liver fibrosis, however the mechanism has not yet been elucidated. The molecular basis of HSC activation involves changes in the regulation of gene expression without changes in the genome sequence, namely, via epigenetic regulation. DNA methylation is a key focus of epigenetic research, as it affects the expression of fibrosis-related, metabolism-related, and tumor suppressor genes. Increasing studies have shown that DNA methylation is closely related to several physiological and pathological processes including HSC activation and liver fibrosis. This review aimed to discuss the mechanism of DNA methylation in the pathogenesis of liver fibrosis, explore DNA methylation inhibitors as potential therapies for liver fibrosis, and provide new insights on the prevention and clinical treatment of liver fibrosis.
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Affiliation(s)
- Shi-Yi Lyu
- Department of Radiology, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
| | - Wang Xiao
- Department of Gastrointestinal Surgery, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
| | - Guang-Zu Cui
- XiangYa School of Medicine, Central South University, Changsha, Hunan, China
| | - Cheng Yu
- Department of Radiology, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
| | - Huan Liu
- Department of Radiology, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
| | - Min Lyu
- Department of Radiology, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
| | - Qian-Ya Kuang
- Department of Radiology, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
| | - En-Hua Xiao
- Department of Radiology, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
| | - Yong-Heng Luo
- Department of Radiology, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China
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Ramos-Tovar E, Muriel P. Free radicals, antioxidants, nuclear factor-E2-related factor-2 and liver damage. VITAMINS AND HORMONES 2022; 121:271-292. [PMID: 36707137 DOI: 10.1016/bs.vh.2022.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The liver performs various biochemical and molecular functions. Its location as a portal to blood arriving from the intestines makes it susceptible to several insults, leading to diverse pathologies, including alcoholic liver disease, viral infections, nonalcoholic steatohepatitis, and hepatocellular carcinoma, which are causes of death worldwide. Illuminating the molecular mechanism underlying hepatic injury will provide targets to develop new therapeutic strategies to fight liver maladies. In this regard, reactive oxygen species (ROS) are well-recognized mediators of liver damage. ROS induce nuclear factor-κB and the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 inflammasome, which are the main proinflammatory signaling pathways that upregulate several proinflammatory and profibrogenic mediators. Additionally, oxygen-derived free radicals induce hepatic stellate cell activation to produce exacerbated quantities of extracellular matrix proteins, leading to fibrosis, cirrhosis and eventually hepatocellular carcinoma. Exogenous and endogenous antioxidants counteract the harmful effects of ROS, preventing liver necroinflammation and fibrogenesis. Therefore, several researchers have demonstrated that the administration of antioxidants, mainly derived from plants, affords beneficial effects on the liver. Notably, nuclear factor-E2-related factor-2 (Nrf2) is a major factor against oxidative stress in the liver. Increasing evidence has demonstrated that Nrf2 plays an important role in liver necroinflammation and fibrogenesis via the induction of antioxidant response element genes. The use of Nrf2 inducers seems to be an interesting approach to prevent/attenuate hepatic disorders, particularly under conditions where ROS play a causative role.
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Affiliation(s)
- Erika Ramos-Tovar
- Postgraduate Studies and Research Section, School of Higher Education in Medicine-IPN, Mexico City, Mexico.
| | - Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico.
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Tao S, Yang L, Wu C, Hu Y, Guo F, Ren Q, Ma L, Fu P. Gambogenic acid alleviates kidney fibrosis via epigenetic inhibition of EZH2 to regulate Smad7-dependent mechanism. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 106:154390. [PMID: 35994849 DOI: 10.1016/j.phymed.2022.154390] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 08/03/2022] [Accepted: 08/10/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Epigenetics regulating gene expression plays important role in kidney fibrosis. Natural products originating from diverse sources including plants and microorganisms are capable to influence epigenetic modifications. Gambogenic acid (GNA) is a caged xanthone extracted from gamboge resin, exudation of Garcinia hanburyi Hook.f., and the effect of GNA on kidney fibrosis with its underlying mechanism on epigenetics remains unknown. PURPOSE This study aimed to explore the role of GNA against kidney fibrogenesis by histone methylation mediating gene expression. METHODS Two experimental mice of unilateral ureteral obstruction (UUO) and folic acid (FA) were given two dosages of GNA (3 and 6 mg/kg/d). TGF-β1 was used to stimulate mouse tubular epithelial (TCMK-1) cells and siRNAs were transfected to verify the underlying mechanisms of GNA. Histological changes were evaluated by HE, MASSON stainings, immunohistochemistry and immunofluorescence. Western blot and qPCR were used to measure protein/gene transcription levels. RESULTS GNA dose-dependently alleviated UUO-induced kidney fibrosis and FA-induced kidney early fibrosis, indicated by the pathology and fibrotic factor changes (α-SMA, collagen I, collagen VI, and fibronectin). Mechanically, GNA reduced enhancer of zeste homolog 2 (EZH2) and H3K27me3, promoted Smad7 transcription, and inhibited TGF-β/Smad3 fibrotic signaling in injured kidneys. Moreover, with TGF-β1-induced EZH2 increasing, GNA suppressed α-SMA, fibronectin and collagen levels in tubular epithelial TCMK-1 cells. Although partially decreasing EZH2, GNA did not influence fibrotic signaling in Smad7 siRNA-transfected TCMK-1 cells. CONCLUSION Epigenetic inhibition of EZH2 by GNA ameliorated kidney fibrogenesis via regulating Smad7-meidated TGF-β/Smad3 signaling.
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Affiliation(s)
- Sibei Tao
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lina Yang
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Chenzhou Wu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Ying Hu
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Fan Guo
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Qian Ren
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Liang Ma
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, China.
| | - Ping Fu
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, China
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Petrou IG, Nikou S, Madduri S, Nifora M, Bravou V, Kalbermatten DF. The Role of Hippo Signaling Pathway and ILK in the Pathophysiology of Human Hypertrophic Scars and Keloids: An Immunohistochemical Investigation. Cells 2022; 11:3426. [PMID: 36359821 PMCID: PMC9657014 DOI: 10.3390/cells11213426] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/22/2022] [Accepted: 10/26/2022] [Indexed: 08/03/2023] Open
Abstract
BACKGROUND Keloids and hypertrophic scars are characterized by abnormal fibroblast activation and proliferation. While their molecular pathogenesis remains unclear, myofibroblasts have been associated with their development. Hippo pathway effectors YAP/TAZ promote cell proliferation and matrix stiffening. Integrin-linked kinase (ILK), a central component of focal adhesions that mediates cell-matrix interactions, has been linked to tissue repair and fibrosis. The aim of this study was to investigate the expression of key Hippo pathway molecules and ILK in hypertrophic scars and keloids. METHODS YAP/TAZ, TEAD4, ILK and a-SMA expression were evaluated by immunohistochemistry in keloids (n = 55), hypertrophic scars (n = 38) and normal skin (n = 14). RESULTS The expression of YAP/TAZ, TEAD4, ILK and a-SMA was higher in fibroblasts of keloids compared to hypertrophic scars while negative in normal skin. There was a significant positive correlation between the expression of ILK and Hippo pathway effectors. CONCLUSIONS Our results suggest that the deregulation of Hippo signaling and ILK are implicated in keloid and hypertrophic scar formation.
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Affiliation(s)
- Ilias G. Petrou
- Department of Plastic, Reconstructive and Aesthetic Surgery, Faculty of Medicine, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland
| | - Sofia Nikou
- Department of Anatomy, School of Medicine, University of Patras, 26504 Rio Patras, Greece
| | - Srinivas Madduri
- Department of Plastic, Reconstructive and Aesthetic Surgery, Faculty of Medicine, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland
| | - Martha Nifora
- Department of Histopathology, “St.-Andrew” General Hospital of Patras, 26332 Patras, Greece
| | - Vasiliki Bravou
- Department of Anatomy, School of Medicine, University of Patras, 26504 Rio Patras, Greece
| | - Daniel F. Kalbermatten
- Department of Plastic, Reconstructive and Aesthetic Surgery, Faculty of Medicine, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland
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Deshpande A, Shetty PMV, Frey N, Rangrez AY. SRF: a seriously responsible factor in cardiac development and disease. J Biomed Sci 2022; 29:38. [PMID: 35681202 PMCID: PMC9185982 DOI: 10.1186/s12929-022-00820-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 05/27/2022] [Indexed: 11/10/2022] Open
Abstract
The molecular mechanisms that regulate embryogenesis and cardiac development are calibrated by multiple signal transduction pathways within or between different cell lineages via autocrine or paracrine mechanisms of action. The heart is the first functional organ to form during development, which highlights the importance of this organ in later stages of growth. Knowledge of the regulatory mechanisms underlying cardiac development and adult cardiac homeostasis paves the way for discovering therapeutic possibilities for cardiac disease treatment. Serum response factor (SRF) is a major transcription factor that controls both embryonic and adult cardiac development. SRF expression is needed through the duration of development, from the first mesodermal cell in a developing embryo to the last cell damaged by infarction in the myocardium. Precise regulation of SRF expression is critical for mesoderm formation and cardiac crescent formation in the embryo, and altered SRF levels lead to cardiomyopathies in the adult heart, suggesting the vital role played by SRF in cardiac development and disease. This review provides a detailed overview of SRF and its partners in their various functions and discusses the future scope and possible therapeutic potential of SRF in the cardiovascular system.
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Affiliation(s)
- Anushka Deshpande
- Department of Internal Medicine III, Cardiology and Angiology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.,Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partner site Hamburg/Kiel/Lübeck, Kiel, Germany
| | - Prithviraj Manohar Vijaya Shetty
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Norbert Frey
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Ashraf Yusuf Rangrez
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany. .,DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
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Epithelial plasticity, epithelial-mesenchymal transition, and the TGF-β family. Dev Cell 2021; 56:726-746. [PMID: 33756119 DOI: 10.1016/j.devcel.2021.02.028] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 01/04/2021] [Accepted: 02/23/2021] [Indexed: 12/15/2022]
Abstract
Epithelial cells repress epithelial characteristics and elaborate mesenchymal characteristics to migrate to other locations and acquire new properties. Epithelial plasticity responses are directed through cooperation of signaling pathways, with TGF-β and TGF-β-related proteins playing prominent instructive roles. Epithelial-mesenchymal transitions (EMTs) directed by activin-like molecules, bone morphogenetic proteins, or TGF-β regulate metazoan development and wound healing and drive fibrosis and cancer progression. In carcinomas, diverse EMTs enable stem cell generation, anti-cancer drug resistance, genomic instability, and localized immunosuppression. This review discusses roles of TGF-β and TGF-β-related proteins, and underlying molecular mechanisms, in epithelial plasticity in development and wound healing, fibrosis, and cancer.
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Chen F, Sheng L, Xu C, Li J, Ali I, Li H, Cai Y. Ufbp1, a Key Player of Ufm1 Conjugation System, Protects Against Ketosis-Induced Liver Injury via Suppressing Smad3 Activation. Front Cell Dev Biol 2021; 9:676789. [PMID: 34307359 PMCID: PMC8297976 DOI: 10.3389/fcell.2021.676789] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 06/02/2021] [Indexed: 01/06/2023] Open
Abstract
The dairy cattle suffer from severe liver dysfunction during the pathogenesis of ketosis. The Ufm1 conjugation system is crucial for liver development and homeostasis. Ufm1 binding protein (Ufbp1) is a putative Ufm1 target and an integral component, but its role in ketosis-induced liver injury is unclear so far. The purpose of this study is to explore the key role of Ufbp1 in liver fibrosis caused by ketosis in vivo and in vitro. Liver tissues were collected from ketotic cows and Ufbp1 conditional knockout (CKO) mice in vivo. However, Ufbp1–/– mouse embryonic fibroblast cells and Hela cells were used for in vitro validation. Subsequently, various assays were performed to reveal the underlying molecular mechanisms of the Ufbp1 protective effect. In this study, hepatic fibrosis, endoplasmic reticulum (ER) stress, and apoptosis were reported in the liver of ketotic cows, fibrotic markers (alpha-smooth muscle actin, Collagen1) and ER stress markers (glucose-regulated protein 78, CEBP homologous protein) were upregulated remarkably, and the apoptosis-related genes (Bcl2, Bax) were in line with expectations. Interestingly, Ufbp1 expression was almost disappeared, and Smad2/Smad3 protein was largely phosphorylated in the liver of ketotic cows, but Ufbp1 deletion caused Smad3 phosphorylation apparently, rather than Smad2, and elevated ER stress was observed in the CKO mice model. At the cellular level, Ufbp1 deficiency led to serious fibrotic and ER stress response, Smad3 was activated by phosphorylation significantly and then was translocated into the nucleus, whereas p-Smad2 was largely unaffected in embryonic fibroblast cells. Ufbp1 overexpression obviously suppressed Smad3 phosphorylation in Hela cells. Ufbp1 was found to be in full combination with Smad3 using endogenous immunoprecipitation. Taken together, our findings suggest that downregulation or ablation of Ufbp1 leads to Smad3 activation, elevated ER stress, and hepatocyte apoptosis, which in turn causes liver fibrosis. Ufbp1 plays a protective role in ketosis-induced liver injury.
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Affiliation(s)
- Fanghui Chen
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Le Sheng
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Chenjie Xu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Jun Li
- College of Life Sciences, Anhui Normal University, Wuhu, China
| | - Ilyas Ali
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Honglin Li
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Yafei Cai
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
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Xie W, He M, Liu Y, Huang X, Song D, Xiao Y. CircPlekha7 plays an anti-fibrotic role in intrauterine adhesions by modulating endometrial stromal cell proliferation and apoptosis. J Reprod Dev 2020; 66:493-504. [PMID: 32801258 PMCID: PMC7768166 DOI: 10.1262/jrd.2019-165] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 07/14/2020] [Indexed: 12/12/2022] Open
Abstract
Circular RNA (circRNA) plays a key role in the development and progression of several diseases; however, its role in intrauterine adhesions (IUAs) is not well understood. This study aims to investigate the expression profiles and potential role of circRNA in IUA. RNA-sequencing was performed to screen for abnormally expressed circRNAs in TGF-β1-induced IUA endometrial stromal cell (ESC) model (IUA group) and an SMAD3 inhibitor, SIS3-treated IUA ESC model (SIS3 group). Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to uncover the key functions and pathways. Interaction networks were constructed and analyzed based on the competing endogenous RNA hypothesis of circRNA. CircRNAs were validated by Sanger sequencing and quantitative polymerase chain reaction (qPCR). Cell proliferation and apoptosis were measured using MTS and flow cytometry, respectively. The protein and mRNA expression levels of fibrosis-related proteins were measured using western blotting and reverse transcription-qPCR, respectively. A total of 66 circRNAs were differentially expressed between the IUA and SIS3 groups. CircPlekha7 was identified as one of the significantly upregulated circRNAs in the SIS3 group. Overexpression of circPlekha7 enhanced apoptosis, decreased the viability of ESCs, and suppressed the expression of α-SMA, collagen I, and SMAD3 in ESCs; whereas knockdown of circPlekha7 exhibited opposite results. Altogether, the results indicate that circPlekha7 plays an anti-fibrotic role in IUA and may serve as a promising prognostic biomarker for patients with IUA. Therefore, overexpression of circPlekha7 could be a potential treatment strategy for IUA.
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Affiliation(s)
- Wei Xie
- Hysteroscopic Centre, Fu Xing Hospital, Capital Medical University, Beijing100038, China
| | - Min He
- Department of Reproductive Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China
| | - Yuhuan Liu
- Hysteroscopic Centre, Fu Xing Hospital, Capital Medical University, Beijing100038, China
| | - Xiaowu Huang
- Hysteroscopic Centre, Fu Xing Hospital, Capital Medical University, Beijing100038, China
| | - Dongmei Song
- Hysteroscopic Centre, Fu Xing Hospital, Capital Medical University, Beijing100038, China
| | - Yu Xiao
- Hysteroscopic Centre, Fu Xing Hospital, Capital Medical University, Beijing100038, China
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Mehmood A, Zhao L, Ishaq M, Zad OD, Zhao L, Wang C, Usman M, Lian Y, Xu M. Renoprotective effect of stevia residue extract on adenine-induced chronic kidney disease in mice. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.103983] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
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12
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Alyaseer AAA, de Lima MHS, Braga TT. The Role of NLRP3 Inflammasome Activation in the Epithelial to Mesenchymal Transition Process During the Fibrosis. Front Immunol 2020; 11:883. [PMID: 32508821 PMCID: PMC7251178 DOI: 10.3389/fimmu.2020.00883] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 04/16/2020] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is considered a complex form of tissue damage commonly present in the end stage of many diseases. It is also related to a high percentage of death, whose predominant characteristics are an excessive and abnormal deposition of fibroblasts and myofibroblasts -derived extracellular matrix (ECM) components. Epithelial-to-mesenchymal transition (EMT), a process in which epithelial cells gradually change to mesenchymal ones, is a major contributor in the pathogenesis of fibrosis. The key mediator of EMT is a multifunctional cytokine called transforming growth factor-β (TGF-β) that acts as the main inducer of the ECM assembly and remodeling through the phosphorylation of Smad2/3, which ultimately forms a complex with Smad4 and translocates into the nucleus. On the other hand, the bone morphogenic protein-7 (BMP-7), a member of the TGF family, reverses EMT by directly counteracting TGF-β induced Smad-dependent cell signaling. NLRP3 (NACHT, LRR, and PYD domains-containing protein 3), in turn, acts as cytosolic sensors of microbial and self-derived molecules and forms an immune complex called inflammasome in the context of inflammatory commitments. NLRP3 inflammasome assembly is triggered by extracellular ATP, reactive oxygen species (ROS), potassium efflux, calcium misbalance, and lysosome disruption. Due to its involvement in multiple diseases, NLRP3 has become one of the most studied pattern-recognition receptors (PRRs). Nevertheless, the role of NLRP3 in fibrosis development has not been completely elucidated. In this review, we described the relation of the previously mentioned fibrosis pathway with the NLRP3 inflammasome complex formation, especially EMT-related pathways. For now, it is suggested that the EMT happens independently from the oligomerization of the whole inflammasome complex, requiring just the presence of the NLRP3 receptor and the ASC protein to trigger the EMT events, and we will present different pieces of research that give controversial point of views.
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Affiliation(s)
| | | | - Tarcio Teodoro Braga
- Department of Pathology, Federal University of Parana, Curitiba, Brazil.,Instituto Carlos Chagas, Fiocruz-Parana, Curitiba, Brazil
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Zheng XP, Nie Q, Feng J, Fan XY, Jin YL, Chen G, Du JW. Kidney-targeted baicalin-lysozyme conjugate ameliorates renal fibrosis in rats with diabetic nephropathy induced by streptozotocin. BMC Nephrol 2020; 21:174. [PMID: 32398108 PMCID: PMC7216346 DOI: 10.1186/s12882-020-01833-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 04/29/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is one of the most common and serious complications of diabetes, and is the most important cause of death for diabetic patients. Baicalin (BAI) has anti-oxidative, anti-inflammatory and anti-apoptotic activities, which play a role in attenuating insulin resistance and protecting the kidney. Moreover, cell-specific targeting of renal tubular cells is an approach to enhance drug accumulation in the kidney. METHODS Forty-five Sprague-Dawley rats were divided into four groups. A diabetes model was created using streptozotocin (STZ) intraperitoneally injection. The four groups included: Control group (n = 10), DN (n = 15), BAI treatment (BAI; n = 10) and BAI-LZM treatment (BAI-LZM; n = 10) groups. In the current study, the renoprotection and anti-fibrotic effects of BAI-lysozyme (LZM) conjugate were further investigated in rats with DN induced by STZ compared with BAI treatment alone. RESULTS The results suggest that BAI-LZM better ameliorates renal impairment, metabolic disorder and renal fibrosis than BAI alone in rats with DN, and the potential regulatory mechanism likely involves inhibiting inflammation via the nuclear factor-κB signaling pathway, inhibiting extracellular matrix accumulation via the transforming growth factor-β/Smad3 pathway and regulating cell proliferation via the insulin-like growth factor (IGF)-1/IGF-1 receptor/p38 Mitogen-activated protein kinase (MAPK) pathway. BAI and the kidney-targeted BAI-LZM can utilize the body's cytoprotective pathways to reactivate autophagy (as indicated by the autophagy markers mechanistic target of rapamycin and sirtuin 1 to ameliorate DN outcomes. CONCLUSIONS Our data support the traditional use of S. baicalensis as an important anti-DN traditional chinese medicine (TCM), and BAI, above all BAI-LZM, is a promising source for the identification of molecules with anti-DN effects.
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Affiliation(s)
- Xiao-Peng Zheng
- Department of basic medical sciences, Taizhou University hospital, Taizhou University, No 1139 Shifu Road, Jiaojiang District, Taizhou, 318000, China
- College of Basic Medical Sciences, Jiamusi University, No 148 Xuefu Street, Jiamusi, 154007, China
| | - Qing Nie
- Weifang centers for disease control and prevention, No 4801 Huixian Road, Gaoxin Distric, Weifang, 261061, Shandong Province, China
| | - Jing Feng
- Department of basic medical sciences, Taizhou University hospital, Taizhou University, No 1139 Shifu Road, Jiaojiang District, Taizhou, 318000, China
- College of Basic Medical Sciences, Jiamusi University, No 148 Xuefu Street, Jiamusi, 154007, China
| | - Xiao-Yan Fan
- Department of basic medical sciences, Taizhou University hospital, Taizhou University, No 1139 Shifu Road, Jiaojiang District, Taizhou, 318000, China
| | - Yue-Lei Jin
- Department of basic medical sciences, Taizhou University hospital, Taizhou University, No 1139 Shifu Road, Jiaojiang District, Taizhou, 318000, China
| | - Guang Chen
- Department of basic medical sciences, Taizhou University hospital, Taizhou University, No 1139 Shifu Road, Jiaojiang District, Taizhou, 318000, China.
| | - Ji-Wei Du
- Nursing department, Xiang'An Hospital, Xiamen University, Xiamen, 361005, China.
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Dan Q, Shi Y, Rabani R, Venugopal S, Xiao J, Anwer S, Ding M, Speight P, Pan W, Alexander RT, Kapus A, Szászi K. Claudin-2 suppresses GEF-H1, RHOA, and MRTF, thereby impacting proliferation and profibrotic phenotype of tubular cells. J Biol Chem 2019; 294:15446-15465. [PMID: 31481470 DOI: 10.1074/jbc.ra118.006484] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 08/21/2019] [Indexed: 12/19/2022] Open
Abstract
The tight junctional pore-forming protein claudin-2 (CLDN-2) mediates paracellular Na+ and water transport in leaky epithelia and alters cancer cell proliferation. Previously, we reported that tumor necrosis factor-α time-dependently alters CLDN-2 expression in tubular epithelial cells. Here, we found a similar expression pattern in a mouse kidney injury model (unilateral ureteral obstruction), consisting of an initial increase followed by a drop in CLDN-2 protein expression. CLDN-2 silencing in LLC-PK1 tubular cells induced activation and phosphorylation of guanine nucleotide exchange factor H1 (GEF-H1), leading to Ras homolog family member A (RHOA) activation. Silencing of other claudins had no such effects, and re-expression of an siRNA-resistant CLDN-2 prevented RHOA activation, indicating specific effects of CLDN-2 on RHOA. Moreover, kidneys from CLDN-2 knockout mice had elevated levels of active RHOA. Of note, CLDN-2 silencing reduced LLC-PK1 cell proliferation and elevated expression of cyclin-dependent kinase inhibitor P27 (P27KIP1) in a GEF-H1/RHOA-dependent manner. P27KIP1 silencing abrogated the effects of CLDN-2 depletion on proliferation. CLDN-2 loss also activated myocardin-related transcription factor (MRTF), a fibrogenic RHOA effector, and elevated expression of connective tissue growth factor and smooth muscle actin. Finally, CLDN-2 down-regulation contributed to RHOA activation and smooth muscle actin expression induced by prolonged tumor necrosis factor-α treatment, because they were mitigated by re-expression of CLDN-2. Our results indicate that CLDN-2 suppresses GEF-H1/RHOA. CLDN-2 down-regulation, for example, by inflammation, can reduce proliferation and promote MRTF activation through RHOA. These findings suggest that the initial CLDN-2 elevation might aid epithelial regeneration, and CLDN-2 loss could contribute to fibrotic reprogramming.
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Affiliation(s)
- Qinghong Dan
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Yixuan Shi
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Razieh Rabani
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Shruthi Venugopal
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Jenny Xiao
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Shaista Anwer
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Mei Ding
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Pam Speight
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Wanling Pan
- Departments of Pediatrics and Physiology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
| | - R Todd Alexander
- Departments of Pediatrics and Physiology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
| | - András Kapus
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada.,Department of Surgery, University of Toronto, Ontario M5B 1T8, Canada
| | - Katalin Szászi
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada .,Department of Surgery, University of Toronto, Ontario M5B 1T8, Canada
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Isorhamnetin Inhibits Liver Fibrosis by Reducing Autophagy and Inhibiting Extracellular Matrix Formation via the TGF- β1/Smad3 and TGF- β1/p38 MAPK Pathways. Mediators Inflamm 2019; 2019:6175091. [PMID: 31467486 PMCID: PMC6701280 DOI: 10.1155/2019/6175091] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/25/2019] [Accepted: 06/16/2019] [Indexed: 02/07/2023] Open
Abstract
Objective Liver fibrosis is a consequence of wound-healing responses to chronic liver insult and may progress to liver cirrhosis if not controlled. This study investigated the protection against liver fibrosis by isorhamnetin. Methods Mouse models of hepatic fibrosis were established by intraperitoneal injection of carbon tetrachloride (CCl4) or bile duct ligation (BDL). Isorhamnetin 10 or 30 mg/kg was administered by gavage 5 days per week for 8 weeks in the CCl4 model and for 2 weeks in the BDL model. Protein and mRNA expressions were assayed by western blotting, immunohistochemistry, and quantitative real-time polymerase chain reaction. Results Isorhamnetin significantly inhibited liver fibrosis in both models, inhibiting hepatic stellate cell (HSC) activation, extracellular matrix (ECM) deposition, and autophagy. The effects were associated with downregulation of transforming growth factor β1 (TGF-β1) mediation of Smad3 and p38 mitogen-activated protein kinase (MAPK) signaling pathways. Conclusion Isorhamnetin protected against liver fibrosis by reducing ECM formation and autophagy via inhibition of TGF-β1-mediated Smad3 and p38 MAPK signaling pathways.
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Avila-Carrasco L, Majano P, Sánchez-Toméro JA, Selgas R, López-Cabrera M, Aguilera A, González Mateo G. Natural Plants Compounds as Modulators of Epithelial-to-Mesenchymal Transition. Front Pharmacol 2019; 10:715. [PMID: 31417401 PMCID: PMC6682706 DOI: 10.3389/fphar.2019.00715] [Citation(s) in RCA: 137] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 06/05/2019] [Indexed: 12/13/2022] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) is a self-regulated physiological process required for tissue repair that, in non-controled conditions may lead to fibrosis, angiogenesis, loss of normal organ function or cancer. Although several molecular pathways involved in EMT regulation have been described, this process does not have any specific treatment. This article introduces a systematic review of effective natural plant compounds and their extract that modulates the pathological EMT or its deleterious effects, through acting on different cellular signal transduction pathways both in vivo and in vitro. Thereby, cryptotanshinone, resveratrol, oxymatrine, ligustrazine, osthole, codonolactone, betanin, tannic acid, gentiopicroside, curcumin, genistein, paeoniflorin, gambogic acid and Cinnamomum cassia extracts inhibit EMT acting on transforming growth factor-β (TGF-β)/Smads signaling pathways. Gedunin, carnosol, celastrol, black rice anthocyanins, Duchesnea indica, cordycepin and Celastrus orbiculatus extract downregulate vimectin, fibronectin and N-cadherin. Sulforaphane, luteolin, celastrol, curcumin, arctigenin inhibit β-catenin signaling pathways. Salvianolic acid-A and plumbagin block oxidative stress, while honokiol, gallic acid, piperlongumine, brusatol and paeoniflorin inhibit EMT transcription factors such as SNAIL, TWIST and ZEB. Plectranthoic acid, resveratrol, genistein, baicalin, polyphyllin I, cairicoside E, luteolin, berberine, nimbolide, curcumin, withaferin-A, jatrophone, ginsenoside-Rb1, honokiol, parthenolide, phoyunnanin-E, epicatechin-3-gallate, gigantol, eupatolide, baicalin and baicalein and nitidine chloride inhibit EMT acting on other signaling pathways (SIRT1, p38 MAPK, NFAT1, SMAD, IL-6, STAT3, AQP5, notch 1, PI3K/Akt, Wnt/β-catenin, NF-κB, FAK/AKT, Hh). Despite the huge amount of preclinical data regarding EMT modulation by the natural compounds of plant, clinical translation is poor. Additionally, this review highlights some relevant examples of clinical trials using natural plant compounds to modulate EMT and its deleterious effects. Overall, this opens up new therapeutic alternatives in cancer, inflammatory and fibrosing diseases through the control of EMT process.
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Affiliation(s)
- Lorena Avila-Carrasco
- Therapeutic and Pharmacology Department, Health and Human Science Research, Academic Unit of Human Medicine and Health Sciences, Autonomous University of Zacatecas, Zacatecas, Mexico
| | - Pedro Majano
- Molecular Biology Unit, Research Institute of University Hospital La Princesa (IP), Madrid, Spain
| | - José Antonio Sánchez-Toméro
- Department and Nephrology, Research Institute of University Hospital La Princesa (IP), Madrid, Spain.,Renal research network REDINREN, Madrid, Spain
| | - Rafael Selgas
- Research Institute of La Paz (IdiPAZ), University Hospital La Paz, Madrid, Spain.,Renal research network REDINREN, Madrid, Spain
| | - Manuel López-Cabrera
- Renal research network REDINREN, Madrid, Spain.,Molecular Biology Research Centre Severo Ochoa, Spanish Council for Scientific Research (CSIC), Madrid, Spain
| | - Abelardo Aguilera
- Molecular Biology Unit, Research Institute of University Hospital La Princesa (IP), Madrid, Spain.,Renal research network REDINREN, Madrid, Spain
| | - Guadalupe González Mateo
- Research Institute of La Paz (IdiPAZ), University Hospital La Paz, Madrid, Spain.,Renal research network REDINREN, Madrid, Spain.,Molecular Biology Research Centre Severo Ochoa, Spanish Council for Scientific Research (CSIC), Madrid, Spain
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Zabini D, Granton E, Hu Y, Miranda MZ, Weichelt U, Breuils Bonnet S, Bonnet S, Morrell NW, Connelly KA, Provencher S, Ghanim B, Klepetko W, Olschewski A, Kapus A, Kuebler WM. Loss of SMAD3 Promotes Vascular Remodeling in Pulmonary Arterial Hypertension via MRTF Disinhibition. Am J Respir Crit Care Med 2019; 197:244-260. [PMID: 29095649 DOI: 10.1164/rccm.201702-0386oc] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
RATIONALE Vascular remodeling in pulmonary arterial hypertension (PAH) results from smooth muscle cell hypertrophy and proliferation of vascular cells. Loss of BMPR-II (bone morphogenetic protein receptor 2) signaling and increased signaling via TGF-β (transforming growth factor β) and its downstream mediators SMAD (small body size [a C. elegans protein] mothers against decapentaplegic [a Drosophila protein family])-2/3 has been proposed to drive lung vascular remodeling; yet, proteomic analyses indicate a loss of SMAD3 in PAH. OBJECTIVES We proposed that SMAD3 may be dysregulated in PAH and that loss of SMAD3 may present a pathophysiological master switch by disinhibiting its interaction partner, MRTF (myocardin-related transcription factor), which drives muscle protein expression. METHODS SMAD3 levels were measured in lungs from PAH patients, rats treated either with Sugen/hypoxia or monocrotaline (MCT), and in mice carrying a BMPR2 mutation. In vitro, effects of SMAD3 or BMPR2 silencing or SMAD3 overexpression on cell proliferation or smooth muscle hypertrophy were assessed. In vivo, the therapeutic and prophylactic potential of CCG1423, an inhibitor of MRTF, was investigated in Sugen/hypoxia rats. MEASUREMENTS AND MAIN RESULTS SMAD3 was downregulated in lungs of patients with PAH and in pulmonary arteries of three independent PAH animal models. TGF-β treatment replicated the loss of SMAD3 in human pulmonary artery smooth muscle cells (huPASMCs) and human pulmonary artery endothelial cells. SMAD3 silencing increased proliferation and migration in huPASMCs and human pulmonary artery endothelial cells. Coimmunoprecipitation revealed reduced interaction of MRTF with SMAD3 in TGF-β-treated huPASMCs and pulmonary arteries of PAH animal models. In huPASMCs, loss of SMAD3 or BMPR-II increased smooth muscle actin expression, which was attenuated by MRTF inhibition. Conversely, SMAD3 overexpression prevented TGF-β-induced activation of an MRTF reporter and reduced actin stress fibers in BMPR2-silenced huPASMCs. MRTF inhibition attenuated PAH and lung vascular remodeling in Sugen/hypoxia rats. CONCLUSIONS Loss of SMAD3 presents a novel pathomechanism in PAH that promotes vascular cell proliferation and-via MRTF disinhibition-hypertrophy of huPASMCs, thereby reconciling the parallel induction of a synthetic and contractile huPASMC phenotype.
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Affiliation(s)
- Diana Zabini
- 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.,2 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
| | - Elise Granton
- 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Yijie Hu
- 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Maria Zena Miranda
- 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Ulrike Weichelt
- 3 Department of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Sandra Breuils Bonnet
- 4 Pulmonary Hypertension Group of the Institute of Cardiology and Pulmonology, Laval University, Quebec City, Québec, Canada
| | - Sébastien Bonnet
- 4 Pulmonary Hypertension Group of the Institute of Cardiology and Pulmonology, Laval University, Quebec City, Québec, Canada
| | - Nicholas W Morrell
- 5 Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
| | - Kim A Connelly
- 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Steeve Provencher
- 4 Pulmonary Hypertension Group of the Institute of Cardiology and Pulmonology, Laval University, Quebec City, Québec, Canada
| | - Bahil Ghanim
- 6 Department of Thoracic Surgery, Medical University, Vienna, Austria; and
| | - Walter Klepetko
- 6 Department of Thoracic Surgery, Medical University, Vienna, Austria; and
| | - Andrea Olschewski
- 2 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
| | - Andras Kapus
- 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.,7 Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Wolfgang M Kuebler
- 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.,3 Department of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.,7 Department of Surgery, University of Toronto, Toronto, Ontario, Canada
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18
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Impact of single nucleotide polymorphisms on the efficacy and toxicity of EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer patients. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 781:63-70. [PMID: 31416579 DOI: 10.1016/j.mrrev.2019.04.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 04/04/2019] [Accepted: 04/08/2019] [Indexed: 01/11/2023]
Abstract
EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the treatment of choice for advanced-stage (IIIB-IV) NSCLC patients with mutations in EGFR. However, EGFR-TKIs clinical outcomes vary from person to person and these inter-individual differences may be due to genetic factors such as single nucleotide polymorphisms (SNPs). SNPs in genes involved in EGFR-TKIs pharmacodynamics, metabolism and mechanism of action have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with EGFR-TKIs. Here we review the influence of gene polymorphisms in the EGFR pathway on clinical outcome and toxicity to EGFR-TKIs in advanced NSCLC patients. The EGFR-216 polymorphism has reported a strong association between response and/or survival to EGFR-TKIs in Caucasian population. Similarly, the effect of EGFR-CA repeats polymorphisms on survival of advanced NSCLC patients treated with EGFR-TKIs have been confirmed both in Caucasian and Asian population. The influence on toxicity of the -216, -191, CA repeats, Arg497Lys and Asp994Asp polymorphisms in EGFR have also been confirmed. Polymorphisms in AKT (rs1130214 and rs1130233) and SMAD3 (rs6494633, rs11071938 and rs11632964) have been associated with survival in advanced NSCLC patients treated with EGFR-TKIs. However, data come from a limited number of studies and need to be confirmed. Finally, polymorphisms in genes coding proteins of the membrane transporters and cytochrome P450 enzymes have been less extensively investigated. There are few studies with small samples, which complicated the generalization of their role in EGFR-TKIs treatment.
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Ogaly HA, Eltablawy NA, Abd-Elsalam RM. Antifibrogenic Influence of Mentha piperita L. Essential Oil against CCl 4-Induced Liver Fibrosis in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:4039753. [PMID: 29849890 PMCID: PMC5933010 DOI: 10.1155/2018/4039753] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 01/10/2018] [Accepted: 01/18/2018] [Indexed: 12/22/2022]
Abstract
Essential oils of some aromatic plants provide an effective nonmedicinal option to control liver fibrosis. Mentha piperita L. essential oil (MPEO) have been reported to possess protective effects against hepatotoxicity. However, its effect against liver fibrosis remains unknown. The present study investigated the antifibrogenic potential of MPEO and its underlying mechanisms. Forty male rats divided into 4 groups were used: group 1 served as normal control, group 2 (liver fibrosis) received CCl4 (2.5 mL/kg, IP, twice weekly) for 8 weeks, group 3 concurrently received CCl4 plus MPEO (50 mg/kg, IP, daily, from the 3rd week), and group 4 received MPEO only. MPOE significantly improved the liver injury markers, lipid peroxidation (LPO), antioxidant capacity, CYP2E1 gene expressionand liver histology. Furthermore, MPOE ameliorated liver fibrosis as evidenced by the reduced expression of desmin, α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and SMAD3 proteins. In addition, MPOE counteracted the p53 upregulation induced by CCl4 at both mRNA and protein levels. In conclusion, MPOE could effectively attenuate hepatic fibrosis mainly through improving the redox status, suppressing p53 and subsequently modulating TGF-β1 and SMAD3 protein expression. These data promote the use of MPOE as a promising approach in antifibrotic therapy.
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Affiliation(s)
- Hanan A. Ogaly
- Department of Chemistry, College of Sciences, King Khalid University, Abha, Saudi Arabia
| | - Nadia A. Eltablawy
- Biochemistry Division, National Organization for Drug Control and Research (NODCAR), Giza, Egypt
| | - Reham M. Abd-Elsalam
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
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20
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Wang W, Zhou PH, Hu W, Xu CG, Zhou XJ, Liang CZ, Zhang J. Cryptotanshinone hinders renal fibrosis and epithelial transdifferentiation in obstructive nephropathy by inhibiting TGF-β1/Smad3/integrin β1 signal. Oncotarget 2017; 9:26625-26637. [PMID: 29928474 PMCID: PMC6003568 DOI: 10.18632/oncotarget.23803] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 09/03/2017] [Indexed: 01/28/2023] Open
Abstract
Recent studies have reported that CTS can alleviate cardiac fibrosis. However, the effects of CTS on kidney fibrosis and EMT are still unknown. This study explored whether CTS could attenuate tubulointerstitial fibrosis as well as EMT, and investigated the potential underlying mechanisms. In this study, an in vivo UUO mouse model and an in vitro TGF-β1 stimulated normal renal tubular kidney epithelial cell model were established. In UUO model, administration of 50 mg kg-1 day-1 CTS markedly decreased the occurrence of kidney injury and the accumulation of fibronectin and collagen-1. In addition, CTS reduced the expression level of α-SMA but retained E-cadherin in obstructed kidneys. In vitro, CTS suppressed the expression of fibronectin, collagen-1 and α-SMA but retained that of E-cadherin. Furthermore, CTS selectively abolished the activation of Smad3 and suppressed the nuclear translocation of Smad2, Smad3 and Smad4. CTS could block the promoter activity of integrin β1 induced by Smad3. Furthermore, CTS inhibited Smad3 binding to integrin β1 promoter sequences. These data suggest that CTS can ameliorate kidney fibrosis and EMT, at least in part, by inhibiting the TGF-β1/Smad3/integrin β1 signaling pathway.
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Affiliation(s)
- Wei Wang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University and Institute of Urology, Anhui Medical University, Hefei, Anhui, 232200, China.,Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, China
| | - Pang-Hu Zhou
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, China
| | - Wei Hu
- Department of Urology, The First Affiliated Hospital of Nan-Hua University, Henyang, Hunan, 421001, China
| | - Chang-Geng Xu
- Department of Urology, Wuhan Central Hospital, Wuhan, Hubei Province, 430014, China
| | - Xiang-Jun Zhou
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, China
| | - Chao-Zhao Liang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University and Institute of Urology, Anhui Medical University, Hefei, Anhui, 232200, China
| | - Jie Zhang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, China.,Huangshi Central Hospital, Hubei Polytechnic University, Huangshi, Hubei Province, 435000, China
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21
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Wang X, Gao JL, Zhao MM, Zhu HX, Tian YX, Li R, Jiang XH, Yu L, Tian JR, Cui JZ. Therapeutic effects of conditioned medium from bone marrow-derived mesenchymal stem cells on epithelial-mesenchymal transition in A549 cells. Int J Mol Med 2017; 41:659-668. [PMID: 29207055 PMCID: PMC5752235 DOI: 10.3892/ijmm.2017.3284] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 10/04/2017] [Indexed: 01/07/2023] Open
Abstract
Pulmonary fibrosis (PF) is a chronic lung disease. The transforming growth factor-β1 (TGF-β1)/Smad3 signaling pathway plays an important role in the pathogenesis of pulmonary fibrosis. Bone marrow-derived mesenchymal stem cells (BMSCs) have been shown to be a modulator of the molecular aspects of the fibrosis pathway. However, it is still unknown as to whether the conditioned medium from BMSCs (BMSCs-CM) inhibits the epithelial-mesenchymal transition (EMT) process. This study confirmed the hypothesis that BMSCs-CM exerts an anti-fibrotic effect on human type II alveolar epithelial cells (A549) by suppressing the phosphorylation of Smad3. We used the A549 cells in vitro to detect morphological evidence of EMT by phase-contrast microscopy. These cells were randomly divided into 4 groups as follows: the control group, the TGF-β1 group, the SIS3 (specific inhibitor of Smad3) group and the BMSCs-CM group. The immunofluorescence method was used to determined the location of E-cadherin (E-calcium mucins; E-cad), α-smooth muscle actin (α-SMA) and p-Smad3. The expression levels of E-cad, CK8, α-SMA, vimentin, p-Smad3, Snail1, collagen I (COLI) and collagen III (COLIII) were detected by western blot analysis. Following exposure to TGF-β1, the A549 cells displayed a spindle-shaped fibroblast-like morphology. In accordance with these morphological changes, the expression levels of E-cad and CK8 were downregulated, while the expression levels of α-SMA and vimentin were upregulated. Along with this process, the expression levels of p-Smad3, Snail1, COLI and COLIII were increased. However, the cells in the BMSCs-CM group and SIS3 group exhibited a decrease in the levels of α-SMA and vimentin (which had been upregulated by TGF-β1), and an increase in the levels of E-cad and CK8 expression (which had been downregulated by TGF-β1). On the whole, these results indicated that BMSCs-CM suppressed the EMT which might be associated with TGF-β1/Smad3. This study provides the theoretical basis for the research of the mechanisms responsible for pulmonary disease.
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Affiliation(s)
- Xin Wang
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Jun-Ling Gao
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Man-Man Zhao
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Hui-Xing Zhu
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Yan-Xia Tian
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Ran Li
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Xiao-Hua Jiang
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Lei Yu
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Jing-Rui Tian
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Jian-Zhong Cui
- Department of Neurosurgery, Tangshan Workers' Hospital, Tangshan, Hebei 063000, P.R. China
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22
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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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23
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Gasparics Á, Sebe A. MRTFs- master regulators of EMT. Dev Dyn 2017; 247:396-404. [PMID: 28681541 DOI: 10.1002/dvdy.24544] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 06/20/2017] [Accepted: 06/28/2017] [Indexed: 12/19/2022] Open
Abstract
Recent evidence implicates the myocardin-related transcription factors (MRTFs) as key mediators of the phenotypic plasticity leading to the conversion of various cell types into myofibroblasts. This review highlights the function of MRTFs during development, fibrosis and cancer, and the role of MRTFs during epithelial-mesenchymal transitions (EMTs) underlying these processes. EMT is a sequentially orchestrated process where cells undergo a rearrangement of their cell contacts and activate a fibrogenic and myogenic expression program. MRTFs interact with and regulate the major signaling pathways and the expression of key markers and transcription factors involved in EMT. These functions indicate a central role for MRTFs in controlling the process of EMT. Developmental Dynamics 247:396-404, 2018. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Ákos Gasparics
- Semmelweis University, Department of Pathophysiology, Budapest, Hungary.,Semmelweis University, 1st Department of Obstetrics and Gynecology, Budapest, Hungary
| | - Attila Sebe
- Semmelweis University, Department of Pathophysiology, Budapest, Hungary.,Paul Ehrlich Institute, Division of Medical Biotechnology, Langen, Germany
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24
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Miranda MZ, Bialik JF, Speight P, Dan Q, Yeung T, Szászi K, Pedersen SF, Kapus A. TGF-β1 regulates the expression and transcriptional activity of TAZ protein via a Smad3-independent, myocardin-related transcription factor-mediated mechanism. J Biol Chem 2017; 292:14902-14920. [PMID: 28739802 DOI: 10.1074/jbc.m117.780502] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 06/30/2017] [Indexed: 12/20/2022] Open
Abstract
Hippo pathway transcriptional coactivators TAZ and YAP and the TGF-β1 (TGFβ) effector Smad3 regulate a common set of genes, can physically interact, and exhibit multilevel cross-talk regulating cell fate-determining and fibrogenic pathways. However, a key aspect of this cross-talk, TGFβ-mediated regulation of TAZ or YAP expression, remains uncharacterized. Here, we show that TGFβ induces robust TAZ but not YAP protein expression in both mesenchymal and epithelial cells. TAZ levels, and to a lesser extent YAP levels, also increased during experimental kidney fibrosis. Pharmacological or genetic inhibition of Smad3 did not prevent the TGFβ-induced TAZ up-regulation, indicating that this canonical pathway is dispensable. In contrast, inhibition of p38 MAPK, its downstream effector MK2 (e.g. by the clinically approved antifibrotic pirferidone), or Akt suppressed the TGFβ-induced TAZ expression. Moreover, TGFβ elevated TAZ mRNA in a p38-dependent manner. Myocardin-related transcription factor (MRTF) was a central mediator of this effect, as MRTF silencing/inhibition abolished the TGFβ-induced TAZ expression. MRTF overexpression drove the TAZ promoter in a CC(A/T-rich)6GG (CArG) box-dependent manner and induced TAZ protein expression. TGFβ did not act by promoting nuclear MRTF translocation; instead, it triggered p38- and MK2-mediated, Nox4-promoted MRTF phosphorylation and activation. Functionally, higher TAZ levels increased TAZ/TEAD-dependent transcription and primed cells for enhanced TAZ activity upon a second stimulus (i.e. sphingosine 1-phosphate) that induced nuclear TAZ translocation. In conclusion, our results uncover an important aspect of the cross-talk between TGFβ and Hippo signaling, showing that TGFβ induces TAZ via a Smad3-independent, p38- and MRTF-mediated and yet MRTF translocation-independent mechanism.
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Affiliation(s)
- Maria Zena Miranda
- From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital.,Biochemistry, University of Toronto, Toronto, Ontario M5B 1T8N, Canada and
| | - Janne Folke Bialik
- From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital.,the Department of Cell and Developmental Biology, University of Copenhagen, Copenhagen DK-2100, Denmark
| | - Pam Speight
- From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital
| | - Qinghong Dan
- From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital
| | - Tony Yeung
- From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital
| | - Katalin Szászi
- From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital.,Departments of Surgery and
| | - Stine F Pedersen
- the Department of Cell and Developmental Biology, University of Copenhagen, Copenhagen DK-2100, Denmark
| | - András Kapus
- From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, .,Biochemistry, University of Toronto, Toronto, Ontario M5B 1T8N, Canada and.,Departments of Surgery and
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25
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Carthy JM. TGFβ signaling and the control of myofibroblast differentiation: Implications for chronic inflammatory disorders. J Cell Physiol 2017; 233:98-106. [PMID: 28247933 DOI: 10.1002/jcp.25879] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 02/27/2017] [Indexed: 12/24/2022]
Abstract
The myofibroblast is a highly specialized cell type that plays a critical role during normal tissue wound healing, but also contributes pathologically to chronic inflammatory conditions such as fibrosis and cancer. As fibrotic conditions continue to be a major burden to the public health system, novel therapies that target the function of myofibroblasts may show promise in the clinic. The cytokine transforming growth factor β (TGFβ) is the most potent known inducer of myofibroblast differentiation and thus represents a powerful target to modify myofibroblast function during disease. This review focuses on our current understanding of the key signaling pathways activated by TGFβ during myofibroblast differentiation.
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Affiliation(s)
- Jonathon M Carthy
- Faculty of Medicine, Division of Brain Sciences, Imperial College London, London, UK
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26
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Zheng L, Zhang C, Li L, Hu C, Hu M, Sidikejiang N, Wang X, Lin M, Rong R. Baicalin ameliorates renal fibrosis via inhibition of transforming growth factor β1 production and downstream signal transduction. Mol Med Rep 2017; 15:1702-1712. [PMID: 28260014 PMCID: PMC5364985 DOI: 10.3892/mmr.2017.6208] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 12/19/2016] [Indexed: 12/23/2022] Open
Abstract
Previous studies have demonstrated the potential antifibrotic effects of baicalin in vitro, via examination of 21 compounds isolated from plants. However, its biological activity and underlying mechanisms of action in vivo remain to be elucidated. The present study aimed to evaluate the effect of baicalin on renal fibrosis in vivo, and the potential signaling pathways involved. A unilateral ureteral obstruction (UUO)‑induced renal fibrosis model was established using Sprague‑Dawley rats. Baicalin was administrated intraperitoneally every 2 days for 10 days. The degree of renal damage and fibrosis was investigated by histological assessment, and detection of fibronectin and collagen I mRNA expression levels. Epithelial‑mesenchymal transition (EMT) markers, transforming growth factor-β1 (TGF-β1) levels and downstream phosphorylation of mothers against decapentaplegic 2/3 (Smad2/3) were examined in vivo and in an NRK‑52E rat renal tubular cell line in vitro. Baicalin was demonstrated to markedly ameliorate renal fibrosis and suppress EMT, as evidenced by reduced interstitial collagen accumulation, decreased fibronectin and collagen I mRNA expression levels, upregulation of N‑ and E‑cadherin expression levels, and downregulation of α‑smooth muscle actin and vimentin expression. Furthermore, baicalin decreased TGF‑β1 expression levels in serum and kidney tissue following UUO, and suppressed Smad2/3 phosphorylation in rat kidney tissue. In vitro studies identified that baicalin may inhibit the phosphorylation of Smad2/3 under the same TGF‑β1 concentration. In conclusion, baicalin may protect against renal fibrosis, potentially via inhibition of TGF‑β1 production and its downstream signal transduction.
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Affiliation(s)
- Long Zheng
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Chao Zhang
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Long Li
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Chao Hu
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Mushuang Hu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Niyazi Sidikejiang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Xuanchuan Wang
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Miao Lin
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Ruiming Rong
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
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27
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Vascular Transdifferentiation in the CNS: A Focus on Neural and Glioblastoma Stem-Like Cells. Stem Cells Int 2016; 2016:2759403. [PMID: 27738435 PMCID: PMC5055959 DOI: 10.1155/2016/2759403] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 09/05/2016] [Indexed: 01/12/2023] Open
Abstract
Glioblastomas are devastating and extensively vascularized brain tumors from which glioblastoma stem-like cells (GSCs) have been isolated by many groups. These cells have a high tumorigenic potential and the capacity to generate heterogeneous phenotypes. There is growing evidence to support the possibility that these cells are derived from the accumulation of mutations in adult neural stem cells (NSCs) as well as in oligodendrocyte progenitors. It was recently reported that GSCs could transdifferentiate into endothelial-like and pericyte-like cells both in vitro and in vivo, notably under the influence of Notch and TGFβ signaling pathways. Vascular cells derived from GBM cells were also observed directly in patient samples. These results could lead to new directions for designing original therapeutic approaches against GBM neovascularization but this specific reprogramming requires further molecular investigations. Transdifferentiation of nontumoral neural stem cells into vascular cells has also been described and conversely vascular cells may generate neural stem cells. In this review, we present and discuss these recent data. As some of them appear controversial, further validation will be needed using new technical approaches such as high throughput profiling and functional analyses to avoid experimental pitfalls and misinterpretations.
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28
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Shin K, Hwang SG, Choi IJ, Ko YG, Jeong J, Kwon H. Fbxw7β, E3 ubiquitin ligase, negative regulation of primary myoblast differentiation, proliferation and migration. Anim Sci J 2016; 88:712-719. [PMID: 27594513 DOI: 10.1111/asj.12687] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Revised: 06/10/2016] [Accepted: 06/21/2016] [Indexed: 12/24/2022]
Abstract
Satellite cells attached to skeletal muscle fibers play a crucial role in skeletal muscle regeneration. During regeneration, the satellite cells proliferate, migrate to the damaged region, and fuse to each other. Although it is important to determine the cellular mechanisms controlling myoblast behavior, their regulators are not well understood. In this study, we evaluated the roles of Fbxw7 in primary myoblasts and determined its potential as a therapeutic target for muscle disease. We originally found that Fbxw7β, one of the E3 ubiquitin ligase Fbxw7 subtypes, negatively regulates differentiation, proliferation and migration of myoblasts and satellite cells on muscle fiber. However, these phenomena were not observed in myoblasts expressing a dominant-negative, F-box deleted Fbxw7β, mutant. Our results suggest that myoblast differentiation potential and muscle regeneration can be regulated by Fbxw7β.
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Affiliation(s)
- Kyungshin Shin
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Science, Seoul, South Korea.,Department of Biotechnology, Korea University, Seoul, South Korea
| | - Sang-Gu Hwang
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Science, Seoul, South Korea
| | - Ik Joon Choi
- Department of Otorhinolaryngology-Head and Neck Surgery, Korea Cancer Center Hospital, Seoul, South Korea
| | - Young-Gyu Ko
- College of Life Sciences and Biotechnology, Korea University, Seoul, South Korea
| | - Jaemin Jeong
- Department of Surgery, Hanyang University College of Medicine, Seoul, South Korea
| | - Heechung Kwon
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Science, Seoul, South Korea
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29
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Cell-cell contact and matrix adhesion promote αSMA expression during TGFβ1-induced epithelial-myofibroblast transition via Notch and MRTF-A. Sci Rep 2016; 6:26226. [PMID: 27194451 PMCID: PMC4872162 DOI: 10.1038/srep26226] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 04/29/2016] [Indexed: 01/07/2023] Open
Abstract
During epithelial-mesenchymal transition (EMT) epithelial cells lose cell-cell adhesion, exhibit morphological changes, and upregulate the expression of cytoskeletal proteins. Previous studies have demonstrated that complete disruption of cell-cell contact can promote transforming growth factor (TGF)-β1-induced EMT and the expression of the myofibroblast marker alpha smooth muscle actin (αSMA). Furthermore, increased cell spreading mediates TGFβ1-induced αSMA expression during EMT. Here, we sought to examine how the presence of partial cell-cell contacts impacts EMT. A microfabrication approach was employed to decouple the effects of cell-cell contact and cell-matrix adhesion in TGFβ1-induced EMT. When cell spreading is controlled, the presence of partial cell-cell contacts enhances expression of αSMA. Moreover, cell spreading and intercellular contacts together control the subcellular localization of activated Notch1 and myocardin related transcription factor (MRTF)-A. Knockdown of Notch1 or MRTF-A as well as pharmacological inhibition of these pathways abates the cell-cell contact mediated expression of αSMA. These data suggest that the interplay between cell-matrix adhesion and intercellular adhesion is an important determinant for some aspects of TGFβ1-induced EMT.
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30
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Speight P, Kofler M, Szászi K, Kapus A. Context-dependent switch in chemo/mechanotransduction via multilevel crosstalk among cytoskeleton-regulated MRTF and TAZ and TGFβ-regulated Smad3. Nat Commun 2016; 7:11642. [PMID: 27189435 PMCID: PMC4873981 DOI: 10.1038/ncomms11642] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 04/15/2016] [Indexed: 01/12/2023] Open
Abstract
Myocardin-related transcription factor (MRTF) and TAZ are major mechanosensitive transcriptional co-activators that link cytoskeleton organization to gene expression. Despite many similarities in their regulation, their physical and/or functional interactions are unknown. Here we show that MRTF and TAZ associate partly through a WW domain-dependent mechanism, and exhibit multilevel crosstalk affecting each other's expression, transport and transcriptional activity. Specifically, MRTF is essential for TAZ expression; TAZ and MRTF inhibit each other's cytosolic mobility and stimulus-induced nuclear accumulation; they antagonize each other's stimulatory effect on the α-smooth muscle actin (SMA) promoter, which harbours nearby cis-elements for both, but synergize on isolated TEAD-elements. Importantly, TAZ confers Smad3 sensitivity to the SMA promoter. Thus, TAZ is a context-dependent switch during mechanical versus mechano/chemical signalling, which inhibits stretch-induced but is indispensable for stretch+TGFβ-induced SMA expression. Crosstalk between these cytoskeleton-regulated factors seems critical for fine-tuning mechanical and mechanochemical transcriptional programmes underlying myofibroblast transition, wound healing and fibrogenesis.
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Affiliation(s)
- Pam Speight
- Keenan Research Centre for Biomedical Science of St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada M5B 1T8
| | - Michael Kofler
- Keenan Research Centre for Biomedical Science of St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada M5B 1T8
| | - Katalin Szászi
- Keenan Research Centre for Biomedical Science of St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada M5B 1T8.,Department Surgery, University of Toronto, Toronto, Ontario, Canada M5P 1T5
| | - András Kapus
- Keenan Research Centre for Biomedical Science of St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada M5B 1T8.,Department Surgery, University of Toronto, Toronto, Ontario, Canada M5P 1T5.,Department Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8
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31
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Xu F, Liu C, Zhou D, Zhang L. TGF-β/SMAD Pathway and Its Regulation in Hepatic Fibrosis. J Histochem Cytochem 2016; 64:157-67. [PMID: 26747705 DOI: 10.1369/0022155415627681] [Citation(s) in RCA: 558] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 12/23/2015] [Indexed: 02/06/2023] Open
Abstract
Transforming growth factor-beta1 (TGF-β1), a key member in the TGF-β superfamily, plays a critical role in the development of hepatic fibrosis. Its expression is consistently elevated in affected organs, which correlates with increased extracellular matrix deposition. SMAD proteins have been studied extensively as pivotal intracellular effectors of TGF-β1, acting as transcription factors. In the context of hepatic fibrosis, SMAD3 and SMAD4 are pro-fibrotic, whereas SMAD2 and SMAD7 are protective. Deletion of SMAD3 inhibits type I collagen expression and blocks epithelial-myofibroblast transition. In contrast, disruption of SMAD2 upregulates type I collagen expression. SMAD4 plays an essential role in fibrosis disease by enhancing SMAD3 responsive promoter activity, whereas SMAD7 negatively mediates SMAD3-induced fibrogenesis. Accumulating evidence suggests that divergent miRNAs participate in the liver fibrotic process, which partially regulates members of the TGF-β/SMAD signaling pathway. In this review, we focus on the TGF-β/SMAD and other relative signaling pathways, and discussed the role and molecular mechanisms of TGF-β/SMAD in the pathogenesis of hepatic fibrosis. Moreover, we address the possibility of novel therapeutic approaches to hepatic fibrosis by targeting to TGF-β/SMAD signaling.
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Affiliation(s)
- Fengyun Xu
- School of Pharmacy (FX, DZ, LZ),Anhui Medical University, Hefei 230022, ChinaInstitute for Liver Diseases (FX, DZ, LZ)
| | - Changwei Liu
- Anhui Medical University, Hefei 230022, ChinaDepartment of Pharmacy, The First Affiliated Hospital of Anhui Medical University (CL)
| | - Dandan Zhou
- School of Pharmacy (FX, DZ, LZ),Anhui Medical University, Hefei 230022, ChinaInstitute for Liver Diseases (FX, DZ, LZ)
| | - Lei Zhang
- School of Pharmacy (FX, DZ, LZ),Anhui Medical University, Hefei 230022, ChinaInstitute for Liver Diseases (FX, DZ, LZ)
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32
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Tamiya S, Kaplan HJ. Role of epithelial–mesenchymal transition in proliferative vitreoretinopathy. Exp Eye Res 2016; 142:26-31. [DOI: 10.1016/j.exer.2015.02.008] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Revised: 02/09/2015] [Accepted: 02/10/2015] [Indexed: 01/10/2023]
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33
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Abstract
A few human tumor types have been modeled in mice using genetic or chemical tools. The final goal of these efforts is to establish models that mimic not only the location and cellular origin of human cancers but also their genetic aberrations and morphologic appearances. The latter has been neglected by most investigators, and comparative histopathology of human versus mouse cancers is not readily available. This issue is exacerbated by the fact that some human malignancies comprise a whole spectrum of cancer subtypes that differ molecularly and morphologically. Lung cancer is a paradigm that appears not only as non-small cell and small-cell lung cancer but comprises a plethora of subtypes with distinct morphologic features. This review discusses species-specific and common morphological features of non-small cell lung cancer in mice and humans. Potential inconsistencies and the need for refined genetic tools are discussed in the context of a comparative analysis between commonly employed RAS-induced mouse tumors and human lung cancers.
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Affiliation(s)
- Helmut H Popper
- Institute of Pathology, Research Unit Molecular Lung & Pleura Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036, Graz, Austria,
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34
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Zhang L, Liu C, Meng XM, Huang C, Xu F, Li J. Smad2 protects against TGF-β1/Smad3-mediated collagen synthesis in human hepatic stellate cells during hepatic fibrosis. Mol Cell Biochem 2014; 400:17-28. [PMID: 25351340 DOI: 10.1007/s11010-014-2258-1] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Accepted: 10/17/2014] [Indexed: 12/11/2022]
Abstract
With structural similarity but functional diversity, Smad2 and Smad3 interact with each other to mediate transforming growth factor-β (TGF-β)-triggered signaling transduction. However, in the hepatic fibrosis, the detailed roles of R-Smads, and interaction between Smad2 and Smad3 are still undefined. In this setting, we established a rat model of CCl4-induced hepatic fibrosis in vivo and TGF-β1-treated hepatic stellate cell model in vitro to detect whether Smad2 and Smad3 play distinct roles in mediating liver fibrogenesis. Results indicated that both phosphorylation of Smad2 and Smad3 were detected in the hepatic stellate cells of liver fibrotic tissues and cells. Furthermore, In vitro data demonstrated that knockdown of Smad2 in human hepatic stellate cells increased expression of collagen I (Col.I), tissue inhibitor of metalloproteinase-1 (TIMP-1) whereas decreasing expression of the matrix metalloproteinases-2(MMP-2) in presence of TGF-β1 compared with control group. In contrast, knockdown of Smad3 significantly reduced TGF-β1-induced Col.I production. These findings were further evident by the results that overexpression of Smad2 attenuated the expression of Col.I and TIMP-1, but enhanced MMP-2 whereas overexpression of Smad3 showed the opposite effect. Furthermore, Smad2 suppressed the phosphorylation and nuclear translocation of Smad3, which may protect against Smad3-mediated fibrotic response. Collectively, Smad2 may be a potential therapeutic target for the treatment of hepatic fibrosis.
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Affiliation(s)
- Lei Zhang
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China
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Zhu H, Cao M, Figueroa JA, Cobos E, Uretsky BF, Chiriva-Internati M, Hermonat PL. AAV2/8-hSMAD3 gene delivery attenuates aortic atherogenesis, enhances Th2 response without fibrosis, in LDLR-KO mice on high cholesterol diet. J Transl Med 2014; 12:252. [PMID: 25236373 PMCID: PMC4189750 DOI: 10.1186/s12967-014-0252-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 09/02/2014] [Indexed: 12/01/2022] Open
Abstract
Background Inflammation is a key etiologic component in atherogenesis and transforming growth factor beta 1 (TGFβ1) is a well known anti-inflammatory cytokine which potentially might be used to limit it. Yet TGFβ1 is pleiomorphic, causing fibrosis, cell taxis, and under certain circumstances, can even worsen inflammation. SMAD3 is an important member of TGFβ1′s signal transduction pathway, but is a fully intracellular protein. Objectives With the hope of attenuating TGFβ1′s adverse systemic effects (eg. fibrosis) and accentuating its anti-inflammatory activity, we proposed the use of human (h)SMAD3 as an intracellular substitute for TGFβ1. Study design To test this hypothesis adeno-associated virus type 2/8 (AAV)/hSMAD3 or AAV/Neo (control) was tail vein injected into the low density lipoprotein receptor knockout (LDLR-KO) mice, then placed on a high-cholesterol diet (HCD). Results The hSMAD3 delivery was associated with significantly lower atherogenesis as measured by larger aortic cross sectional area, thinner aortic wall thickness, and lower aortic systolic blood velocity compared with Neo gene-treated controls. HSMAD3 delivery also resulted in fewer aortic macrophages by immunohistochemistry for CD68 and ITGAM, and quantitative reverse transcriptase polymerase chain reaction analysis of EMR and ITGAM. Overall, aortic cytokine expression showed an enhancement of Th2 response (higher IL-4 and IL-10); while Th1 response (IL-12) was lower with hSMAD3 delivery. While TGFβ1 is often associated with increased fibrosis, AAV/hSMAD3 delivery exhibited no increase of collagen 1A2 or significantly lower 2A1 expression in the aorta compared with Neo-delivery. Connective tissue growth factor (CTGF), a mediator of TGFβ1/SMAD3-induced fibrosis, was unchanged in hSMAD3-delivered aortas. In the liver, all three of these genes were down-regulated by hSMAD3 gene delivery. Conclusion These data strongly suggest that AAV/hSMAD3 delivery gave anti-atherosclerosis therapeutic effect without the expected undesirable effect of TGFβ1-associated fibrosis.
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SNPs in the transforming growth factor-β pathway as predictors of outcome in advanced lung adenocarcinoma with EGFR mutations treated with gefitinib. Ann Oncol 2014; 25:1584-90. [DOI: 10.1093/annonc/mdu172] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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Li H, Yuan X, Li J, Tang X. Implication of Smad2 and Smad3 in Transforming Growth Factor-β-induced Posterior Capsular Opacification of Human Lens Epithelial Cells. Curr Eye Res 2014; 40:386-97. [DOI: 10.3109/02713683.2014.925932] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Charbonney E, Speight P, Kapus A. How do your contacts (or their absence) shape your fate? Tissue Barriers 2014; 1:e23699. [PMID: 24665378 PMCID: PMC3875604 DOI: 10.4161/tisb.23699] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Revised: 01/18/2013] [Accepted: 01/21/2013] [Indexed: 11/19/2022] Open
Abstract
Tissue accumulation of contractile myofibroblasts is a key feature of a multitude of fibrotic diseases. Myofibroblast generation either from epithelial or mesenchymal precursors involves the activation of a myogenic program, hallmarked by the expression of α-smooth muscle actin (SMA). Recent research suggests that this robust phenotypic reprogramming requires two critical inputs: the fibrogenic cytokine transforming growth factor-β1 (TGFβ) and an injury (or absence) of intercellular junctions. This two-hit paradigm of epithelial-myofibroblast transition (EMyT) postulates that the injured (contact-deprived) epithelium is locally and selectively sensitive (topically susceptible) to the transforming effect of TGFβ, while the intact areas are quite resistant to the phenotype-changing effect of this cytokine. Searching for molecular mechanisms underlying the synergy between contact injury and TGFβ, we found that an interplay among three multifunctional transcriptional (co)activators, the junction component β-catenin, the TGFβ receptor target Smad3, and the actin cytoskeleton-regulated myocardin-related transcription factor (MRTF) controls the magnitude and timing of SMA expression.1 Moreover, this regulation is realized not only at the transcriptional level. Notably, these factors form a pretranscriptional circuit, in which they impact each other’s activity and stability. Based on this recent paper we ponder about the mechanisms of cellular plasticity in the context of EMyT. We propose that topical susceptibility to TGFβ, triggered by cell contact-modulated pretranscriptional and transcriptional control is realized through the crosstalk of a few master regulators, whose coordinated action tailors SMA expression and contributes to the major decision of whether injury leads to healing or fibrosis.
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Affiliation(s)
- Emmanuel Charbonney
- Keenan Research Centre; Li Ka Shing Knowledge Institute; St. Michael's Hospital and Department of Surgery; University of Toronto; Toronto, ON Canada
| | - Pam Speight
- Keenan Research Centre; Li Ka Shing Knowledge Institute; St. Michael's Hospital and Department of Surgery; University of Toronto; Toronto, ON Canada
| | - András Kapus
- Keenan Research Centre; Li Ka Shing Knowledge Institute; St. Michael's Hospital and Department of Surgery; University of Toronto; Toronto, ON Canada
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Szaszi K, Amoozadeh Y. New Insights into Functions, Regulation, and Pathological Roles of Tight Junctions in Kidney Tubular Epithelium. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2014; 308:205-71. [DOI: 10.1016/b978-0-12-800097-7.00006-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Kato H, Fu YY, Zhu J, Wang L, Aafaqi S, Rahkonen O, Slorach C, Traister A, Leung CH, Chiasson D, Mertens L, Benson L, Weisel RD, Hinz B, Maynes JT, Coles JG, Caldarone CA. Pulmonary vein stenosis and the pathophysiology of "upstream" pulmonary veins. J Thorac Cardiovasc Surg 2013; 148:245-53. [PMID: 24084286 DOI: 10.1016/j.jtcvs.2013.08.046] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 08/10/2013] [Accepted: 08/16/2013] [Indexed: 10/26/2022]
Abstract
BACKGROUND Surgical and catheter-based interventions on pulmonary veins are associated with pulmonary vein stenosis (PVS), which can progress diffusely through the "upstream" pulmonary veins. The mechanism has been rarely studied. We used a porcine model of PVS to assess disease progression with emphasis on the potential role of endothelial-mesenchymal transition (EndMT). METHODS Neonatal piglets underwent bilateral pulmonary vein banding (banded, n = 6) or sham operations (sham, n = 6). Additional piglets underwent identical banding and stent implantation in a single-banded pulmonary vein 3 weeks postbanding (stented, n = 6). At 7 weeks postbanding, hemodynamics and upstream PV pathology were assessed. RESULTS Banded piglets developed pulmonary hypertension. The upstream pulmonary veins exhibited intimal thickening associated with features of EndMT, including increased transforming growth factor (TGF)-β1 and Smad expression, loss of endothelial and gain of mesenchymal marker expression, and coexpression of endothelial and mesenchymal markers in banded pulmonary vein intimal cells. These immunopathologic changes and a prominent myofibroblast phenotype in the remodeled pulmonary veins were consistently identified in specimens from patients with PVS, in vitro TGF-β1-stimulated cells isolated from piglet and human pulmonary veins, and human umbilical vein endothelial cells. After stent implantation, decompression of a pulmonary vein was associated with reappearance of endothelial marker expression, suggesting the potential for plasticity in the observed pathologic changes, followed by rapid in-stent restenosis. CONCLUSIONS Neonatal pulmonary vein banding in piglets recapitulates critical aspects of clinical PVS and highlights a pathologic profile consistent with EndMT, supporting the rationale for evaluating therapeutic strategies designed to exploit reversibility of upstream pulmonary vein pathology.
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Affiliation(s)
- Hideyuki Kato
- Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada
| | - Yaqin Yana Fu
- Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada
| | - Jiaquan Zhu
- Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada
| | - Lixing Wang
- Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada
| | - Shabana Aafaqi
- Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada
| | - Otto Rahkonen
- Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Cameron Slorach
- Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Alexandra Traister
- Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada
| | - Chung Ho Leung
- Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada
| | - David Chiasson
- Division of Pathology and Paediatric Laboratory Medicine, Laboratory of Tissue Repair and Regeneration, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Luc Mertens
- Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Lee Benson
- Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Richard D Weisel
- Division of Cardiac Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - Boris Hinz
- Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
| | - Jason T Maynes
- Division of Anaesthesia and Pain Medicine and Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada
| | - John G Coles
- Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada
| | - Christopher A Caldarone
- Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada.
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Speight P, Nakano H, Kelley TJ, Hinz B, Kapus A. Differential topical susceptibility to TGFβ in intact and injured regions of the epithelium: key role in myofibroblast transition. Mol Biol Cell 2013; 24:3326-36. [PMID: 24006486 PMCID: PMC3814143 DOI: 10.1091/mbc.e13-04-0220] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Intact and cell contact–deprived regions of an epithelial monolayer are differentially sensitive to the transforming effect of TGFβ. This topical susceptibility is mediated by the interplay between TGFβ- and cell contact–dependent transcription factors and might play a key role in the cell biology of wound healing and fibrosis. Induction of epithelial–myofibroblast transition (EMyT), a robust fibrogenic phenotype change hallmarked by α-smooth muscle actin (SMA) expression, requires transforming growth factor-β1 (TGFβ) and the absence/uncoupling of intracellular contacts. This suggests that an “injured” epithelium may be topically susceptible to TGFβ. To explore this concept, we use an epithelial wound model in which intact and contact-deprived regions of the same monolayer can be analyzed simultaneously. We show that TGFβ elicits dramatically different responses at these two loci. SMA expression and initially enhanced nuclear Smad3 accumulation followed by Smad3 mRNA and protein down-regulation occur exclusively at the wound. Mechanistically, three transcriptional coactivators whose localization is regulated by cell contact integrity are critical for these local effects. These are myocardin-related transcription factor (MRTF), the driver of the SMA promoter; β-catenin, which counteracts the known inhibitory effect of Smad3 on MRTF and maintains MRTF protein stability and mRNA expression in the wound; and TAZ, a Hippo effector and Smad3 retention factor. Remarkably, active TAZ stimulates the SMA and suppresses the Smad3 promoter, whereas TAZ silencing prevents wound-restricted expression of SMA and loss of Smad3. Such locus-specific reprogramming might play key roles in wound healing and the susceptibility of the injured epithelium to fibrogenesis.
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Affiliation(s)
- Pam Speight
- Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Department of Surgery, University of Toronto, Toronto, ON M5B 1W8, Canada Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan Division of Pediatric Pulmonology, Case Western Reserve University, Cleveland, OH 44106 Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, ON M5S 3E2, Canada
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Fintha A, Gasparics Á, Fang L, Erdei Z, Hamar P, Mózes MM, Kökény G, Rosivall L, Sebe A. Characterization and role of SCAI during renal fibrosis and epithelial-to-mesenchymal transition. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 182:388-400. [PMID: 23178076 DOI: 10.1016/j.ajpath.2012.10.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Revised: 09/27/2012] [Accepted: 10/16/2012] [Indexed: 01/17/2023]
Abstract
During progressive tubulointerstitial fibrosis, renal tubular epithelial cells transform into α-smooth muscle actin (SMA)-expressing myofibroblasts via epithelial-to-mesenchymal transition (EMT). SMA expression is regulated by transforming growth factor (TGF)-β1 and cell contact disruption, through signaling events targeting the serum response factor-myocardin-related transcription factor (MRTF) complex. MRTFs are important regulators of fibrosis, tumor cell invasion, and metastasis. Consistent with the role of MRTFs in tumor progression, suppressor of cancer cell invasion (SCAI) was recently identified as a negative regulator of MRTF. Herein, we studied the role of SCAI in a fibrotic EMT model established on LLC-PK1 cells. SCAI overexpression prevented SMA promoter activation induced by TGF-β1. When co-expressed, it inhibited the stimulatory effects of MRTF-A, MRTF-B or the constitutive active forms of RhoA, Rac1, or Cdc42 on the SMA promoter. SCAI interfered with TGF-β1-induced SMA, connective tissue growth factor, and calponin protein expression; it rescued TGF-β1-induced E-cadherin down-regulation. IHC studies on human kidneys showed that SCAI expression is reduced during fibrosis. Kidneys of diabetic rats and mice with unilateral ureteral obstruction depicted significant loss of SCAI expression. In parallel with the decrease of SCAI protein expression, diabetic rat and mouse kidneys with unilateral ureteral obstruction showed SMA expression, as evidenced by using Western blot analysis. Finally, TGF-β1 treatment of LLC-PK1 cells attenuated SCAI protein expression. These data suggest that SCAI is a novel transcriptional cofactor that regulates EMT and renal fibrosis.
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Affiliation(s)
- Attila Fintha
- 2(nd) Department of Pathology, Semmelweis University, 1089 Budapest, Hungary
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Insel PA, Murray F, Yokoyama U, Romano S, Yun H, Brown L, Snead A, Lu D, Aroonsakool N. cAMP and Epac in the regulation of tissue fibrosis. Br J Pharmacol 2012; 166:447-56. [PMID: 22233238 DOI: 10.1111/j.1476-5381.2012.01847.x] [Citation(s) in RCA: 112] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Fibrosis, the result of excess deposition of extracellular matrix (ECM), in particular collagen, leads to scarring and loss of function in tissues that include the heart, lung, kidney and liver. The second messenger cAMP can inhibit the formation and extent of ECM during this late phase of inflammation, but the mechanisms for these actions of cAMP and of agents that elevate tissue cAMP levels are not well understood. In this article, we review the fibrotic process and focus on two recently recognized aspects of actions of cAMP and its effector Epac (Exchange protein activated by cAMP): (a) blunting of epithelial-mesenchymal transformation (EMT) and (b) down-regulation of Epac expression by profibrotic agents (e.g. TGF-β, angiotensin II), which may promote tissue fibrosis by decreasing Epac-mediated antifibrotic actions. Pharmacological approaches that raise cAMP or blunt the decrease in Epac expression by profibrotic agents may thus be strategies to block or perhaps reverse tissue fibrosis. LINKED ARTICLES This article is part of a themed section on Novel cAMP Signalling Paradigms. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue-2.
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Affiliation(s)
- Paul A Insel
- Departments of Pharmacology Medicine, University of California San Diego, La Jolla, CA 92093, USA.
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Gjorevski N, Boghaert E, Nelson CM. Regulation of Epithelial-Mesenchymal Transition by Transmission of Mechanical Stress through Epithelial Tissues. CANCER MICROENVIRONMENT : OFFICIAL JOURNAL OF THE INTERNATIONAL CANCER MICROENVIRONMENT SOCIETY 2012; 5:29-38. [PMID: 21748438 PMCID: PMC3343202 DOI: 10.1007/s12307-011-0076-5] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/20/2010] [Accepted: 06/30/2011] [Indexed: 01/16/2023]
Abstract
Epithelial-mesenchymal transition (EMT) is a phenotypic shift wherein epithelial cells lose or loosen attachments to their neighbors and assume a mesenchymal-like morphology. EMT drives a variety of developmental processes, but may also be adopted by tumor cells during neoplastic progression. EMT is regulated by both biochemical and physical signals from the microenvironment, including mechanical stress, which is increasingly recognized to play a major role in development and disease progression. Biological systems generate, transmit and concentrate mechanical stress into spatial patterns; these gradients in mechanical stress may serve to spatially pattern developmental and pathologic EMTs. Here we review how epithelial tissues generate and respond to mechanical stress gradients, and highlight the mechanisms by which mechanical stress regulates and patterns EMT.
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Affiliation(s)
- Nikolce Gjorevski
- Department of Chemical & Biological Engineering, Princeton University, A321 Engineering Quadrangle, Princeton, NJ 08544 USA
| | - Eline Boghaert
- Department of Chemical & Biological Engineering, Princeton University, A321 Engineering Quadrangle, Princeton, NJ 08544 USA
| | - Celeste M. Nelson
- Department of Chemical & Biological Engineering, Princeton University, A321 Engineering Quadrangle, Princeton, NJ 08544 USA
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Cardiac Fibrosis in Human Transplanted Hearts Is Mainly Driven by Cells of Intracardiac Origin. J Am Coll Cardiol 2012; 59:1008-16. [DOI: 10.1016/j.jacc.2011.11.036] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2011] [Revised: 11/22/2011] [Accepted: 11/29/2011] [Indexed: 11/21/2022]
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Sipos F, Galamb O. Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions in the colon. World J Gastroenterol 2012; 18:601-608. [PMID: 22363130 PMCID: PMC3281216 DOI: 10.3748/wjg.v18.i7.601] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2011] [Revised: 07/08/2011] [Accepted: 07/15/2011] [Indexed: 02/06/2023] Open
Abstract
Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions are well established biological events which have an important role in not just normal tissue and organ development, but in the pathogenesis of diseases. Increasing evidence has established their presence in the human colon during colorectal carcinogenesis and cancer invasion, chronic inflammation-related fibrosis and in the course of mucosal healing. A large body of evidence supports the role for transforming growth factor-β and its downstream Smad signaling, the phosphatidylinositol 3'-kinase/Akt/mTOR axis, the Ras-mitogen-activated protein kinase/Snail/Slug and FOXC2 pathway, and Hedgehog signaling and microRNAs in the development of colorectal cancers via epithelial-to-mesenchymal transition. C-met and Frizzled-7, among others, seem to be the principle effectors of mesenchymal-to-epithelial transition, hence have a role not just in mucosal regeneration but in the progression of colonic wall fibrosis. Here we discuss a role for these pathways in the initiation and development of the transition events. A better understanding of their induction and regulation may lead to the identification of pathways and factors that could be potent therapeutic targets. The inhibition of epithelial-to-mesenchymal transition using mTOR kinase inhibitors targeting the ATP binding pocket and which inhibit both mTORC1 and mTORC2, RNA aptamers or peptide mimetics, such as a Wnt5A-mimetic, may all be useful in both cancer treatment and delaying fibrosis, while the induction of mesenchymal-to-epithelial transition in induced pluripotent stem cells may enhance epithelial healing in the case of severe mucosal damage. The preliminary results of the current studies are promising, but more clinical investigations are needed to develop new and safe therapeutic strategies for diseases of the colon.
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Erbin inhibits TGF-β1-induced EMT in renal tubular epithelial cells through an ERK-dependent pathway. J Mol Med (Berl) 2011; 90:563-74. [DOI: 10.1007/s00109-011-0833-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2011] [Revised: 10/17/2011] [Accepted: 10/31/2011] [Indexed: 01/24/2023]
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BMP-7/TGF-β1 signalling in myoblasts: components involved in signalling and BMP-7-dependent blockage of TGF-β-mediated CTGF expression. Eur J Cell Biol 2011; 91:450-63. [PMID: 22099397 DOI: 10.1016/j.ejcb.2011.09.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2011] [Revised: 08/15/2011] [Accepted: 09/08/2011] [Indexed: 11/22/2022] Open
Abstract
We and others have recently described the antagonistic role of Bone morphogenetic protein-7 (BMP-7) in TGF-β signalling and myogenic differentiation. To specify the underlying mechanism(s), we here analysed the expression and function of the individual components mediating TGF-β1 and BMP-7 responses. We found that BMP-7 at a concentration of 25 ng/ml induces signalling exclusively via ALK2 and ALK3 leading to the activation of Smad1 and Smad5 and subsequent expression of Id proteins. In contrast, low doses of TGF-β1 (0.1 ng/ml) lead to an exclusive activation of ALK5 and phosphorylation of Smad2 and Smad3 that regulate specific target genes including connective tissue growth factor (CTGF). CTGF is rapidly induced by TGF-β1 already 1h after stimulation and reduced by BMP-7 application. Smad1/Smad5 or Id1/2 overexpression reduced the TGF-β1-mediated expression of CTGF. However, although siRNA-mediated knock down of Alk2/3 or Smad1/5 counteracts the BMP-7 effect on basal CTGF expression there was no consistent reversion of the observed BMP-7 effect on TGF-β1-mediated CTGF expression. Moreover, ALK5 inhibition using the SB431542 inhibitor significantly affected CTGF expression only at later time points whereas ERK1/2 inhibition completely abrogated CTGF expression. These findings point towards a regulatory role of BMP-7 that relies on modulation of Mitogen-activated protein kinases rather than mechanisms that are exclusively driven by differential Smad activation.
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Charbonney E, Speight P, Masszi A, Nakano H, Kapus A. β-catenin and Smad3 regulate the activity and stability of myocardin-related transcription factor during epithelial-myofibroblast transition. Mol Biol Cell 2011; 22:4472-85. [PMID: 21965288 PMCID: PMC3226468 DOI: 10.1091/mbc.e11-04-0335] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Two novel mechanisms are shown by which injury of intercellular junctions via β-catenin promotes epithelial–myofibroblast transition. β-Catenin interacts with Smad3, thereby preventing the inhibitory effect of the latter on myocardin-related transcription factor (MRTF), and maintains MRTF stability by inhibiting Smad3-mediated, GSK-3β–dependent degradation of MRTF. Injury to the adherens junctions (AJs) synergizes with transforming growth factor-β1 (TGFβ) to activate a myogenic program (α-smooth muscle actin [SMA] expression) in the epithelium during epithelial–myofibroblast transition (EMyT). Although this synergy plays a key role in organ fibrosis, the underlying mechanisms have not been fully defined. Because we recently showed that Smad3 inhibits myocardin-related transcription factor (MRTF), the driver of the SMA promoter and many other CC(A/T)-rich GG element (CArG) box–dependent cytoskeletal genes, we asked whether AJ components might affect SMA expression through interfering with Smad3. We demonstrate that E-cadherin down-regulation potentiates, whereas β-catenin knockdown inhibits, SMA expression. Contact injury and TGFβ enhance the binding of β-catenin to Smad3, and this interaction facilitates MRTF signaling by two novel mechanisms. First, it inhibits the Smad3/MRTF association and thereby allows the binding of MRTF to its myogenic partner, serum response factor (SRF). Accordingly, β-catenin down-regulation disrupts the SRF/MRTF complex. Second, β-catenin maintains the stability of MRTF by suppressing the Smad3-mediated recruitment of glycogen synthase kinase-3β to MRTF, an event that otherwise leads to MRTF ubiquitination and degradation and the consequent loss of SRF/MRTF–dependent proteins. Thus β-catenin controls MRTF-dependent transcription and emerges as a critical regulator of an array of cytoskeletal genes, the “CArGome.”
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Affiliation(s)
- Emmanuel Charbonney
- Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Department of Surgery, University of Toronto, Toronto, ON M5B 1W8, Canada
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Plaas A, Velasco J, Gorski DJ, Li J, Cole A, Christopherson K, Sandy JD. The relationship between fibrogenic TGFβ1 signaling in the joint and cartilage degradation in post-injury osteoarthritis. Osteoarthritis Cartilage 2011; 19:1081-90. [PMID: 21624477 DOI: 10.1016/j.joca.2011.05.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Revised: 05/05/2011] [Accepted: 05/07/2011] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To review the literature on modulation of chondrocyte activities in the osteoarthritic joint, and to discuss these changes in relation to established hard and soft tissue repair paradigms, with an emphasis on transforming growth factor beta (TGFβ1)-mediated signaling which can promote either a chondrogenic or fibrogenic phenotype. METHODS Papers addressing the close relationship between repair in general, and the specific post-injury response of joint tissues are summarized. Different interpretations of the role of TGFβ1 in the emergence of an "osteoarthritic" chondrocyte are compared and the phenotypic plasticity of "reparative" progenitor cells is examined. Lastly, emerging data on a central role for A-Disintegrin-And-Metalloproteinase-with-Thrombospondin-like-Sequences-5 (ADAMTS5) activity in modulating TGFβ1 signaling through activin receptor-like kinase 1 (ALK1) and activin receptor-like kinase 5 (ALK5) pathways is discussed. RESULTS The review illustrates how a transition from ALK5-mediated fibrogenic signaling to ALK1-mediated chondrogenic signaling in joint cells represents the critical transition from a non-reparative to a reparative cell phenotype. Data from cell and in vivo studies illustrates the mechanism by which ablation of ADAMTS5 activity allows the transition to reparative chondrogenesis. Multiple large gene expression studies of normal and osteoarthritis (OA) human cartilages (CAs) also support an important role for TGFβ1-mediated pro-fibrogenic activities during disease progression. CONCLUSIONS We conclude that progressive articular CA damage in post-injury OA results primarily from biomechanical, cell biologic and mediator changes that promote a fibroblastic phenotype in joint cells. Since ADAMTS5 and TGFβ1 appear to control this process, agents which interfere with their activities may not only enhance endogenous CA repair in vivo, but also improve the properties of tissue-engineered CA for implantation.
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Affiliation(s)
- A Plaas
- Department of Internal Medicine (Rheumatology), Rush University Medical Center, Chicago, IL, USA
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