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Wang XL, Yang M, Wang Y. Roles of transforming growth factor-β signaling in liver disease. World J Hepatol 2024; 16:973-979. [PMID: 39086528 PMCID: PMC11287609 DOI: 10.4254/wjh.v16.i7.973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 03/04/2024] [Accepted: 05/24/2024] [Indexed: 07/26/2024] Open
Abstract
In this editorial we expand the discussion on the article by Zhang et al published in the recent issue of the World Journal of Hepatology. We focus on the diagnostic and therapeutic targets identified on the basis of the current understanding of the molecular mechanisms of liver disease. Transforming growth factor-β (TGF-β) belongs to a structurally related cytokine super family. The family members display different time- and tissue-specific expression patterns associated with autoimmunity, inflammation, fibrosis, and tumorigenesis; and, they participate in the pathogenesis of many diseases. TGF-β and its related signaling pathways have been shown to participate in the progression of liver diseases, such as injury, inflammation, fibrosis, cirrhosis, and cancer. The often studied TGF-β/Smad signaling pathway has been shown to promote or inhibit liver fibrosis under different circumstances. Similarly, the early immature TGF-β molecule functions as a tumor suppressor, inducing apoptosis; but, its interaction with the mitogenic molecule epidermal growth factor alters this effect, activating anti-apoptotic signals that promote liver cancer development. Overall, TGF-β signaling displays contradictory effects in different liver disease stages. Therefore, the use of TGF-β and related signaling pathway molecules for diagnosis and treatment of liver diseases remains a challenge and needs further study. In this editorial, we aim to review the evidence for the use of TGF-β signaling pathway molecules as diagnostic or therapeutic targets for different liver disease stages.
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Affiliation(s)
- Xiao-Ling Wang
- Clinical Laboratory, Shanxi Academy of Traditional Chinese Medicine, Taiyuan 030012, Shanxi Province, China.
| | - Meng Yang
- Clinical Laboratory, Shanxi Academy of Traditional Chinese Medicine, Taiyuan 030012, Shanxi Province, China
| | - Ying Wang
- Clinical Laboratory, Shanxi Academy of Traditional Chinese Medicine, Taiyuan 030012, Shanxi Province, China
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Jönsson C, Bergram M, Kechagias S, Nasr P, Ekstedt M. Activin A levels in metabolic dysfunction-associated steatotic liver disease associates with fibrosis and the PNPLA3 I148M variant. Scand J Gastroenterol 2024; 59:737-741. [PMID: 38563432 DOI: 10.1080/00365521.2024.2334804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 03/11/2024] [Accepted: 03/20/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver condition worldwide. There is an urgent need to develop new biomarkers to assess disease severity and to define patients with a progressive phenotype. Activin A is a new promising biomarker with conflicting results about liver fibrosis. In this study we investigate levels of Activin A in patients with biopsy proven MASLD. We assess levels of Activin A in regard to fibrosis stage and genetic variant I148M in the patatin-like phospholipase domain-containing protein 3 (PNPLA3). METHODS Activin A levels were assessed in plasma samples from patients with biopsy-proven MASLD in a cross-sectional study. All patients were clinically evaluated and the PNPLA3 I148M genotype of the cohort was assessed. FINDINGS 41 patients were included and 27% of these had advanced fibrosis. In MASLD patients with advanced fibrosis, Activin A levels was higher (p < 0.001) and could classify advanced fibrosis with an AUROC for activin A of 0.836 (p < 0.001). Patients homozygous for PNPLA3 I148M G/G had higher levels of activin A than non-homozygotes (p = 0.027). CONCLUSIONS Circulating activin A levels were associated with advanced fibrosis and could be a potential blood biomarker for identifying advanced fibrosis in MASLD. Patients with the risk genotype PNPLA3 I148M G/G had higher levels of activin A proposing activin A as a contributor of the transition from simple steatosis to a fibrotic phenotype.
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Affiliation(s)
- Cecilia Jönsson
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Martin Bergram
- Division of Prevention, Rehabilitation and Community Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Stergios Kechagias
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Patrik Nasr
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
- Wallenberg Centre for Molecular Medicine, Linköping University, Linköping, Sweden
| | - Mattias Ekstedt
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
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de Haan LR, van Golen RF, Heger M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol Rev 2024; 76:500-558. [PMID: 38697856 DOI: 10.1124/pharmrev.123.000955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/24/2024] [Accepted: 02/08/2024] [Indexed: 05/05/2024] Open
Abstract
The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.
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Affiliation(s)
- Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Rowan F van Golen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
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Lan X, Guo L, Hu C, Zhang Q, Deng J, Wang Y, Chen ZJ, Yan J, Li Y. Fibronectin mediates activin A-promoted human trophoblast migration and acquisition of endothelial-like phenotype. Cell Commun Signal 2024; 22:61. [PMID: 38263146 PMCID: PMC10807102 DOI: 10.1186/s12964-023-01463-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 12/27/2023] [Indexed: 01/25/2024] Open
Abstract
BACKGROUND During human early placentation, a proportion of extravillous trophoblasts (EVTs) migrate to the maternal decidua, differentiating into endovascular EVTs to remodel spiral arteries and ensure the establishment of blood circulation at the maternal-fetal interface. Inadequate EVT migration and endovascular differentiation are closely associated with adverse pregnancy outcomes such as miscarriage. Activin A and fibronectin are both secretory molecules abundantly expressed at the maternal-fetal interface. Activin A has been reported to regulate EVT biological functions. However, whether fibronectin mediates activin A-promoted EVT migration and acquisition of endothelial-like phenotype as well as the underlying molecular mechanisms remain unknown. Additionally, the role of fibronectin in pregnancy establishment and maintenance warrants further investigation. METHODS Primary and immortalized (HTR8/SVneo) human EVTs were used as in vitro study models. Cultured human first-trimester chorionic villous explants were utilized for ex vivo validation. A local fibronectin knockdown model in ICR mouse uteri, achieved by nonviral in vivo transfection with small interfering RNA (siRNA) targeting fibronectin 1 (si-Fn1), was employed to explore the roles of fibronectin in the establishment and maintenance of early pregnancy. RESULTS Our results showed that activin A treatment significantly induced fibronectin 1 (FN1) mRNA expression and fibronectin protein production, which is essential for human trophoblast migration and endothelial-like tube formation. Both basal and activin A-upregulated fibronectin expression were abolished by the TGF-β type I receptor inhibitor SB431542 or siRNA-mediated knockdown of activin receptor-like kinase (ALK4) or SMAD4. Moreover, activin A-increased trophoblast migration and endothelial-like tube formation were attenuated following the depletion of fibronectin. Fibronectin knockdown via intrauterine siRNA administration reduced CD31 and cytokeratin 8 (CK8) expression at the maternal-fetal interface, resulting in a decrease in the number of implantation sites and embryos. CONCLUSIONS Our study demonstrates that activin A promotes trophoblast cell migration and acquisition of endothelial-like phenotype via ALK4-SMAD2/3-SMAD4-mediated fibronectin upregulation. Furthermore, through a local fibronectin knockdown model in mouse uteri, we found that the absence of fibronectin at the maternal-fetal interface impedes endovascular migration of trophoblasts and decidual vascularization, thereby interfering with early embryo implantation and the maintenance of pregnancy. These findings provide novel insights into placental development during early pregnancy establishment and contribute to the advancement of therapeutic approaches for managing pregnancy complications related to trophoblast dysfunction.
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Affiliation(s)
- Xiangxin Lan
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, Shandong, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, 250012, Shandong, China
- Medical Integration and Practice Center, Shandong University, Jinan, 250012, Shandong, China
| | - Ling Guo
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, Shandong, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, 250012, Shandong, China
- Medical Integration and Practice Center, Shandong University, Jinan, 250012, Shandong, China
| | - Cuiping Hu
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, Shandong, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, 250012, Shandong, China
- Medical Integration and Practice Center, Shandong University, Jinan, 250012, Shandong, China
| | - Qian Zhang
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, Shandong, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, 250012, Shandong, China
- Medical Integration and Practice Center, Shandong University, Jinan, 250012, Shandong, China
| | - Jianye Deng
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, Shandong, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, 250012, Shandong, China
- Medical Integration and Practice Center, Shandong University, Jinan, 250012, Shandong, China
| | - Yufeng Wang
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, Shandong, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, 250012, Shandong, China
- Medical Integration and Practice Center, Shandong University, Jinan, 250012, Shandong, China
| | - Zi-Jiang Chen
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, Shandong, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, 250012, Shandong, China
- Medical Integration and Practice Center, Shandong University, Jinan, 250012, Shandong, China
- Research Unit of Gametogenesis and Health of ART-Offspring Chinese Academy of Medical Sciences (No. 2021RU001), Jinan, 250012, Shandong, China
| | - Junhao Yan
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, Shandong, China.
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, 250012, Shandong, China.
- Medical Integration and Practice Center, Shandong University, Jinan, 250012, Shandong, China.
| | - Yan Li
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, Shandong, China.
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, 250012, Shandong, China.
- Medical Integration and Practice Center, Shandong University, Jinan, 250012, Shandong, China.
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Zhang C, Sun C, Zhao Y, Ye B, Yu G. Signaling pathways of liver regeneration: Biological mechanisms and implications. iScience 2024; 27:108683. [PMID: 38155779 PMCID: PMC10753089 DOI: 10.1016/j.isci.2023.108683] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2023] Open
Abstract
The liver possesses a unique regenerative ability to restore its original mass, in this regard, partial hepatectomy (PHx) and partial liver transplantation (PLTx) can be executed smoothly and safely, which has important implications for the treatment of liver disease. Liver regeneration (LR) can be the very complicated procedure that involves multiple cytokines and transcription factors that interact with each other to activate different signaling pathways. Activation of these pathways can drive the LR process, which can be divided into three stages, namely, the initiation, progression, and termination stages. Therefore, it is important to investigate the pathways involved in LR to elucidate the mechanism of LR. This study reviews the latest research on the key signaling pathways in the different stages of LR.
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Affiliation(s)
- Chunyan Zhang
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Caifang Sun
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Yabin Zhao
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Bingyu Ye
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - GuoYing Yu
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
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Hamang M, Yaden B, Dai G. Gastrointestinal pharmacology activins in liver health and disease. Biochem Pharmacol 2023; 214:115668. [PMID: 37364623 PMCID: PMC11234865 DOI: 10.1016/j.bcp.2023.115668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/06/2023] [Accepted: 06/20/2023] [Indexed: 06/28/2023]
Abstract
Activins are a subgroup of the TGFβ superfamily of growth and differentiation factors, dimeric in nature and consisting of two inhibin beta subunits linked via a disulfide bridge. Canonical activin signaling occurs through Smad2/3, with negative feedback initiated by Smad6/7 following signal transduction, which binds activin type I receptor preventing phosphorylation of Smad2/3 and activation of downstream signaling. In addition to Smad6/7, other inhibitors of activin signaling have been identified as well, including inhibins (dimers of an inhibin alpha and beta subunit), BAMBI, Cripto, follistatin, and follistatin-like 3 (fstl3). To date, activins A, B, AB, C, and E have been identified and isolated in mammals, with activin A and B having the most characterization of biological activity. Activin A has been implicated as a regulator of several important functions of liver biology, including hepatocyte proliferation and apoptosis, ECM production, and liver regeneration; the role of other subunits of activin in liver physiology are less understood. There is mounting data to suggest a link between dysregulation of activins contributing to various hepatic diseases such as inflammation, fibrosis, and hepatocellular carcinoma, and emerging studies demonstrating the protective and regenerative effects of inhibiting activins in mouse models of liver disease. Due to their importance in liver biology, activins demonstrate utility as a therapeutic target for the treatment of hepatic diseases such as cirrhosis, NASH, NAFLD, and HCC; further research regarding activins may provide diagnostic or therapeutic opportunity for those suffering from various liver diseases.
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Affiliation(s)
- Matthew Hamang
- Department of Biology, School of Science, Indiana University - Purdue University Indianapolis, IN, United States.
| | - Benjamin Yaden
- Department of Biology, School of Science, Indiana University - Purdue University Indianapolis, IN, United States.
| | - Guoli Dai
- Department of Biology, School of Science, Indiana University - Purdue University Indianapolis, IN, United States.
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Ma JT, Xia S, Zhang BK, Luo F, Guo L, Yang Y, Gong H, Yan M. The pharmacology and mechanisms of traditional Chinese medicine in promoting liver regeneration: A new therapeutic option. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 116:154893. [PMID: 37236047 DOI: 10.1016/j.phymed.2023.154893] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/04/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023]
Abstract
BACKGROUND The liver is renowned for its remarkable regenerative capacity to restore its structure, size and function after various types of liver injury. However, in patients with end-stage liver disease, the regenerative capacity is inhibited and liver transplantation is the only option. Considering the limitations of liver transplantation, promoting liver regeneration is suggested as a new therapeutic strategy for liver disease. Traditional Chinese medicine (TCM) has a long history of preventing and treating various liver diseases, and some of them have been proven to be effective in promoting liver regeneration, suggesting the therapeutic potential in liver diseases. PURPOSE This review aims to summarize the molecular mechanisms of liver regeneration and the pro-regenerative activity and mechanism of TCM formulas, extracts and active ingredients. METHODS We conducted a systematic search in PubMed, Web of Science and the Cochrane Library databases using "TCM", "liver regeneration" or their synonyms as keywords, and classified and summarized the retrieved literature. The PRISMA guidelines were followed. RESULTS Forty-one research articles met the themes of this review and previous critical studies were also reviewed to provide essential background information. Current evidences indicate that various TCM formulas, extracts and active ingredients have the effect on stimulating liver regeneration through modulating JAK/STAT, Hippo, PI3K/Akt and other signaling pathways. Besides, the mechanisms of liver regeneration, the limitation of existing studies and the application prospect of TCM to promote liver regeneration are also outlined and discussed in this review. CONCLUSION This review supports TCM as new potential therapeutic options for promoting liver regeneration and repair of the failing liver, although extensive pharmacokinetic and toxicological studies, as well as elaborate clinical trials, are still needed to demonstrate safety and efficacy.
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Affiliation(s)
- Jia-Ting Ma
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Shuang Xia
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Bi-Kui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Fen Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Lin Guo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Yan Yang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Hui Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China.
| | - Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China.
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Wang Y, Hamang M, Culver A, Jiang H, Yanum J, Garcia V, Lee J, White E, Kusumanchi P, Chalasani N, Liangpunsakul S, Yaden BC, Dai G. Activin B promotes the initiation and progression of liver fibrosis. Hepatol Commun 2022; 6:2812-2826. [PMID: 35866567 PMCID: PMC9512478 DOI: 10.1002/hep4.2037] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 06/01/2022] [Accepted: 06/14/2022] [Indexed: 11/09/2022] Open
Abstract
The role of activin B, a transforming growth factor β (TGFβ) superfamily cytokine, in liver health and disease is largely unknown. We aimed to investigate whether activin B modulates liver fibrogenesis. Liver and serum activin B, along with its analog activin A, were analyzed in patients with liver fibrosis from different etiologies and in mouse acute and chronic liver injury models. Activin B, activin A, or both was immunologically neutralized in mice with progressive or established carbon tetrachloride (CCl4 )-induced liver fibrosis. Hepatic and circulating activin B was increased in human patients with liver fibrosis caused by several liver diseases. In mice, hepatic and circulating activin B exhibited persistent elevation following the onset of several types of liver injury, whereas activin A displayed transient increases. The results revealed a close correlation of activin B with liver injury regardless of etiology and species. Injured hepatocytes produced excessive activin B. Neutralizing activin B largely prevented, as well as improved, CCl4 -induced liver fibrosis, which was augmented by co-neutralizing activin A. Mechanistically, activin B mediated the activation of c-Jun-N-terminal kinase (JNK), the induction of inducible nitric oxide synthase (iNOS) expression, and the maintenance of poly (ADP-ribose) polymerase 1 (PARP1) expression in injured livers. Moreover, activin B directly induced a profibrotic expression profile in hepatic stellate cells (HSCs) and stimulated these cells to form a septa structure. Conclusions: We demonstrate that activin B, cooperating with activin A, mediates the activation or expression of JNK, iNOS, and PARP1 and the activation of HSCs, driving the initiation and progression of liver fibrosis.
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Affiliation(s)
- Yan Wang
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Matthew Hamang
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Alexander Culver
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Huaizhou Jiang
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Jennifer Yanum
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Veronica Garcia
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Joonyong Lee
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Emily White
- College of ScienceDepartment of Biological SciencesPurdue UniversityWest LafayetteIndianaUSA
| | - Praveen Kusumanchi
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Naga Chalasani
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
- Department of Biochemistry and Molecular BiologyIndiana University School of MedicineIndianapolisIndianaUSA
- Roudebush Veterans Administration Medical CenterIndianapolisIndianaUSA
| | - Benjamin C. Yaden
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
| | - Guoli Dai
- Department of BiologySchool of ScienceCenter for Developmental and Regenerative BiologyIndiana University–Purdue University IndianapolisIndianapolisIndianaUSA
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Bloise E, Ciarmela P, Dela Cruz C, Luisi S, Petraglia F, Reis FM. Activin A in Mammalian Physiology. Physiol Rev 2019; 99:739-780. [DOI: 10.1152/physrev.00002.2018] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be combined with alpha subunits to form inhibins. Activins were discovered in 1986 following the isolation of inhibins from porcine follicular fluid, and were characterized as ovarian hormones that stimulate follicle stimulating hormone (FSH) release by the pituitary gland. In particular, activin A was shown to be the isoform of greater physiological importance in humans. The current understanding of activin A surpasses the reproductive system and allows its classification as a hormone, a growth factor, and a cytokine. In more than 30 yr of intense research, activin A was localized in female and male reproductive organs but also in other organs and systems as diverse as the brain, liver, lung, bone, and gut. Moreover, its roles include embryonic differentiation, trophoblast invasion of the uterine wall in early pregnancy, and fetal/neonate brain protection in hypoxic conditions. It is now recognized that activin A overexpression may be either cytostatic or mitogenic, depending on the cell type, with important implications for tumor biology. Activin A also regulates bone formation and regeneration, enhances joint inflammation in rheumatoid arthritis, and triggers pathogenic mechanisms in the respiratory system. In this 30-yr review, we analyze the evidence for physiological roles of activin A and the potential use of activin agonists and antagonists as therapeutic agents.
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Affiliation(s)
- Enrrico Bloise
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Pasquapina Ciarmela
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Cynthia Dela Cruz
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Stefano Luisi
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Felice Petraglia
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Fernando M. Reis
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
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Activin-A causes Hepatic stellate cell activation via the induction of TNFα and TGFβ in Kupffer cells. Biochim Biophys Acta Mol Basis Dis 2017; 1864:891-899. [PMID: 29287776 DOI: 10.1016/j.bbadis.2017.12.031] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 12/06/2017] [Accepted: 12/22/2017] [Indexed: 01/14/2023]
Abstract
BACKGROUND & AIMS TGFβ superfamily member Activin-A is a multifunctional hormone/cytokine expressed in multiple tissues and cells, where it regulates cellular differentiation, proliferation, inflammation and tissue architecture. High activin-A levels have been reported in alcoholic cirrhosis and non-alcoholic steatohepatitis (NASH). Our aim was to identify the cell types involved in the fibrotic processes induced by activin-A in liver and verify the liver diseases that this molecule can be found increased. METHODS We studied the effect of activin-A on mouse primary Kupffer cells (KCs) and Hepatic Stellate cells (HSCs) and the levels of activin-A and its inhibitor follistatin in the serum of patients from a large panel of liver diseases. RESULTS Activin-A is expressed by mouse hepatocytes, HSCs and Liver Sinusoid Endothelial cells but not KCs. Each cell type expresses different activin receptor combinations. HSCs are unresponsive to activin-A due to downregulation/desensitization of type-II activin receptors, while KCs respond by increasing the expression/production of TNFα και TGFβ1. In the presence of KCs or conditioned medium from activin-A treated KCs, HSCs switch to a profibrogenic phenotype, including increased collagen and αSMA expression and migratory capacity. Incubation of activin-A treated KC conditioned medium with antibodies against TNFα and TGFβ1 partially blocks its capacity to activate HSCs. Only patients with alcoholic liver diseases and NASH cirrhosis have significantly higher activin-A levels and activin-A/follistatin ratio. CONCLUSIONS Activin-A may induce fibrosis in NASH and alcoholic cirrhosis via activation of KCs to express pro-inflammatory molecules that promote HSC-dependent fibrogenesis and could be a target for future anti-fibrotic therapies.
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Tao Y, Wang M, Chen E, Tang H. Liver Regeneration: Analysis of the Main Relevant Signaling Molecules. Mediators Inflamm 2017; 2017:4256352. [PMID: 28947857 PMCID: PMC5602614 DOI: 10.1155/2017/4256352] [Citation(s) in RCA: 122] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 07/19/2017] [Accepted: 08/10/2017] [Indexed: 02/06/2023] Open
Abstract
Liver regeneration is a highly organized tissue regrowth process and is the most important reaction of the liver to injury. The overall process of liver regeneration includes three phases: priming stage, proliferative phase, and termination phase. The initial step aims to induce hepatocytes to be sensitive to growth factors with the aid of some cytokines, including TNF-α and IL-6. The proliferation phase promotes hepatocytes to re-enter G1 with the stimulation of growth factors. While during the termination stage, hepatocytes will discontinue to proliferate to maintain normal liver mass and function. Except for cytokine- and growth factor-mediated pathways involved in regulating liver regeneration, new substances and technologies emerge to influence the regenerative process. Here, we reviewed novel and important signaling molecules involved in the process of liver regeneration to provide a cue for further research.
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Affiliation(s)
- Yachao Tao
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Menglan Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Enqiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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12
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Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A. Proc Natl Acad Sci U S A 2017; 114:3993-3998. [PMID: 28348240 DOI: 10.1073/pnas.1613392114] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Endothelial cells (ECs) not only are important for oxygen delivery but also act as a paracrine source for signals that determine the balance between tissue regeneration and fibrosis. Here we show that genetic inactivation of flow-induced transcription factor Krüppel-like factor 2 (KLF2) in ECs results in reduced liver damage and augmentation of hepatocyte proliferation after chronic liver injury by treatment with carbon tetrachloride (CCl4). Serum levels of GLDH3 and ALT were significantly reduced in CCl4-treated EC-specific KLF2-deficient mice. In contrast, transgenic overexpression of KLF2 in liver sinusoidal ECs reduced hepatocyte proliferation. KLF2 induced activin A expression and secretion from endothelial cells in vitro and in vivo, which inhibited hepatocyte proliferation. However, loss or gain of KLF2 expression did not change capillary density and liver fibrosis, but significantly affected hepatocyte proliferation. Taken together, the data demonstrate that KLF2 induces an antiproliferative secretome, including activin A, which attenuates liver regeneration.
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13
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de Jonge J, Olthoff KM. Liver regeneration. BLUMGART'S SURGERY OF THE LIVER, BILIARY TRACT AND PANCREAS, 2-VOLUME SET 2017:93-109.e7. [DOI: 10.1016/b978-0-323-34062-5.00006-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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14
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Ding ZY, Jin GN, Wang W, Sun YM, Chen WX, Chen L, Liang HF, Datta PK, Zhang MZ, Zhang B, Chen XP. Activin A-Smad Signaling Mediates Connective Tissue Growth Factor Synthesis in Liver Progenitor Cells. Int J Mol Sci 2016; 17:408. [PMID: 27011166 PMCID: PMC4813263 DOI: 10.3390/ijms17030408] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 03/02/2016] [Accepted: 03/02/2016] [Indexed: 01/19/2023] Open
Abstract
Liver progenitor cells (LPCs) are activated in chronic liver damage and may contribute to liver fibrosis. Our previous investigation reported that LPCs produced connective tissue growth factor (CTGF/CCN2), an inducer of liver fibrosis, yet the regulatory mechanism of the production of CTGF/CCN2 in LPCs remains elusive. In this study, we report that Activin A is an inducer of CTGF/CCN2 in LPCs. Here we show that expression of both Activin A and CTGF/CCN2 were upregulated in the cirrhotic liver, and the expression of Activin A positively correlates with that of CTGF/CCN2 in liver tissues. We go on to show that Activin A induced de novo synthesis of CTGF/CCN2 in LPC cell lines LE/6 and WB-F344. Furthermore, Activin A contributed to autonomous production of CTGF/CCN2 in liver progenitor cells (LPCs) via activation of the Smad signaling pathway. Smad2, 3 and 4 were all required for this induction. Collectively, these results provide evidence for the fibrotic role of LPCs in the liver and suggest that the Activin A-Smad-CTGF/CCN2 signaling in LPCs may be a therapeutic target of liver fibrosis.
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Affiliation(s)
- Ze-Yang Ding
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Guan-Nan Jin
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Wei Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Yi-Min Sun
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Wei-Xun Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Lin Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Hui-Fang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Pran K Datta
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
| | - Ming-Zhi Zhang
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, TN 37235, USA.
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Xiao-Ping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Islam MS, Catherino WH, Protic O, Janjusevic M, Gray PC, Giannubilo SR, Ciavattini A, Lamanna P, Tranquilli AL, Petraglia F, Castellucci M, Ciarmela P. Role of activin-A and myostatin and their signaling pathway in human myometrial and leiomyoma cell function. J Clin Endocrinol Metab 2014; 99:E775-85. [PMID: 24606069 PMCID: PMC4010707 DOI: 10.1210/jc.2013-2623] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
CONTEXT Uterine leiomyomas are highly prevalent benign tumors of premenopausal women and the most common indication for hysterectomy. However, the exact etiology of this tumor is not fully understood. OBJECTIVE The objective of the study was to evaluate the role of activin-A and myostatin and their signaling pathways in human myometrial and leiomyoma cells. DESIGN This was a laboratory study. SETTING Myometrial and leiomyoma cells (primary and cell lines) were cultured in vitro. PATIENTS The study included premenopausal women who were admitted to the hospital for myomectomy or hysterectomy. INTERVENTIONS Primary myometrial and leiomyoma cells and/or cell lines were treated with activin-A (4 nM) and myostatin (4 nM) for different days of interval (to measure proliferation rate) or 30 minutes (to measure signaling molecules) or 48 hours to measure proliferating markers, extracellular matrix mRNA, and/or protein expression by real-time PCR, Western blot, and/or immunocytochemistry. RESULTS We found that activin-A and myostatin significantly reduce cell proliferation in primary myometrial cells but not in leiomyoma cells as measured by a CyQUANT cell proliferation assay kit. Reduced expression of proliferating cell nuclear antigen and Ki-67 were also observed in myometrial cells in response to activin-A and myostatin treatment. Activin-A also significantly increased mRNA expression of fibronectin, collagen1A1, and versican in primary leiomyoma cells. Finally, we found that activin-A and myostatin activate Smad-2/3 signaling but do not affect ERK or p38 signaling in both myometrial and leiomyoma cells. CONCLUSIONS This study results suggest that activin-A and myostatin can exert antiproliferative and/or fibrotic effects on these cell types via Smad-2/3 signaling.
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Voumvouraki A, Notas G, Koulentaki M, Georgiadou M, Klironomos S, Kouroumalis E. Increased serum activin-A differentiates alcoholic from cirrhosis of other aetiologies. Eur J Clin Invest 2012; 42:815-22. [PMID: 22304651 DOI: 10.1111/j.1365-2362.2012.02647.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Activin-A is a molecule of the TGF superfamily, implicated in liver fibrosis, regeneration and stem cell differentiation. However, data on activins in liver diseases are few. We therefore studied serum levels of activin-A in chronic liver diseases. To identify the origin of activin-A, levels in the hepatic vein were also estimated. MATERIALS AND METHODS Nineteen controls and 162 patients participated in the study: 39 with hepatocellular carcinoma (HCC: 19 viral associated and 20 alcohol associated), 18 with chronic hepatitis C (CHC), 47 with primary biliary cirrhosis (26 PBC stage I-II and 21 stage IV), 22 with alcoholic cirrhosis (AC, hepatic vein blood available in 16), 20 with HCV cirrhosis (hepatic vein blood available in 18) and 16 patients with alcoholic fatty liver with mild to moderate fibrosis but no cirrhosis. RESULTS Activin-A levels were significantly increased (P < 0·001) in serum of patients with AC (median 673 pg/mL, range 449-3279), compared with either controls (149 pg/mL, 91-193) or patients with viral cirrhosis (189 pg/mL, 81-480), CHC (142 pg/mL, 65-559) PBC stage I-II (100 pg/mL, 59-597) and PBC stage IV (104 pg/mL, 81-579). Only patients with AC-associated HCC had significantly increased levels of activin-A (2403 pg/mL, 1561-7220 pg/mL). Activin-A serum levels could accurately discriminate AC from cirrhosis of other aetiologies and noncirrhotic alcoholic fatty liver with fibrosis. CONCLUSIONS Increased serum levels of activin-A only in patients with alcohol-related cirrhosis or HCC suggest a possible role of this molecule in the pathophysiology of AC. Further research is warranted to elucidate its role during the profibrotic process and its possible clinical applications.
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Affiliation(s)
- Argyro Voumvouraki
- University Hospital Department of Gastroenterology, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece
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Taki-Eldin A, Zhou L, Xie HY, Zheng SS. Liver regeneration after liver transplantation. ACTA ACUST UNITED AC 2012; 48:139-53. [PMID: 22572792 DOI: 10.1159/000337865] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 02/07/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND/PURPOSE The liver has a remarkable capacity to regenerate after injury or resection. The aim of this review is to outline the mechanisms and factors affecting liver regeneration after liver transplantation. METHODS Relevant studies were reviewed using Medline, PubMed and Springer databases. RESULTS A variety of cytokines (such as interleukin-6 and tumor necrosis factor-α), growth factors (like hepatocyte growth factor and transforming growth factor-α) and cells are involved in liver regeneration. Several factors affect liver regeneration after transplantation such as ischemic injury, graft size, immunosuppression, steatosis, donor age and viral hepatitis. CONCLUSION Liver regeneration has been studied for many years. However, further research is essential to reveal the complex processes affecting liver regeneration, which may provide novel strategies in the management of liver transplantation recipients and donors.
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Affiliation(s)
- A Taki-Eldin
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Abstract
The liver is the body's most important detoxification organ and has an extreme ability to regenerate. The regeneration process can be divided into three stages: initiation, proliferation and termination. Most of previous studies focus on the initial stage and proliferative stage, while the mechanism for the proper termination of liver regeneration is still poorly understood. The termination stage involves a variety of cytokines and growth factors, which mainly function to inhibit mitogen-mediated liver cell growth-promoting effect and promote the apoptosis of excessively proliferating liver cells. In this paper we will discuss the major factors involved in the termination of liver regeneration.
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Abstract
Liver fibrosis is the result of the entire organism responding to a chronic injury. Every cell type in the liver contributes to the fibrosis. This paper first discusses key intracellular signaling pathways that are induced during liver fibrosis. The paper then examines the effects of these signaling pathways on the major cell types in the liver. This will provide insights into the molecular pathophysiology of liver fibrosis and should identify therapeutic targets.
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Jonge JD, Olthoff KM. Liver regeneration. BLUMGART'S SURGERY OF THE LIVER, PANCREAS AND BILIARY TRACT 2012:87-101.e6. [DOI: 10.1016/b978-1-4377-1454-8.00005-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Smad phosphoisoform signals in acute and chronic liver injury: similarities and differences between epithelial and mesenchymal cells. Cell Tissue Res 2011; 347:225-43. [PMID: 21626291 PMCID: PMC3250618 DOI: 10.1007/s00441-011-1178-6] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Accepted: 04/15/2011] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma (HCC) usually arises from hepatic fibrosis caused by chronic inflammation. In chronic liver damage, hepatic stellate cells undergo progressive activation to myofibroblasts (MFB), which are important extracellular-matrix-producing mesenchymal cells. Concomitantly, perturbation of transforming growth factor (TGF)-β signaling by pro-inflammatory cytokines in the epithelial cells of the liver (hepatocytes) promotes both fibrogenesis and carcinogenesis (fibro-carcinogenesis). Insights into fibro-carcinogenic effects on chronically damaged hepatocytes have come from recent detailed analyses of the TGF-β signaling process. Smad proteins, which convey signals from TGF-β receptors to the nucleus, have intermediate linker regions between conserved Mad homology (MH) 1 and MH2 domains. TGF-β type I receptor and pro-inflammatory cytokine-activated kinases differentially phosphorylate Smad2 and Smad3 to create phosphoisoforms phosphorylated at the COOH-terminal, linker, or both (L/C) regions. After acute liver injury, TGF-β-mediated pSmad3C signaling terminates hepatocytic proliferation induced by the pro-inflammatory cytokine-mediated mitogenic pSmad3L pathway; TGF-β and pro-inflammatory cytokines synergistically enhance collagen synthesis by activated hepatic stellate cells via pSmad2L/C and pSmad3L/C pathways. During chronic liver disease progression, pre-neoplastic hepatocytes persistently affected by TGF-β together with pro-inflammatory cytokines come to exhibit the same carcinogenic (mitogenic) pSmad3L and fibrogenic pSmad2L/C signaling as do MFB, thereby accelerating liver fibrosis while increasing risk of HCC. This review of Smad phosphoisoform-mediated signals examines similarities and differences between epithelial and mesenchymal cells in acute and chronic liver injuries and considers Smad linker phosphorylation as a potential target for the chemoprevention of fibro-carcinogenesis.
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Shen H, Liu T, Zhang L, Zheng PY, Ji G, Xing LJ. Pathogenesis of increased sensitivity of hepatocytes to injury in non-alcoholic fatty liver disease. Shijie Huaren Xiaohua Zazhi 2010; 18:685-688. [DOI: 10.11569/wcjd.v18.i7.685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is closely associated with genetic, environmental, and metabolic stress. Elevated sensitivity of hepatocytes to injury is found in NAFLD in some circumstances, such as exposure to hepatotoxic substances (carbon tetrachloride, alcohol) and cholestasis. Mitochondrial dysfunction, free fatty acids, oxidative stress, inflammatory factor and calcium overload in hepatocytes play an important role in the pathogenesis of increased sensitivity of hepatocytes to injury in NAFLD. Further elucidation of the pathogenesis of hepatocyte sensitivity to injury may provide a new strategy for prevention and treatment of NAFLD.
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Kreidl E, Oztürk D, Metzner T, Berger W, Grusch M. Activins and follistatins: Emerging roles in liver physiology and cancer. World J Hepatol 2009; 1:17-27. [PMID: 21160961 PMCID: PMC2999257 DOI: 10.4254/wjh.v1.i1.17] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2009] [Revised: 09/10/2009] [Accepted: 09/17/2009] [Indexed: 02/06/2023] Open
Abstract
Activins are secreted proteins belonging to the TGF-β family of signaling molecules. Activin signals are crucial for differentiation and regulation of cell proliferation and apoptosis in multiple tissues. Signal transduction by activins relies mainly on the Smad pathway, although the importance of crosstalk with additional pathways is increasingly being recognized. Activin signals are kept in balance by antagonists at multiple levels of the signaling cascade. Among these, follistatin and FLRG, two members of the emerging family of follistatin-like proteins, can bind secreted activins with high affinity, thereby blocking their access to cell surface-anchored activin receptors. In the liver, activin A is a major negative regulator of hepatocyte proliferation and can induce apoptosis. The functions of other activins expressed by hepatocytes have yet to be more clearly defined. Deregulated expression of activins and follistatin has been implicated in hepatic diseases including inflammation, fibrosis, liver failure and primary cancer. In particular, increased follistatin levels have been found in the circulation and in the tumor tissue of patients suffering from hepatocellular carcinoma as well as in animal models of liver cancer. It has been argued that up-regulation of follistatin protects neoplastic hepatocytes from activin-mediated growth inhibition and apoptosis. The use of follistatin as biomarker for liver tumor development is impeded, however, due to the presence of elevated follistatin levels already during preceding stages of liver disease. The current article summarizes our evolving understanding of the multi-faceted activities of activins and follistatins in liver physiology and cancer.
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Affiliation(s)
- Emanuel Kreidl
- Emanuel Kreidl, Deniz Öztürk, Thomas Metzner, Walter Berger, Michael Grusch, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, Vienna A-1090, Austria
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Ren XJ, Guan GJ, Liu G, Zhang T, Liu GH. Effect of activin A on tubulointerstitial fibrosis in diabetic nephropathy. Nephrology (Carlton) 2009; 14:311-20. [PMID: 19298640 DOI: 10.1111/j.1440-1797.2008.01059.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
AIM The effect of activin A on tubulointerstitial fibrosis in diabetic nephropathy (DN) using streptozotocin (STZ)-induced diabetic rats and high glucose-cultured HK-2 cells was investigated. METHODS Male Wistar rats were randomized into a normal control group (NC) and diabetes mellitus group (DM). Diabetes was induced by i.p. injection of STZ. Six rats were respectively killed 4, 8, 12 and 16 weeks after model establishment in each group. The changes of kidney weight/bodyweight (KW/BW), urine albumin excretion rate (AER) and creatinine clearance rate (Ccr) were determined. The morphology of tubulointerstitium was observed by light microscopy. Further biochemical analysis was provided using immunohistochemistry and real-time polymerase chain reaction. The different parameters in high glucose-cultured HK-2 cells were monitored by western blotting or enzyme-linked immunosorbent assay (ELISA) and the intervention of rh-follistatin on them was investigated. RESULTS Compared with the NC group, there was marked enlargement in the levels of KW/BW, AER, Ccr and interstitial fibrosis index, and the production of P-Smad2/3 and fibronectin in the DM group from 8 to 16 weeks. Activin betaA, mainly located in tubular epithelial cells, was significantly higher in the DM group than that in the NC group throughout the study periods. Follistatin was abundant in the NC group, but was diminished gradually in the DM group. High glucose may facilitate the synthesis of activin betaA, transforming growth factor (TGF)-beta, P-Smad2/3 and fibronectin in HK-2 cells while rh-follistatin inhibited them except TGF-beta. CONCLUSION Activin A is involved in tubulointerstitial fibrosis in DN by inducing the production of fibronectin through Smad signal pathway.
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Affiliation(s)
- Xiao-Jun Ren
- Department of Nephropathy, the Second Affiliated Hospital, Medical College of Shandong University, 247 Beiyuan Street, Jinan, China.
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Gressner OA, Lahme B, Siluschek M, Rehbein K, Weiskirchen R, Gressner AM. Intracrine signalling of activin A in hepatocytes upregulates connective tissue growth factor (CTGF/CCN2) expression. Liver Int 2008; 28:1207-16. [PMID: 18397232 DOI: 10.1111/j.1478-3231.2008.01729.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND/AIMS Up to now, the effect of activin A on the expression of the important transforming growth factor (TGF)-beta downstream modulator connective tissue growth factor (CTGF) is not known, but might be of relevance for the functional effects of this cytokine on several liver cell types. METHODS In this study, activin A-dependent CTGF expression in hepatocytes (PC) primed by exogenous activin A and in PC maintained under complete activin-free culture conditions was analysed by Western blots, metabolic labelling, gene silencing, reverse transcriptase-polymerase chain reaction (RT-PCR) and CTGF reporter gene assays. This study was supplemented by immunocytochemical staining of activin A and CTGF in PC of injured liver. RESULTS Using alkaline phosphatase alpha-alkaline phosphatase staining, it is demonstrated that activin A becomes increasingly detectable during the course of CCl(4)-liver damage. Addition of activin A to cultured PC induced CTGF protein expression via phosphorylation of Smad2 and Smad3. This induction can be inhibited by the antagonist follistatin and alpha-activin A antibody respectively. When PC were cultured under serum(i.e. activin A)-free culture conditions, a time-dependent increase of activin expression during the course of the culture was proven by RT-PCR. Silencing of inhibin beta(A) gene expression under serum-free conditions by small interfering RNAs greatly suppressed CTGF synthesis and the phosphorylations of Smad2 and Smad3. However, both the extracellularly acting follistatin and the alpha-activin A antibody could not inhibit spontaneous CTGF expression, which, however, was achieved by the cell-permeable TGF-beta Alk4/Alk5 receptor-kinase-inhibitor SB431542. CONCLUSIONS In conclusion, the results point to activin A as an inducer of CTGF synthesis in PC. Intracellular activin A contributes to spontaneous CTGF expression in PC independent of exogenous activin A, which is proposed to occur via Alk4/Alk5-receptors. The findings might be important for many actions of activin A on the liver.
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Affiliation(s)
- Olav A Gressner
- Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, Aachen, Germany.
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26
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Yamamoto Y, Ono T, Dhar DK, Yamanoi A, Tachibana M, Tanaka T, Nagasue N. Role of peroxisome proliferator-activated receptor-gamma (PPARgamma) during liver regeneration in rats. J Gastroenterol Hepatol 2008; 23:930-7. [PMID: 18565023 DOI: 10.1111/j.1440-1746.2008.05370.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear receptor superfamily, is widely expressed in adipocytes and other tissues, including the liver. Several reports have shown that PPARgamma activation induced cell-cycle arrest and apoptosis in tumor cells. We investigated the role of the PPARgamma/ligand system and the effect of the PPARgamma agonist during liver regeneration. METHODS Expression of PPARgamma and serum levels of 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) by enzyme immunoassay were evaluated in rats following partial hepatectomy (PH group). Further, the effect of the PPARgamma agonist, pioglitazone, on liver regeneration (PH + PGZ group) was evaluated by proliferating cell nuclear antigen labeling index, relative liver weight, and expression of cell-cycle regulators. RESULTS The number of PPARgamma-stained hepatocytes decreased at 24 h (PH, 15.8 +/- 2.2%; sham, 35.5 +/- 2.4%; P < 0.001) and increased in the late phase of liver regeneration compared to the sham-operated group (P < 0.001 at 48-120 h). The peaks of serum 15d-PGJ2 (627.0 +/- 91.1 pg/ml) and PPARgamma expression (90.6 +/- 3.1%) coincided in the late phase of liver regeneration. Also, oral administration of pioglitazone inhibited hepatocyte proliferation, in terms of the proliferating cell nuclear antigen (PCNA) labeling index and p27 expression during the late phase of liver regeneration, and caused a transient reduction in liver mass when compared to the PH group. CONCLUSIONS These results indicate that the PPARgamma/ligand system may be one of the key negative regulators of hepatocyte proliferation and may be responsible for the inhibition of liver growth in the late phase of liver regeneration.
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Affiliation(s)
- Yoshio Yamamoto
- Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, Enyacho, Izumo, Japan.
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27
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Neuman MG, Sha K, Esguerra R, Zakhari S, Winkler RE, Hilzenrat N, Wyse J, Cooper CL, Seth D, Gorrell MD, Haber PS, McCaughan GW, Leo MA, Lieber CS, Voiculescu M, Buzatu E, Ionescu C, Dudas J, Saile B, Ramadori G. Inflammation and repair in viral hepatitis C. Dig Dis Sci 2008; 53:1468-87. [PMID: 17994278 DOI: 10.1007/s10620-007-0047-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2007] [Accepted: 09/26/2007] [Indexed: 02/07/2023]
Abstract
Hepatitis C viral infection (HCV) results in liver damage leading to inflammation and fibrosis of the liver and increasing rates of hepatic decompensation and hepatocellular carcinoma (HCC). However, the host's immune response and viral determinants of liver disease progression are poorly understood. This review will address the determinants of liver injury in chronic HCV infection and the risk factors leading to rapid disease progression. We aim to better understand the factors that distinguish a relatively benign course of HCV from one with progression to cirrhosis. We will accomplish this task by discussion of three topics: (1) the role of cytokines in the adaptive immune response against the HCV infection; (2) the progression of fibrosis; and (3) the risk factors of co-morbidity with alcohol and human immunodeficiency virus (HIV) in HCV-infected individuals. Despite recent improvements in treating HCV infection using pegylated interferon alpha (PEGIFN-alpha) and ribavirin, about half of individuals infected with some genotypes, for example genotypes 1 and 4, will not respond to treatment or cannot be treated because of contraindications. This review will also aim to describe the importance of IFN-alpha-based therapies in HCV infection, ways of monitoring them, and associated complications.
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Affiliation(s)
- Manuela G Neuman
- In Vitro Drug Safety and Biotechnology, Department of Pharmacology, Biophysics and Global Health, Institute of Drug Research, University of Toronto, Toronto, ON, Canada.
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28
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Dai G, He L, Bu P, Wan YJY. Pregnane X receptor is essential for normal progression of liver regeneration. Hepatology 2008; 47:1277-87. [PMID: 18167061 DOI: 10.1002/hep.22129] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
UNLABELLED Pregnane X receptor (PXR) mediates xenobiotic and endobiotic metabolism as well as hepatocyte proliferation. To determine the role of PXR in liver regeneration, 2/3 partial hepatectomy (PH) was performed on wild-type and PXR-null mice. Our results showed that hepatic steatosis was markedly suppressed in mice lacking PXR 36 hours after PH, concomitant with reduction of hepatocyte proliferation at the same time point. Gene expression analysis revealed the role of PXR in regulating the transcription of genes involved in lipid uptake, transport, biosynthesis, oxidation, and storage during liver regeneration. When PXR was absent, the second wave of hepatocyte proliferation was severely suppressed, which was accompanied by the inactivation of STAT3. Lack of PXR inhibited the second phase of liver growth, leading to 17% less liver mass at the anticipated end point of liver regeneration (day 10). CONCLUSION PXR is required for normal progression of liver regeneration by modulating lipid homeostasis and regulating hepatocyte proliferation.
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Affiliation(s)
- Guoli Dai
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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29
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Deli A, Kreidl E, Santifaller S, Trotter B, Seir K, Berger W, Schulte-Hermann R, Rodgarkia-Dara C, Grusch M. Activins and activin antagonists in hepatocellular carcinoma. World J Gastroenterol 2008; 14:1699-709. [PMID: 18350601 PMCID: PMC2695910 DOI: 10.3748/wjg.14.1699] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In many parts of the world hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood. There is increasing evidence that activins, which are members of the transforming growth factor β (TGFβ) superfamily of growth and differentiation factors, could play important roles in liver carcinogenesis. Activins are disulphide-linked homo- or heterodimers formed from four different β subunits termed βA, βB, βC, and βE, respectively. Activin A, the dimer of two βA subunits, is critically involved in the regulation of cell growth, apoptosis, and tissue architecture in the liver, while the hepatic function of other activins is largely unexplored so far. Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG, and at the cell membrane antagonistic co-receptors like Cripto or BAMBI. Additionally, in the intracellular space inhibitory Smads can modulate and control activin activity. Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation, fibrosis and development of cancer. The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.
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Zhang HJ, Liu ZH, Chen FF, Ma D, Zhou J, Tai GX. Activin receptor-interacting protein 2 expression and its biological function in mouse hepatocytes. Shijie Huaren Xiaohua Zazhi 2008; 16:350-355. [DOI: 10.11569/wcjd.v16.i4.350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the activin receptor-interacting protein 2 (ARIP2) expression and its biological function in hepatocytes.
METHODS: Expression of ARIP2 in mouse liver tissue and hepatoma cell line Hepal-6 cells was detected by Western blot, immunohistochemistry and cytochemical staining. Effect of ARIP2 on activin-induced gene transcription was analyzed using CAGA-lux plasmid. Effect of over-expression of ARIP2 on the proliferation of Hepal-6 cells was assayed with MTT method.
RESULTS: ARIP2 was expressed in mouse liver tissue and Hepal-6 cells. The expression of ARIP2 in activin A-stimulated Hepal-6 cells was increased in a time-dependent manner, and peaked at 24 h. There was a significant difference in the expression level of ARIP2 on Hepal-6 cells at 12 and 24 h in contrast with the control group (1.01 ± 0.16, 1.62 ± 0.26 vs 0.82 ± 0.11, P < 0.05, P < 0.01). pcDNA3-ARIP2-transfected Hepal-6 cells obviously suppressed the gene transcription induced by activin A. MTT assay displayed that activin A (5 μg/L and 10 μg/L) remarkably inhibited the proliferation of Hepal-6 cells, the A570 nm value was 1.59 ± 0.03 and 1.49 ± 0.04 vs 1.79±0.07, respectively (P < 0.05, P < 0.01). ARIP2 over-expression in Hepal-6 cells significantly blocked the inhibitory effects of activin A (5 μg/L and 10 μg/L) on the proliferation of Hepal-6 cells.
CONCLUSION: ARIP2 can be expected to become a regulation target of genes in treatment of liver injury induced by activin.
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McLean CA, Cleland H, Moncrieff NJ, Barton RJ, de Kretser DM, Phillips DJ. Temporal expression of activin in acute burn wounds—From inflammatory cells to fibroblasts. Burns 2008; 34:50-5. [PMID: 17644256 DOI: 10.1016/j.burns.2007.01.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2006] [Accepted: 01/29/2007] [Indexed: 11/24/2022]
Abstract
Activin A is a member of the transforming growth factor-beta (TGF-beta) family of cytokines and growth factors and upregulation of this protein has been linked with a number of disease processes associated with chronic inflammation and fibrosis. Its potential involvement in burns has not yet been investigated. We therefore studied the localization of activin in tissue sections from excised mid- and deep dermal and full thickness cutaneous burn by immunohistochemistry. There was cell-specific temporal expression in tissues with prominent expression from day 4 onwards in lymphocytes and histiocytes and expression from day 8 onwards in reactive fibroblasts and endothelial cells. Immunopositivity over the first 18 days persisted in reactive fibroblasts and lymphocytes although the latter were in most circumstances decreasing in number. These data are consistent with activin A being central to the inflammatory and repair phases occurring in burnt skin and early scar formation. Modulation of activin expression and actions may, therefore, be a target for the management of burns.
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Affiliation(s)
- Catriona A McLean
- Department of Anatomical Pathology, The Alfred Hospital, Melbourne, Australia
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32
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Zhang HJ, Tai GX, Zhou J, Ma D, Liu ZH. Regulation of activin receptor-interacting protein 2 expression in mouse hepatoma Hepa1-6 cells and its relationship with collagen type IV. World J Gastroenterol 2007; 13:5501-5. [PMID: 17907296 PMCID: PMC4171287 DOI: 10.3748/wjg.v13.i41.5501] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the regulation of activin receptor-interacting protein 2 (ARIP2) expression and its possible relationships with collagen type IV (collagen IV) in mouse hepatoma cell line Hepal-6 cells.
METHODS: The ARIP2 mRNA expression kinetics in Hepal-6 cells was detected by RT-PCR, and its regulation factors were analyzed by treatment with signal transduction activators such as phorbol 12-myristate 13-acetate (PMA), forskolin and A23187. After pcDNA3-ARIP2 was transfected into Hepal-6 cells, the effects of ARIP2 overexpression on activin type II receptor (ActRII) and collagen IV expression were evaluated.
RESULTS: The expression levels of ARIP2 mRNA in Hapel-6 cells were elevated in time-dependent manner 12 h after treatment with activin A and endotoxin LPS, but not changed evidently in the early stage of stimulation (2 or 4 h). The ARIP2 mRNA expression was increased after stimulated with signal transduction activators such as PMA and forskolin in Hepal-6 cells, whereas decreased after treatment with A23187 (25.3% ± 5.7% vs 48.1% ± 3.6%, P < 0.01). ARIP2 overexpression could remarkably suppress the expression of ActRIIA mRNA in dose-dependent manner, but has no effect on ActRIIB in Hepal-6 cells induced by activin A. Furthermore, we have found that overexpression of ARIP2 could inhibit collagen IV mRNA and protein expressions induced by activin A in Hapel-6 cells.
CONCLUSION: These findings suggest that ARIP2 expression can be influenced by various factors. ARIP2 may participate in the negative feedback regulation of signal transduction in the late stage by affecting the expression of ActRIIA and play an important role in regulation of development of liver fibrosis induced by activin.
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MESH Headings
- Activin Receptors, Type II/genetics
- Activin Receptors, Type II/metabolism
- Activins/metabolism
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism
- Adenylyl Cyclases/metabolism
- Animals
- Calcimycin/pharmacology
- Calcium/metabolism
- Carcinoma, Hepatocellular/enzymology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Cell Line, Tumor
- Colforsin/pharmacology
- Collagen Type IV/genetics
- Collagen Type IV/metabolism
- Enzyme Activators/pharmacology
- Gene Expression Regulation, Neoplastic/drug effects
- Ionophores/pharmacology
- Kinetics
- Lipopolysaccharides/pharmacology
- Liver Neoplasms/enzymology
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Mice
- Protein Kinase C/metabolism
- RNA, Messenger/metabolism
- Signal Transduction/drug effects
- Signal Transduction/genetics
- Tetradecanoylphorbol Acetate/pharmacology
- Transfection
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Affiliation(s)
- Hong-Jun Zhang
- Department of Immunology, School of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
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Stoick-Cooper CL, Moon RT, Weidinger G. Advances in signaling in vertebrate regeneration as a prelude to regenerative medicine. Genes Dev 2007; 21:1292-315. [PMID: 17545465 DOI: 10.1101/gad.1540507] [Citation(s) in RCA: 218] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
While all animals have evolved strategies to respond to injury and disease, their ability to functionally recover from loss of or damage to organs or appendages varies widely damage to skeletal muscle, but, unlike amphibians and fish, they fail to regenerate heart, lens, retina, or appendages. The relatively young field of regenerative medicine strives to develop therapies aimed at improving regenerative processes in humans and is predicated on >40 years of success with bone marrow transplants. Further progress will be accelerated by implementing knowledge about the molecular mechanisms that regulate regenerative processes in model organisms that naturally possess the ability to regenerate organs and/or appendages. In this review we summarize the current knowledge about the signaling pathways that regulate regeneration of amphibian and fish appendages, fish heart, and mammalian liver and skeletal muscle. While the cellular mechanisms and the cell types involved in regeneration of these systems vary widely, it is evident that shared signals are involved in tissue regeneration. Signals provided by the immune system appear to act as triggers of many regenerative processes. Subsequently, pathways that are best known for their importance in regulating embryonic development, in particular fibroblast growth factor (FGF) and Wnt/beta-catenin signaling (as well as others), are required for progenitor cell formation or activation and for cell proliferation and specification leading to tissue regrowth. Experimental activation of these pathways or interference with signals that inhibit regenerative processes can augment or even trigger regeneration in certain contexts.
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Affiliation(s)
- Cristi L Stoick-Cooper
- Department of Pharmacology, Howard Hughes Medical Institute, and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, Washington 98195, USA
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Rodgarkia-Dara C, Vejda S, Erlach N, Losert A, Bursch W, Berger W, Schulte-Hermann R, Grusch M. The activin axis in liver biology and disease. Mutat Res 2006; 613:123-37. [PMID: 16997617 DOI: 10.1016/j.mrrev.2006.07.002] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2006] [Revised: 07/27/2006] [Accepted: 07/27/2006] [Indexed: 12/22/2022]
Abstract
Activins are a closely related subgroup within the TGFbeta superfamily of growth and differentiation factors. They consist of two disulfide-linked beta subunits. Four mammalian activin beta subunits termed beta(A), beta(B), beta(C), and beta(E), respectively, have been identified. Activin A, the homodimer of two beta(A) subunits, has important regulatory functions in reproductive biology, embryonic development, inflammation, and tissue repair. Several intra- and extracellular antagonists, including the activin-binding proteins follistatin and follistatin-related protein, serve to fine-tune activin A activity. In the liver there is compelling evidence that activin A is involved in the regulation of cell number by inhibition of hepatocyte replication and induction of apoptosis. In addition, activin A stimulates extracellular matrix production in hepatic stellate cells and tubulogenesis of sinusoidal endothelial cells, and thus contributes to restoration of tissue architecture during liver regeneration. Accumulating evidence from animal models and from patient data suggests that deregulation of activin A signaling contributes to pathologic conditions such as hepatic inflammation and fibrosis, acute liver failure, and development of liver cancer. Increased production of activin A was suggested to be a contributing factor to impaired hepatocyte regeneration in acute liver failure and to overproduction of extracellular matrix in liver fibrosis. Recent evidence suggests that escape of (pre)neoplastic hepatocytes from growth control by activin A through overexpression of follistatin and reduced activin production contributes to hepatocarcinogenesis. The role of the activin subunits beta(C) and beta(E), which are both highly expressed in hepatocytes, is still quite incompletely understood. Down-regulation in liver tumors and a growth inhibitory function similar to that of beta(A) has been shown for beta(E). Contradictory results with regard to cell proliferation have been reported for beta(C). The profound involvement of the activin axis in liver biology and in the pathogenesis of severe hepatic diseases suggests activin as potential target for therapeutic interventions.
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Affiliation(s)
- Chantal Rodgarkia-Dara
- Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
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Shi ZH, Liu H, Liu S, Zhang JM, Tu JW. Roles of activin A and hepatocellular apoptosis in the anti-liver fibrosis process induced by Ginkgo biloba extract in rats. Shijie Huaren Xiaohua Zazhi 2006; 14:2060-2066. [DOI: 10.11569/wcjd.v14.i21.2060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of Ginkgo biloba extract (GBE) on CCl4-induced liver fibrosis as well as the underlying mechanisms.
METHODS: Thirty adult male Sprague Dawley rats were randomized into 3 groups: control group (n = 10), model group (n = 10) and treatment group (n = 10). Except the rats in the control group, the others were intraperitoneally injected with 500 mL/L CCl4 (1 mL/kg) to induce liver cirrhosis (twice a week, for 8 weeks). Moreover, the rats in treatment group were intragastrically administered with GBE (0.4 g/kg) for 8 weeks. At the end of the 8th week, all the rats were sacrificed. Blood samples were collected for the determination of biochemical indicators. Tissue samples were used for histopathological examinations. The expression of activin A was determined by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). Hepatocellular apoptosis was determined by the method of terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) method.
RESULTS: The grade of liver fibrosis in treatment group was lower than that in the model group (P < 0.05). The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and albumin (ALB) in treatment group were significantly improved as compared with those in the model group (ALT: 2806.9 ±576.1 nkat/L vs 4452.9 ± 709.5 nkat/L; AST: 5314.2 ± 1042 nkat/L vs 15 743.4 ± 625.8 nkat/L; ALB: 31.0 ± 2.1 g/L vs 21.7 ± 1.8 g/L; all P < 0.05). GBE treatment markedly reduced mRNA and protein levels of activin A (mRNA: 0.42 ± 0.09 vs 0.78 ± 0.15; protein: 4.2 ± 0.8 vs 11.4 ± 1.2; both P < 0.01). In comparison with that in the model group, the apoptosis index was decreased in treatment groups (7.56 ± 3.36 vs 16.06 ± 8.84, P < 0.01).
CONCLUSION: GBE can markedly attenuate the degrees of hepatic fibrosis, and the mechanism may be correlated with the expression of activin A and hepatocellular apoptosis.
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Patella S, Phillips DJ, Tchongue J, de Kretser DM, Sievert W. Follistatin attenuates early liver fibrosis: effects on hepatic stellate cell activation and hepatocyte apoptosis. Am J Physiol Gastrointest Liver Physiol 2006; 290:G137-44. [PMID: 16123203 DOI: 10.1152/ajpgi.00080.2005] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Activin A, a member of the transforming growth factor-beta superfamily, is constitutively expressed in hepatocytes and regulates liver mass through tonic inhibition of hepatocyte DNA synthesis. Follistatin is the main biological inhibitor of activin bioactivity. These molecules may be involved in hepatic fibrogenesis, although defined roles remain unclear. We studied activin and follistatin gene and protein expression in cultured rat hepatic stellate cells (HSCs) and in rats given CCl4 for 8 wk and examined the effect of follistatin administration on the development of hepatic fibrosis. In activated HSCs, activin mRNA was upregulated with high expression levels, whereas follistatin mRNA expression was unchanged from baseline. Activin A expression in normal lobular hepatocytes redistributed to periseptal hepatocytes and smooth muscle actin-positive HSCs in the fibrotic liver. A 32% reduction in fibrosis, maximal at week 4, occurred in CCl4-exposed rats treated with follistatin. Hepatocyte apoptosis decreased by 87% and was maximal at week 4 during follistatin treatment. In conclusion, activin is produced by activated HSCs in vitro and in vivo. Absence of simultaneous upregulation of follistatin gene expression in HSCs suggests that HSC-derived activin is biologically active and unopposed by follistatin. Our in vivo and in vitro results demonstrate that activin-mediated events contribute to hepatic fibrogenesis and that follistatin attenuates early events in fibrogenesis by constraining HSC proliferation and inhibiting hepatocyte apoptosis.
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Affiliation(s)
- Shane Patella
- Centre for Inflammatory Diseases, Monash Institute of Medical Research, Monash University, Melbourne, Victoria 3168, Australia
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37
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Taub R. Adenovirus-mediated overexpression of activin beta(C) subunit accelerates liver regeneration in partially hepatectomized rats. J Hepatol 2005; 43:751-3. [PMID: 16171890 DOI: 10.1016/j.jhep.2005.07.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
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Abstract
Inflammation is a complex process regulated by a cascade of cytokines and growth factors. This review summarizes the emerging evidence implicating activin A and follistatin in the inflammatory process. Our recent studies have highlighted that activin A is released early in the process as part of the circulatory cytokine cascade during acute systemic inflammation. This release occurs concurrently with tumor necrosis factor (TNF)-alpha and prior to that of interleukin (IL)-6 and follistatin. Although, the cellular source(s) of activin A are yet to be established, circulating blood cells and the vascular endothelium are candidates for this rapid release of activin A into the circulation. The release of activin A and follistatin is also observed in the clinical setting, in particular in sepsis. Furthermore activin A is released into cerebrospinal fluid in a model of meningitis in rabbits. The role of activin A in the inflammatory response is poorly understood, however, in vitro data has highlighted that activin A can have both pro- and anti-inflammatory actions on key mediators of the inflammatory response such as TNF-alpha, IL-1beta and IL-6. Furthermore, emerging data would suggest that activin A induction is restricted to certain types of inflammation and its release is dependant upon the inflammatory setting.
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Affiliation(s)
- Kristian L Jones
- Center for Molecular Reproduction and Endocrinology, Monash Institute of Reproduction and Development, 27-31 Wright Street, Clayton 3168, Victoria, Australia
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Abstract
The unusual regenerative properties of the liver are a logical adaptation by organisms, as the liver is the main detoxifying organ of the body and is likely to be injured by ingested toxins. The numerous cytokine- and growth-factor-mediated pathways that are involved in regulating liver regeneration are being successfully dissected using molecular and genetic approaches. So what is known about this process at present and which questions remain?
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Affiliation(s)
- Rebecca Taub
- University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19004, USA.
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40
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Wada W, Maeshima A, Zhang YQ, Hasegawa Y, Kuwano H, Kojima I. Assessment of the function of the betaC-subunit of activin in cultured hepatocytes. Am J Physiol Endocrinol Metab 2004; 287:E247-54. [PMID: 15039147 DOI: 10.1152/ajpendo.00390.2003] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We assessed the function of the beta(C)-subunit of activin in hepatocytes. We studied the effect of conditioned medium of Chinese hamster ovary (CHO) cell line stably expressing the beta(C) gene (CHO-beta(C)) on growth of AML12 hepatocytes. We also examined the effect of recombinant activin C and transfection of the beta(C) gene by using adenovirus vector. CHO-beta(C) secreted activin C, a homodimer of the beta(C), as well as precursors of the beta(C). The conditioned medium of CHO-beta(C) increased both [(3)H]thymidine incorporation and the cell number in AML12 cells. It also supported survival of AML12 cells in a serum-free condition. Recombinant human activin C also increased both [(3)H]thymidine incorporation and the number of AML12 cells. Transfection of AML12 cells with the beta(C)-subunit led to the stimulation of [(3)H]thymidine incorporation. Analysis of the conditioned medium revealed that the beta(C)-subunit formed a heterodimer with the endogenous beta(A), the formation of which was dependent on the amount of beta(C) expressed. Recombinant activin C did not affect the binding of (125)I-activin A to its receptor or follistatin. These results indicate that activin C stimulates growth of AML12 cells. The beta(C)-subunit modifies the function of the beta(A)-subunit by multiple mechanisms.
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Affiliation(s)
- Wataru Wada
- Institute for Molecular and Cellular Regulation, Gunma University, Japan
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Endo D, Kogure K, Hasegawa Y, Maku-uchi M, Kojima I. Activin A augments vascular endothelial growth factor activity in promoting branching tubulogenesis in hepatic sinusoidal endothelial cells. J Hepatol 2004; 40:399-404. [PMID: 15123352 DOI: 10.1016/j.jhep.2003.11.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2003] [Revised: 11/06/2003] [Accepted: 11/14/2003] [Indexed: 12/30/2022]
Abstract
BACKGROUND/AIMS The production of activin A is markedly up-regulated in hepatocytes after partial hepatectomy. This factor tonically inhibits growth of hepatocytes but little is known about its effect on sinusoidal endothelial cells (SEC). In the present study, we investigated whether or not activin A affects growth and differentiation of SEC. METHODS Growth and survival of SEC were measured in monolayer culture. Capillary formation was studied using SEC cultured in a collagen gel. RESULTS SEC could not survive in the absence of vascular endothelial growth factor (VEGF). Activin A had a small effect on prevention of cell death and also enhanced anti-apoptotic action of VEGF. In addition, activin A and VEGF acted synergistically to stimulate cell growth of SEC. In the collagen gel, VEGF induced capillary formation of SEC. Activin A had little effect on branching tubulogenesis by itself but markedly enhanced tubular formation induced by VEGF. Finally, VEGF induced the expression of activin A and activin A increased the expression of VEGF receptors in cultured SEC. CONCLUSIONS Activin A augments VEGF activity in promoting growth and tubulogenesis of SEC.
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Affiliation(s)
- Daisuke Endo
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan
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Liu QH, Li DG, Huang X, You HN, Pan Q, Xu LM, Xu QF, Lu HM. Effect of Activin on extracelluar matrix secretion in isolated rat hepatic stellate cell. Shijie Huaren Xiaohua Zazhi 2003; 11:745-748. [DOI: 10.11569/wcjd.v11.i6.745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of activin A on the extracelluar matrix secretion of rat hepatic stellate cell.
METHODS Hepatic stellate cells were isolated and purified from normal male Sprague-Dawley rat liver by a combination of pronase-collagenase perfusion and density gradient centrifugation. Passaged hepatic stellate cells were divided randomly into eight groups: control group(A group), ACTA 1 μg/L group (B group), ACTA 10 μg/L group(C group), ACTA 100 μg/L group (D group), TGF β1 10 μg/L group(E group), TGF β1 10 μg/L plus ACTA 1 μg/L group(F group), TGF β1 10 μg/L plus ACTA 10 μg/L group(G group), TGF β1 10 μg/L plus ACTA 100 μg/L group(H group). 24 h after incubation secretion of procollagen Ⅲ, collagen Ⅳ and mRNA of collagen Ⅲ in hepatic stellate cells were detected by radioimmunoassays and semi-quantitative RT-PCR method respectively.
RESULTS Extracellular matrix secretion in passaged hepatic stellate cells was enhanced by activin A according to its concentration, the capacity of extracellular matrix secretion by 100 μg/L activin A was equal to that of 10 μg/L TGF β1, extracellular matrix secretion and type Ⅲ collagen mRNA expression in passaged hepatic stellate cells was enhanced by activin A and TGFβ1 in a synergistic manner.
CONCLUSION Activin A may contribute to hepatic fibrogenesis.
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Affiliation(s)
- Qing-Hua Liu
- Department of Gastroenterology of Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China
| | - Ding-Guo Li
- Department of Gastroenterology of Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China
| | - Xin Huang
- Department of Gastroenterology of Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China
| | - Han-Ning You
- Department of Gastroenterology of Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China
| | - Qin Pan
- Department of Gastroenterology of Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China
| | - Lei-Ming Xu
- Department of Gastroenterology of Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China
| | - Qin-Fang Xu
- Department of Gastroenterology of Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China
| | - Han-Ming Lu
- Department of Gastroenterology of Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China
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Gold EJ, Francis RJB, Zimmermann A, Mellor SL, Cranfield M, Risbridger GP, Groome NP, Wheatley AM, Fleming JS. Changes in activin and activin receptor subunit expression in rat liver during the development of CCl4-induced cirrhosis. Mol Cell Endocrinol 2003; 201:143-53. [PMID: 12706302 DOI: 10.1016/s0303-7207(02)00417-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Amounts of betaA-activin, betaC-activin, activin receptor subunits ActRIIA and ActRIIB mRNA, and betaA- and betaC-activin subunit protein immunoreactivity were investigated in male Lewis rats, either untreated or after 5 or 10 weeks of CCl(4) treatment to induce cirrhosis. Apoptosis was assessed histologically and with an in situ cell death detection kit (TUNEL). Reverse transcription and polymerase chain reaction were used to evaluate mRNA levels. Activin betaA- and betaC-subunit immunoreactivity was studied by immunohistochemistry using specific monoclonal antibodies. Hepatocellular apoptosis (P<0.001), increased betaA- and betaC-activin mRNAs (three- to fourfold; P<0.01) and increased betaA- and betaC-activin tissue immunoreactivity were evident, whereas ActRIIA mRNA concentrations fell (30%; P<0.01) after 5 weeks of CCl(4) treatment. The mRNA concentrations at 10 weeks were not significantly different from controls, despite extensive hepatic nodule formation. We conclude that the increased activin subunit expression is associated with apoptosis, rather than hepatic fibrosis and nodule formation.
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Affiliation(s)
- Elspeth J Gold
- Department of Anatomy and Structural Biology and Centre for Gene Research, University of Otago, Otago School of Medical Sciences, P.O. Box 913, Dunedin, New Zealand
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Abstract
The main non-parenchymal cells of the liver, Kupffer cells, sinusoidal endothelial cells and stellate cells, participate in liver growth with respect to both their own proliferation, and effects on hepatocyte proliferation. In the well-characterised paradigm of 70% partial hepatectomy, they undergo DNA synthesis and cell division 20-24h later than the hepatocyte population. They exert both positive and negative influences on hepatocyte proliferation, including provision of an extracellular matrix-bound reservoir of hepatocyte growth factor that is activated after damage; priming of hepatocytes for DNA synthesis through rapid generation of TNF-alpha and IL-6; and generation of factors at later time points that curb hepatocyte DNA synthesis (IL-1, TGF-beta) and initiate reconstruction and reformation of matrix proteins.
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Affiliation(s)
- Raza Malik
- Centre for Hepatology, Royal Free and University College Medical School, Rowland Hill Street, Hampstead, NW3 2PF, London, UK
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Yan J, Ying H, Gu F, He J, Li YL, Liu HM, Xu YH. Cloning and characterization of a mouse liver-specific gene mfrep-1, up-regulated in liver regeneration. Cell Res 2002; 12:353-61. [PMID: 12528893 DOI: 10.1038/sj.cr.7290137] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Human fibrinogen-related protein-1/liver fibrinogen-related protein-1 (HFREP-1/LFIRE-1), a liver-specific protein, is a member of fibrinogen superfamily that exerts various biological activities. However, the function of HFREP-1/LFIRE-1 in liver remains unknown. Here we isolated its mouse ortholog gene-mouse fibrinogen-related protein-1 (mfrep-1), which encoded 314 amino acids, exhibiting 80.4% similarity to HFREP-1/LFIRE-1. Northern blot analysis revealed that 1.2-kb mfrep-1 mRNA was detected selectively in mouse liver. To explore the function of MFREP-1, we examined the levels of mfrep-1 mRNA during regeneration after 70% partial hepatectomy (PHx) in mice. mfrep-1 mRNA increased in the regenerating liver and reached the first shoulder peak at 2-4 h after PHx. Cycloheximide pretreatment could suppress the induction of mfrep-1, indicating the up-regulation of this gene need de novo protein synthesis. Its mRNA continued to elevate at 6 h thereafter and reached the second peak at 24 h. The enhanced expression of mfrep-1 maintained high until 72 h and then declined slowly to the basal level. Immunohistochemistry assessment confirmed the up-regulated expression of MFREP-1 protein in parenchymal cells during liver regeneration. These data suggested that MFREP-1 might play an important role in liver regeneration and be involved in the regulation of cell growth.
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Affiliation(s)
- Jun Yan
- Laboratory of Molecular and Cellular Oncology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
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Patella S, Phillips DJ, de Kretser DM, Evans LW, Groome NP, Sievert W. Characterization of serum activin-A and follistatin and their relation to virological and histological determinants in chronic viral hepatitis. J Hepatol 2001; 34:576-83. [PMID: 11394658 DOI: 10.1016/s0168-8278(00)00029-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND/METHODS Hepatocyte proliferation in viral hepatitis is regulated by a number of growth factors. Activin-A inhibits hepatocyte DNA synthesis while follistatin, a potent activin-A antagonist, promotes liver regeneration. We report the first study of activin-A and follistatin in human viral hepatitis. Sera from 15 normal subjects, 22 hepatitis B and 47 hepatitis C patients were analysed for activin-A and follistatin and correlated with serological and histological markers of liver injury and with specific immunohistochemistry. RESULTS All groups showed immunoreactivity for activin with hepatocyte localisation. Serum activin-A was significantly increased in viral hepatitis patients compared to controls, was greater in hepatitis B compared to hepatitis C, and correlated with serum aminotransferase and hepatitis B viral replication. A concurrent rise in serum follistatin was not observed in either group, but serum follistatin correlated inversely with hepatitis B DNA levels. Although hepatocyte apoptosis in hepatitis C and proliferation in both groups was significantly elevated compared to controls, there was no correlation with serum activin-A or follistatin. CONCLUSIONS Activin-A and follistatin are constitutively expressed in human liver and serum concentrations are increased in viral hepatitis. Dysregulation of the activin/follistatin axis may be linked to hepatitis B replication but does not correlate with hepatocyte apoptosis.
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Affiliation(s)
- S Patella
- Department of Medicine, Centre for Inflammatory Diseases, Monash Medical Centre, Monash University, Clayton, Victoria, Australia
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Liu Z, Zhao M, Yokoyama KK, Li T. Molecular cloning of a cDNA for rat TM4SF4, a homolog of human il-TMP (TM4SF4), and enhanced expression of the corresponding gene in regenerating rat liver(1). BIOCHIMICA ET BIOPHYSICA ACTA 2001; 1518:183-9. [PMID: 11267677 DOI: 10.1016/s0167-4781(01)00170-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
il-TMP (also known as TM4SF4) is a human tetraspanin that is expressed in human intestine and liver. We have cloned a novel cDNA for a rat gene with sequence similar to that of a cDNA for human il-TMP. The cDNA encoded a protein of 202 amino acids, designated rat TM4SF4. The corresponding transcript was detected in rat liver and testis. The expression of rat TM4SF4 was enhanced in regenerating liver after two-thirds partial hepatectomy. It was supposed that rat TM4SF4 might play a role in cell proliferation and in liver regeneration.
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Affiliation(s)
- Z Liu
- Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China
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Huang X, Li DG, Wang ZR, Wei HS, Cheng JL, Zhan YT, Zhou X, Xu QF, Li X, Lu HM. Expression changes of activin A in the development of hepatic fibrosis. World J Gastroenterol 2001; 7:37-41. [PMID: 11819730 PMCID: PMC4688698 DOI: 10.3748/wjg.v7.i1.37] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the expression of activin A, a member of the transforming growth factor (TGF-β) superfamily, recently has been reported to beoverexpressed in liver cirrhosis, in the course of carbon tetrachloride-induced rat hepatic fibrosis.
METHODS: Hepatic fibrosis was induced in rats by subcutaneous injections of 40% carbon tetrachloride oily solution for a period of 1 to 7 weeks. At the end of 1, 2, 3, 4, 5, 6 and 7 weeks after carbon tetrachloride injections, the rats were killed in group (6-10 rats each time) for study. The activin A messenger RNA expression and its protein localization were assessed by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry.
RESULTS: The normal rat liver expressed activin A mRNA and protein, and its expression was transiently decreased and became undetectable after carbon tetrachloride injections for 2 or 3 weeks and then increased gradually. After injection of carbon tetrachloride for 6 and 7 weeks, activin A mRNA and protein expressions were significantly enchanced in rat liver. Compared with that of the normal rat liver. Activin A mRNA expression levels in rats receiving carbon tetrachloride injections for 6 and 7 weeks were 1.6 and 2.2 times that of those in normal rat liver respectively (0.456 ± 0.094 vs 0.286 ± 0.0670, P < 0.01; 0.620 ± 0.134 vs 0.286 ± 0.0670, P < 0.01). Immunohistochemistry showed that activin A expressed in hepatocytes of normal liver, and its expression was decreased in rats receiving carbon tetrachloride for 2 or 3 weeks. Compared with normal liver, activin A expression distribution mode changed in fibrotic liver, being increased significantly in hepatocytes around fibrotic areas.
CONCLUSION: Activin A expression was increased in late stage of hepatic fibrosis, and this may be involved in hepatic fibrosis formation in this period.
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Affiliation(s)
- X Huang
- Gastroenterology Department, Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China
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Abstract
Adult-to-adult living donor liver transplantation has become the subject of a great deal of attention over the last few years. Until the use of the donor right lobe was introduced and demonstrated to be relatively safe, it was not possible to offer this alternative to conventional transplantation to most adults. Recent clinical work has focused on the results of these procedures in both donors and recipients, perfecting surgical techniques for right-lobe transplantation, streamlining donor evaluation protocols, and containing costs. This overview summarizes many of the recent publications and presentations in the field of adult-to-adult living donor liver transplantation.
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Affiliation(s)
- A T Olzinski
- Division of Transplantation, Department of Surgery, University of Rochester Medical Center, Box Surg, 601 Elmwood Avenue, Rochester, NY 14642, USA
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