|
1
|
Zhao W, Zhang J, Guo Q, Wang Q, Zhao H, Xiao F, Han M, Cao Y, Ding R, Yang A, Xie W. Fibulin-1 deficiency alleviates liver fibrosis by inhibiting hepatic stellate cell activation via the p38 MAPK pathway. Cell Mol Life Sci 2025; 82:192. [PMID: 40323446 PMCID: PMC12052672 DOI: 10.1007/s00018-025-05647-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 02/16/2025] [Accepted: 03/04/2025] [Indexed: 05/08/2025]
Abstract
Elastin stabilization has been correlated with the reversibility of fibrosis. Fibulin-1 can participate in elastin assembly, which promotes its stabilization. However, the role of Fibulin-1 in liver fibrosis remains unknown. Here, we performed a proteomics analysis to identify notable changes in Fibulin-1 expression during continuous fibrosis progression and regression. Fibulin-1 expression was dramatically increased in the plasma of patients with cirrhosis as well as in liver fibrosis models and hepatic stellate cells (HSCs) treated with TGF-β1, and significant accumulation of Fibulin-1 was observed in chronic hepatitis B (CHB)- and metabolic dysfunction-associated steatohepatitis (MASH)-related cirrhosis. Functional studies demonstrated that Fibulin-1 silencing inhibited HSC activation, while the opposite effects were observed for Fibulin-1 overexpression in vitro. Furthermore, transcriptomic analysis revealed that Fibulin-1 mediated p38 MAPK pathway activation, which was confirmed by the addition of a p38 MAPK inhibitor. More importantly, Fibulin-1 depletion in a CCl4-induced liver fibrosis model substantially ameliorated fibrosis progression, which was accompanied by decreased profibrogenic gene expression and decreased levels of insoluble elastin. Moreover, activation of the p38 MAPK pathway was inhibited in vivo. The expression of Fibulin-1D, rather than Fibulin-1C, was elevated during liver fibrogenesis, which suggested a major role for Fibulin-1D in liver fibrosis. Next, we established Fibulin-1D/elastin-coated culture models with LX-2 cells. LX-2 cells with extracellular elastin and Fibulin-1D deposition showed more significant profibrotic phenotypic alterations than those with elastin alone. Fibulin-1 deficiency alleviated liver fibrosis by reducing insoluble elastin and HSC activation, and finally, the p38 MAPK pathway might be involved in the effect of Fibulin-1 on HSCs.
Collapse
Affiliation(s)
- Wenshan Zhao
- Center of Liver Diseases, National Medical Centre for Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Jingyu Zhang
- Center of Liver Diseases, National Medical Centre for Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Qingdong Guo
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, People's Republic of China
| | - Qi Wang
- Center of Liver Diseases, National Medical Centre for Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Hong Zhao
- Center of Liver Diseases, National Medical Centre for Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Fan Xiao
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Ming Han
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Ying Cao
- Center of Liver Diseases, National Medical Centre for Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Rui Ding
- Center of Liver Diseases, National Medical Centre for Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Aiting Yang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China.
| | - Wen Xie
- Center of Liver Diseases, National Medical Centre for Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China.
| |
Collapse
|
|
2
|
Valentino G, Widak A, Scopacasa B, Tirinato L, Parrotta EI, Perozziello G, Pujia A, Cuda G, Luciani P, Candeloro P. Raman imaging investigation of hepatic LX-2 cell reversion under different lipidic treatments. J Mater Chem B 2025; 13:4085-4093. [PMID: 40029112 DOI: 10.1039/d4tb02082k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Liver fibrosis resulting from chronic liver injury is characterized by increased extracellular matrix deposition and inflammation, which leads to excessive scar tissue formation. Targeting activated hepatic stellate cells (HSCs), which are the primary drivers of fibrogenesis, stands out as one of the most compelling therapeutic approaches in this regard. In a healthy liver, HSCs remain quiescent and store vitamin A in cytoplasmic lipid droplets. As a consequence of HSC activation and transdifferentiation to a proliferative myofibroblast-like state upon fibrotic stimuli, the distinctive phenotypic feature of the lipid droplets gets lost. While the reversal of activated HSCs is feasible, understanding the quiescent-like state following injury resolution is crucial for effective fibrosis treatment. This study explores the induced quiescent-like state of naïve immortalized human hepatic stellate (LX-2) cells when treated with soybean phospholipid that contains 75% phosphatidylcholine (S80). The lipid profile of the newly formed lipid droplets was analyzed using Raman imaging, which is a label-free technique well-suited for lipidomics. Results indicate the presence of distinct lipid profiles despite maintaining a quiescent-like state, suggesting that diverse mechanisms govern the active-to-inactive state transition. Additionally, our findings support the fact that each hepatic cell state is composed of heterogeneous subpopulations. This emphasizes the complexity of liver fibrosis and highlights the need for a comprehensive understanding of cellular states to develop targeted therapies.
Collapse
Affiliation(s)
- Gina Valentino
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Assumpta Widak
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Bernadette Scopacasa
- BioNEM Lab. and Nanotechnology Research Center, Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Campus Germaneto, Catanzaro, Italy.
| | - Luca Tirinato
- Department of Medical and Surgical Sciences, University "Magna Græcia" of Catanzaro, 88100, Catanzaro, Italy
| | - Elvira Immacolata Parrotta
- Department of Medical and Surgical Sciences, University "Magna Græcia" of Catanzaro, 88100, Catanzaro, Italy
| | - Gerardo Perozziello
- BioNEM Lab. and Nanotechnology Research Center, Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Campus Germaneto, Catanzaro, Italy.
| | - Arturo Pujia
- Department of Medical and Surgical Sciences, University "Magna Græcia" of Catanzaro, 88100, Catanzaro, Italy
| | - Giovanni Cuda
- Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Campus Germaneto, Catanzaro, Italy
| | - Paola Luciani
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Patrizio Candeloro
- BioNEM Lab. and Nanotechnology Research Center, Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Campus Germaneto, Catanzaro, Italy.
| |
Collapse
|
|
3
|
Avolio E, Bassani B, Campanile M, Mohammed KA, Muti P, Bruno A, Spinetti G, Madeddu P. Shared molecular, cellular, and environmental hallmarks in cardiovascular disease and cancer: Any place for drug repurposing? Pharmacol Rev 2025; 77:100033. [PMID: 40148035 DOI: 10.1016/j.pharmr.2024.100033] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 12/17/2024] [Indexed: 03/29/2025] Open
Abstract
Cancer and cardiovascular disease (CVD) are the 2 biggest killers worldwide. Specific treatments have been developed for the 2 diseases. However, mutual therapeutic targets should be considered because of the overlap of cellular and molecular mechanisms. Cancer research has grown at a fast pace, leading to an increasing number of new mechanistic treatments. Some of these drugs could prove useful for treating CVD, which realizes the concept of cancer drug repurposing. This review provides a comprehensive outline of the shared hallmarks of cancer and CVD, primarily ischemic heart disease and heart failure. We focus on chronic inflammation, altered immune response, stromal and vascular cell activation, and underlying signaling pathways causing pathological tissue remodeling. There is an obvious scope for targeting those shared mechanisms, thereby achieving reciprocal preventive and therapeutic benefits. Major attention is devoted to illustrating the logic, advantages, challenges, and viable examples of drug repurposing and discussing the potential influence of sex, gender, age, and ethnicity in realizing this approach. Artificial intelligence will help to refine the personalized application of drug repurposing for patients with CVD. SIGNIFICANCE STATEMENT: Cancer and cardiovascular disease (CVD), the 2 biggest killers worldwide, share several underlying cellular and molecular mechanisms. So far, specific therapies have been developed to tackle the 2 diseases. However, the development of new cardiovascular drugs has been slow compared with cancer drugs. Understanding the intersection between pathological mechanisms of the 2 diseases provides the basis for repurposing cancer therapeutics for CVD treatment. This approach could allow the rapid development of new drugs for patients with CVDs.
Collapse
Affiliation(s)
- Elisa Avolio
- Bristol Heart Institute, Laboratory of Experimental Cardiovascular Medicine, Translational Health Sciences, Bristol Medical School, University of Bristol, United Kingdom.
| | - Barbara Bassani
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry, and Immunology, IRCCS MultiMedica, Milan, Italy
| | - Marzia Campanile
- Laboratory of Cardiovascular Pathophysiology - Regenerative Medicine, IRCCS MultiMedica, Milan, Italy; Department of Biosciences, University of Milan, Milan, Italy
| | - Khaled Ak Mohammed
- Bristol Heart Institute, Laboratory of Experimental Cardiovascular Medicine, Translational Health Sciences, Bristol Medical School, University of Bristol, United Kingdom; Department of Cardiothoracic Surgery, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Paola Muti
- IRCCS MultiMedica, Milan, Italy; Department of Biomedical, Surgical and Dental Health Sciences, University of Milan, Italy
| | - Antonino Bruno
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry, and Immunology, IRCCS MultiMedica, Milan, Italy; Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.
| | - Gaia Spinetti
- Laboratory of Cardiovascular Pathophysiology - Regenerative Medicine, IRCCS MultiMedica, Milan, Italy.
| | - Paolo Madeddu
- Bristol Heart Institute, Laboratory of Experimental Cardiovascular Medicine, Translational Health Sciences, Bristol Medical School, University of Bristol, United Kingdom.
| |
Collapse
|
|
4
|
Gan C, Yuan Y, Shen H, Gao J, Kong X, Che Z, Guo Y, Wang H, Dong E, Xiao J. Liver diseases: epidemiology, causes, trends and predictions. Signal Transduct Target Ther 2025; 10:33. [PMID: 39904973 PMCID: PMC11794951 DOI: 10.1038/s41392-024-02072-z] [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: 06/30/2024] [Revised: 10/06/2024] [Accepted: 11/12/2024] [Indexed: 02/06/2025] Open
Abstract
As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.
Collapse
Affiliation(s)
- Can Gan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuan Yuan
- Aier Institute of Ophthalmology, Central South University, Changsha, China
| | - Haiyuan Shen
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Jinhang Gao
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiangxin Kong
- Engineering and Translational Medicine, Medical College, Tianjin University, Tianjin, China
| | - Zhaodi Che
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yangkun Guo
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China.
| | - Erdan Dong
- Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
| | - Jia Xiao
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
- Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China.
| |
Collapse
|
|
5
|
Zahran RF, El-Sayed LM, Hoye TR, Ayyad SEN. The Dual Therapeutic Potential of Ottelione A on Carbon Tetrachloride-induced Hepatic Toxicity in Mice. Appl Biochem Biotechnol 2023; 195:5966-5979. [PMID: 36729297 PMCID: PMC10511377 DOI: 10.1007/s12010-023-04346-8] [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] [Accepted: 01/10/2023] [Indexed: 02/03/2023]
Abstract
BACKGROUND Some herbal natural products play an important role in protecting organisms from the toxic effect of some xenobiotics. The present study was designed to evaluate the potential therapeutic effects of Ottelione A (OTTE) against carbon tetrachloride(CCl4)-induced toxicity in mice. METHODS Adult male Swiss albino mice were divided into six groups: group I was used as a normal control received olive oil; group II received DMSO; group III received OTTE; group IV received CCl4 in olive oil, (injected i.p) 3 times/week for 6 weeks; group V received the same CCl4 regimen as group IV followed by OTTE injected for 15 days, and group VI first received OTTE injected for 15 days followed by the same CCl4 regimen as group IV. Some biochemical and histological parameters were investigated. RESULTS Our results showed that the administration of CCl4 caused hepatotoxicity, as monitored by the significant increase in biochemical parameters concerning the olive oil group. Treatment with OTTE appeare d to be effective against hepatotoxic and liver changes induced by CCl4, as evidenced by the improvement of the same parameters. CONCLUSION Ottelione A (OTTE) has good antioxidant and therapeutic properties, which can help in preventing CCl4-induced hepatotoxicity in both pre-treatment and post-treatment modes.
Collapse
Affiliation(s)
- Rasha Fekry Zahran
- Biochemistry division, Chemistry Department, Faculty of Science, Damietta University, 34517, Damietta, New-Damietta, Egypt.
| | - Lina Mahmoud El-Sayed
- Biochemistry division, Chemistry Department, Faculty of Science, Damietta University, 34517, Damietta, New-Damietta, Egypt
| | - Thomas Robert Hoye
- Departments of Chemistry and Medicinal Chemistry, University of Minnesota, 55455, Minneapolis, MN, USA
| | - Seif-Eldin Nasr Ayyad
- Department of Chemistry, Faculty of Science, Damietta University, New Damietta, Egypt
| |
Collapse
|
|
6
|
Pei Q, Yi Q, Tang L. Liver Fibrosis Resolution: From Molecular Mechanisms to Therapeutic Opportunities. Int J Mol Sci 2023; 24:ijms24119671. [PMID: 37298621 DOI: 10.3390/ijms24119671] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 05/25/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
The liver is a critical system for metabolism in human beings, which plays an essential role in an abundance of physiological processes and is vulnerable to endogenous or exogenous injuries. After the damage to the liver, a type of aberrant wound healing response known as liver fibrosis may happen, which can result in an excessive accumulation of extracellular matrix (ECM) and then cause cirrhosis or hepatocellular carcinoma (HCC), seriously endangering human health and causing a great economic burden. However, few effective anti-fibrotic medications are clinically available to treat liver fibrosis. The most efficient approach to liver fibrosis prevention and treatment currently is to eliminate its causes, but this approach's efficiency is too slow, or some causes cannot be fully eliminated, which causes liver fibrosis to worsen. In cases of advanced fibrosis, the only available treatment is liver transplantation. Therefore, new treatments or therapeutic agents need to be explored to stop the further development of early liver fibrosis or to reverse the fibrosis process to achieve liver fibrosis resolution. Understanding the mechanisms that lead to the development of liver fibrosis is necessary to find new therapeutic targets and drugs. The complex process of liver fibrosis is regulated by a variety of cells and cytokines, among which hepatic stellate cells (HSCs) are the essential cells, and their continued activation will lead to further progression of liver fibrosis. It has been found that inhibiting HSC activation, or inducing apoptosis, and inactivating activated hepatic stellate cells (aHSCs) can reverse fibrosis and thus achieve liver fibrosis regression. Hence, this review will concentrate on how HSCs become activated during liver fibrosis, including intercellular interactions and related signaling pathways, as well as targeting HSCs or liver fibrosis signaling pathways to achieve the resolution of liver fibrosis. Finally, new therapeutic compounds targeting liver fibrosis are summarized to provide more options for the therapy of liver fibrosis.
Collapse
Affiliation(s)
- Qiying Pei
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Qian Yi
- Department of Physiology, School of Basic Medical Science, Southwest Medical University, Luzhou 646000, China
| | - Liling Tang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| |
Collapse
|
|
7
|
Peng D, Fu M, Wang M, Wei Y, Wei X. Targeting TGF-β signal transduction for fibrosis and cancer therapy. Mol Cancer 2022; 21:104. [PMID: 35461253 PMCID: PMC9033932 DOI: 10.1186/s12943-022-01569-x] [Citation(s) in RCA: 525] [Impact Index Per Article: 175.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 03/18/2022] [Indexed: 02/08/2023] Open
Abstract
Transforming growth factor β (TGF-β) has long been identified with its intensive involvement in early embryonic development and organogenesis, immune supervision, tissue repair, and adult homeostasis. The role of TGF-β in fibrosis and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, overexpressed TGF-β causes epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, cancer-associated fibroblast (CAF) formation, which leads to fibrotic disease, and cancer. Given the critical role of TGF-β and its downstream molecules in the progression of fibrosis and cancers, therapeutics targeting TGF-β signaling appears to be a promising strategy. However, due to potential systemic cytotoxicity, the development of TGF-β therapeutics has lagged. In this review, we summarized the biological process of TGF-β, with its dual role in fibrosis and tumorigenesis, and the clinical application of TGF-β-targeting therapies.
Collapse
|
|
8
|
Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice. Nat Commun 2022; 13:1025. [PMID: 35197460 PMCID: PMC8866405 DOI: 10.1038/s41467-022-28692-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 02/03/2022] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects a large population with incompletely defined mechanism(s). Here we report that Kindlin-2 is dramatically up-regulated in livers in obese mice and patients with NAFLD. Kindlin-2 haploinsufficiency in hepatocytes ameliorates high-fat diet (HFD)-induced NAFLD and glucose intolerance without affecting energy metabolism in mice. In contrast, Kindlin-2 overexpression in liver exacerbates NAFLD and promotes lipid metabolism disorder and inflammation in hepatocytes. A C-terminal region (aa 570-680) of Kindlin-2 binds to and stabilizes Foxo1 by inhibiting its ubiquitination and degradation through the Skp2 E3 ligase. Kindlin-2 deficiency increases Foxo1 phosphorylation at Ser256, which favors its ubiquitination by Skp2. Thus, Kindllin-2 loss down-regulates Foxo1 protein in hepatocytes. Foxo1 overexpression in liver abrogates the ameliorating effect of Kindlin-2 haploinsufficiency on NAFLD in mice. Finally, AAV8-mediated shRNA knockdown of Kindlin-2 in liver alleviates NAFLD in obese mice. Collectively, we demonstrate that Kindlin-2 insufficiency protects against fatty liver by promoting Foxo1 degradation. Here, the authors show that expression of kindlin-2 is increased in patients with nonalcoholic fatty liver disease (NAFLD). In mouse models, specific deletion of kindlin-2 in liver ameliorates, while its overexpression exacerbates, NAFLD by modulating Foxo1 in hepatocytes.
Collapse
|
|
9
|
Cui Q, Wang C, Liu S, Du R, Tian S, Chen R, Geng H, Subramanian S, Niu Y, Wang Y, Yue D. YBX1 knockdown induces renal cell carcinoma cell apoptosis via Kindlin-2. Cell Cycle 2021; 20:2413-2427. [PMID: 34709966 DOI: 10.1080/15384101.2021.1985771] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Among urological tumors, renal cell carcinoma (RCC) is the third-highest mortality rate tumor, and 20%-30% of RCC patients present with metastases at the time of diagnosis. While the treatment of RCC has been improved over the last few years, its mortality stays high. Y-box binding protein 1 (YBX1) is a well-known oncoprotein that has tumor-promoting functions. YBX1 is widely considered to be an attractive therapeutic target in cancer. To develop novel therapeutics to target YBX1, it is of great importance to understand how YBX1 is finely regulated in cancer. Our previous studies showed that YBX1 in RCC cells significantly promoted cell adhesion, migration, and invasion. However, the role of YBX1 in RCC cells apoptosis has not been reported. In this study, we investigated the effect of YBX1 on cell apoptosis and elucidated the mechanisms involved. Results showed that YBX1 regulated RCC cells apoptosis and reactive oxygen species (ROS) generation via Kindlin-2. These findings indicated that YBX1 inhibited RCC cells apoptosis and may serve as a candidate RCC prognostic marker and a potential therapeutic target. Abbreviations: RCC: Renal cell carcinoma; YBX1: Y-box binding protein 1; ROS: Reactive oxygen species; ccRCC: Clear cell renal cell carcinoma; mccRCC: Metastatic clear cell renal cell carcinoma; G3BP1: Ras-GTPase activating protein SH3 domain-binding proteins 1; SPP1: Secreted phosphoprotein 1; NF-κB: Nuclear factor kappa beta; ECM: Extracellular matrix; EMT: Epithelial-mesenchymal transition; PYCR1: Pyrroline-5-carboxylate reductase 1; MEM: Eagle's Minimum Essential Medium; DMEM: Dulbecco's modified Eagle medium; FBS: Fetal bovine serum; PCR: Polymerase chain reaction; shRNA: Short hairpin RNA; siRNA: Small interfering RNA; BSA: Bovine serum albumin; DCFH-DA: 2,7-Dichlorodihydrofluorescein diacetate; FITC: Fluorescein isothiocyanate; PI: Propidium iodide.
Collapse
Affiliation(s)
- Qiqi Cui
- The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin China
| | - Chao Wang
- The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin China
| | - Shuang Liu
- The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin China
| | - Runxuan Du
- The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin China
| | - Shaoping Tian
- The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin China
| | - Ruibing Chen
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin China
| | - Hua Geng
- Center for Intestinal and Liver Inflammation Research, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.,Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Saravanan Subramanian
- Center for Intestinal and Liver Inflammation Research, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.,Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Yuanjie Niu
- The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin China
| | - Yong Wang
- The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin China
| | - Dan Yue
- The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin China
| |
Collapse
|
|
10
|
Mia MS, Jarajapu Y, Rao R, Mathew S. Integrin β1 Promotes Pancreatic Tumor Growth by Upregulating Kindlin-2 and TGF-β Receptor-2. Int J Mol Sci 2021; 22:ijms221910599. [PMID: 34638957 PMCID: PMC8508632 DOI: 10.3390/ijms221910599] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/24/2021] [Accepted: 09/27/2021] [Indexed: 11/16/2022] Open
Abstract
The tumor microenvironment plays a critical role in defining the growth and malignancy of solid tumors. Extracellular matrix (ECM) proteins such as collagen, vitronectin, and fibronectin are major components of the tumor microenvironment. Tumor growth-promoting reciprocal interaction between ECM and cytoplasmic proteins is regulated by the cell surface receptors called integrins. This study investigated the mechanism by which integrin β1 promotes pancreatic tumor growth. In MIA PaCa-2 pancreatic cancer cell line, the loss of integrin β1 protein reduced the ability of cells to proliferate in a 3D matrix and compromised the ability to form a focal adhesion complex. Decreased expression of integrin α5 was observed in KO cells, which resulted in impaired cell spreading and adhesion on vitronectin and fibronectin. Reduced expression of the integrin-associated protein, kindlin-2 was also recorded. The downregulation of kindlin-2 decreased the phosphorylation of Smad2/3 by reducing the expression of TGF-β receptor 2. These results unravel a new mechanism of integrin β1 in tumor growth by modifying the expression of kindlin-2 and TGF-β receptor 2 signaling.
Collapse
Affiliation(s)
- Md Saimon Mia
- Department of Pharmaceutical Sciences, School of Pharmacy, North Dakota State University, Fargo, ND 58108-6050, USA; (M.S.M.); (Y.J.)
| | - Yagna Jarajapu
- Department of Pharmaceutical Sciences, School of Pharmacy, North Dakota State University, Fargo, ND 58108-6050, USA; (M.S.M.); (Y.J.)
| | - Reena Rao
- Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, USA;
| | - Sijo Mathew
- Department of Pharmaceutical Sciences, School of Pharmacy, North Dakota State University, Fargo, ND 58108-6050, USA; (M.S.M.); (Y.J.)
- Correspondence: ; Tel.: +1-701-231-8214
| |
Collapse
|
|
11
|
JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human Graves' Orbital Fibroblasts. Int J Mol Sci 2021; 22:ijms22062952. [PMID: 33799469 PMCID: PMC7998969 DOI: 10.3390/ijms22062952] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/08/2021] [Accepted: 03/12/2021] [Indexed: 12/12/2022] Open
Abstract
Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.
Collapse
|
|
12
|
Pu S, Li Y, Liu Q, Zhang X, Chen L, Li R, Zhang J, Wu T, Tang Q, Yang X, Zhang Z, Huang Y, Kuang J, Li H, Zou M, Jiang W, He J. Inhibition of 5-Lipoxygenase in Hepatic Stellate Cells Alleviates Liver Fibrosis. Front Pharmacol 2021; 12:628583. [PMID: 33679410 PMCID: PMC7930623 DOI: 10.3389/fphar.2021.628583] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/15/2021] [Indexed: 02/05/2023] Open
Abstract
Background and Purpose: Activation of hepatic stellate cells (HSC) is a central driver of liver fibrosis. 5-lipoxygenase (5-LO) is the key enzyme that catalyzes arachidonic acid into leukotrienes. In this study, we examined the role of 5-LO in HSC activation and liver fibrosis. Main Methods: Culture medium was collected from quiescent and activated HSC for target metabolomics analysis. Exogenous leukotrienes were added to culture medium to explore their effect in activating HSC. Genetic ablation of 5-LO in mice was used to study its role in liver fibrosis induced by CCl4 and a methionine-choline-deficient (MCD) diet. Pharmacological inhibition of 5-LO in HSC was used to explore the effect of this enzyme in HSC activation and liver fibrosis. Key Results: The secretion of LTB4 and LTC4 was increased in activated vs. quiescent HSC. LTB4 and LTC4 contributed to HSC activation by activating the extracellular signal-regulated protein kinase pathway. The expression of 5-LO was increased in activated HSC and fibrotic livers of mice. Ablation of 5-LO in primary HSC inhibited both mRNA and protein expression of fibrotic genes. In vivo, ablation of 5-LO markedly ameliorated the CCl4- and MCD diet-induced liver fibrosis and liver injury. Pharmacological inhibition of 5-LO in HSC by targeted delivery of the 5-LO inhibitor zileuton suppressed HSC activation and improved CCl4- and MCD diet-induced hepatic fibrosis and liver injury. Finally, we found increased 5-LO expression in patients with non-alcoholic steatohepatitis and liver fibrosis. Conclusion: 5-LO may play a critical role in activating HSC; genetic ablation or pharmacological inhibition of 5-LO improved CCl4-and MCD diet-induced liver fibrosis.
Collapse
Affiliation(s)
- Shiyun Pu
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Qinhui Liu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Xu Zhang
- Tianjin Key Laboratory of Metabolic Diseases and Department of Physiology, Tianjin Medical University, Tianjin, China
| | - Lei Chen
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Li
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Zhang
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Tong Wu
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Qin Tang
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Xuping Yang
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Zijing Zhang
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Ya Huang
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Jiangying Kuang
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Li
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Min Zou
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Jiang
- Molecular Medicine Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Jinhan He
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
13
|
Godbout E, Son DO, Hume S, Boo S, Sarrazy V, Clément S, Kapus A, Wehrle-Haller B, Bruckner-Tuderman L, Has C, Hinz B. Kindlin-2 Mediates Mechanical Activation of Cardiac Myofibroblasts. Cells 2020; 9:cells9122702. [PMID: 33348602 PMCID: PMC7766948 DOI: 10.3390/cells9122702] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/11/2020] [Accepted: 12/14/2020] [Indexed: 02/07/2023] Open
Abstract
We identify the focal adhesion protein kindlin-2 as player in a novel mechanotransduction pathway that controls profibrotic cardiac fibroblast to myofibroblast activation. Kindlin-2 is co-upregulated with the myofibroblast marker α-smooth muscle actin (α-SMA) in fibrotic rat hearts and in human cardiac fibroblasts exposed to fibrosis-stiff culture substrates and pro-fibrotic TGF-β1. Stressing fibroblasts using ferromagnetic microbeads, stretchable silicone membranes, and cell contraction agonists all result in kindlin-2 translocation to the nucleus. Overexpression of full-length kindlin-2 but not of kindlin-2 missing a putative nuclear localization sequence (∆NLS kindlin-2) results in increased α-SMA promoter activity. Downregulating kindlin-2 with siRNA leads to decreased myofibroblast contraction and reduced α-SMA expression, which is dependent on CC(A/T)-rich GG(CArG) box elements in the α-SMA promoter. Lost myofibroblast features under kindlin-2 knockdown are rescued with wild-type but not ∆NLS kindlin-2, indicating that myofibroblast control by kindlin-2 requires its nuclear translocation. Because kindlin-2 can act as a mechanotransducer regulating the transcription of α-SMA, it is a potential target to interfere with myofibroblast activation in tissue fibrosis.
Collapse
Affiliation(s)
- Elena Godbout
- Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada; (E.G.); (D.O.S.); (S.H.); (S.B.); (V.S.)
| | - Dong Ok Son
- Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada; (E.G.); (D.O.S.); (S.H.); (S.B.); (V.S.)
| | - Stephanie Hume
- Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada; (E.G.); (D.O.S.); (S.H.); (S.B.); (V.S.)
| | - Stellar Boo
- Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada; (E.G.); (D.O.S.); (S.H.); (S.B.); (V.S.)
| | - Vincent Sarrazy
- Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada; (E.G.); (D.O.S.); (S.H.); (S.B.); (V.S.)
| | - Sophie Clément
- Division of Clinical Pathology, University Hospital, University of Geneva School of Medicine, 1211 Geneva 4, Switzerland;
| | - Andras Kapus
- Keenan Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada;
- Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada
| | - Bernhard Wehrle-Haller
- Department of Cell Physiology and Metabolism, Faculty of Medicine, Centre Médical Universitaire, University of Geneva, 1211 Geneva 4, Switzerland;
| | - Leena Bruckner-Tuderman
- Medical Center and Medical Faculty, University of Freiburg, 79104 Freiburg, Germany; (L.B.-T.); (C.H.)
| | - Cristina Has
- Medical Center and Medical Faculty, University of Freiburg, 79104 Freiburg, Germany; (L.B.-T.); (C.H.)
| | - Boris Hinz
- Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada; (E.G.); (D.O.S.); (S.H.); (S.B.); (V.S.)
- Correspondence: ; Tel.: +1-416-978-8728
| |
Collapse
|
|
14
|
Physiopathology of Lifestyle Interventions in Non-Alcoholic Fatty Liver Disease (NAFLD). Nutrients 2020; 12:nu12113472. [PMID: 33198247 PMCID: PMC7697937 DOI: 10.3390/nu12113472] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 11/06/2020] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health problem, and its prevalence has increased in recent years. Diet and exercise interventions are the first-line treatment options, with weight loss via a hypocaloric diet being the most important therapeutic target in NAFLD. However, most NAFLD patients are not able to achieve such weight loss. Therefore, the requisite is the investigation of other effective therapeutic approaches. This review summarizes research on understanding complex pathophysiology underlying dietary approaches and exercise interventions with the potential to prevent and treat NAFLD.
Collapse
|
|
15
|
Wang W, Kansakar U, Markovic V, Sossey-Alaoui K. Role of Kindlin-2 in cancer progression and metastasis. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:901. [PMID: 32793745 DOI: 10.21037/atm.2020.03.64] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cancer metastasis is a complex and multistep process whereby cancer cells escape the confines of the primary site to establish a new residency at distant sites. This multistep process is also known as the invasion-metastasis cascade. The biological and molecular mechanisms that control the invasion-metastasis cascade, which ultimately leads to the spread of cancer cells into distant sites, remain poorly understood. Kindlin-2 (K2) belongs to the 4.1-ezrin-ridixin-moesin (FERM) domain family of proteins, which interact with the cytoplasmic tails of β-integrin subunits, leading to the activation of extensive biological functions. These biological functions include cell migration, differentiation, cancer initiation, development, and invasion. In this review, we will discuss the various molecular signaling pathways that are regulated by K2 during the invasion-metastasis cascade of cancer tumors. These signaling pathways include TGFβ, Wnt/β-Catenin, Hedgehog, p53 and senescence, and cancer stem cell (CSC) maintenance. We will also discuss the molecular signaling pathways that regulate K2 function both at the transcriptional and the posttranslational levels. Finally, we will consider molecular mechanisms to specifically target K2 as novel therapeutic options for cancer treatment.
Collapse
Affiliation(s)
- Wei Wang
- Case Western Reserve University, Cleveland, OH, USA.,Division of Cancer Biology, MetroHealth System, Cleveland, OH, USA
| | - Urna Kansakar
- Case Western Reserve University, Cleveland, OH, USA.,Division of Cancer Biology, MetroHealth System, Cleveland, OH, USA
| | - Vesna Markovic
- Division of Cancer Biology, MetroHealth System, Cleveland, OH, USA
| | - Khalid Sossey-Alaoui
- Case Western Reserve University, Cleveland, OH, USA.,Division of Cancer Biology, MetroHealth System, Cleveland, OH, USA
| |
Collapse
|
|
16
|
Ren Y, Zhang J, Wang M, Bi J, Wang T, Qiu M, Lv Y, Wu Z, Wu R. Identification of irisin as a therapeutic agent that inhibits oxidative stress and fibrosis in a murine model of chronic pancreatitis. Biomed Pharmacother 2020; 126:110101. [PMID: 32199226 DOI: 10.1016/j.biopha.2020.110101] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 03/10/2020] [Accepted: 03/11/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Abnormal activation of pancreatic stellate cells (PSCs) plays a crucial role in the pathogenesis of chronic pancreatitis (CP). Irisin, an exercise-induced hormone, has been shown to mitigate liver fibrosis by inhibiting the activation of hepatic stellate cells. However, the effect of irisin in CP has not been evaluated. METHODS This study aimed to determine whether irisin is protective in CP. CP was induced by 6 IP injections of cerulein (50 μg/kg/body weight). HPSCs were treated with 5 ng/ml TGF-β1 as in vitro experiment. RESULTS Our results showed that repeated cerulein injection induced severe pancreatic injury and fibrosis in mice and the serum irisin level in cerulein-treated mice decreased as in CP patients. Excessive oxidative and ER stress was also present in the pancreas of cerulein-treated mice. Irisin treatment significantly alleviated pancreatic injury and fibrosis, which was associated with reduced oxidative and ER stress. In cultured PSCs, irisin directly inhibited TGF-β-induced α-SMA and collagen I expression. This effect appears to be mediated through downregulation of kindlin-2 and inhibition of the SMAD2/3 pathway. CONCLUSIONS Irisin alleviated pancreatic injury and fibrosis, which was associated with reduced oxidative and ER stress. Thus, irisin may offer therapeutic potential for patients with CP.
Collapse
Affiliation(s)
- Yifan Ren
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China; Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Jia Zhang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China; Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Mengzhou Wang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China; Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Jianbin Bi
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China; Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Tao Wang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China; Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Minglong Qiu
- Department of Orthopedic, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China; Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
| |
Collapse
|
|
17
|
Synergy of Phospholipid-Drug Formulations Significantly Deactivates Profibrogenic Human Hepatic Stellate Cells. Pharmaceutics 2019; 11:pharmaceutics11120676. [PMID: 31842373 PMCID: PMC6969915 DOI: 10.3390/pharmaceutics11120676] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/06/2019] [Accepted: 12/09/2019] [Indexed: 02/06/2023] Open
Abstract
The pivotal role of hepatic stellate cells (HSCs) in orchestrating the bidirectional process of progression and regression of liver fibrosis makes them an ideal target for exploring new antifibrotic therapies. Essential phospholipids (EPLs), with their polyenylphosphatidylcholine (PPC) fraction, either alone or combined with other hepatoprotective substances such as silymarin, are recommended in hepatic impairment, but a scientific rationale for their use is still lacking. Herein, we compared the ability of EPLs to restore quiescent-like features in HSCs with that of dilinoleoylphosphatidylcholine (DLPC), PPC fraction’s main component. Specifically, we screened at the cellular level the antifibrotic effects of PPC formulations in the presence and absence of silymarin, by using LX-2 cells (pro-fibrogenic HSCs) and by assessing the main biochemical hallmarks of the activated and deactivated states of this cell line. We also proved the formulations’ direct effect on the motional order of cell membranes of adherent cells. LX-2 cells, examined for lipid droplets as a quiescence marker, showed that PPCs led to a more prominent deactivation than DLPC. This result was confirmed by a reduction of collagen and α-SMA expression, and by a profound alteration in the cell membrane fluidity. PPC–silymarin formulations deactivated HSCs with a significant synergistic effect. The remarkable bioactivity of PPCs in deactivating fibrogenic HSCs paves the way for the rational design of new therapeutics aimed at managing hepatic fibrosis.
Collapse
|
|
18
|
Dewidar B, Meyer C, Dooley S, Meindl-Beinker N. TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019. Cells 2019; 8:cells8111419. [PMID: 31718044 PMCID: PMC6912224 DOI: 10.3390/cells8111419] [Citation(s) in RCA: 525] [Impact Index Per Article: 87.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/08/2019] [Accepted: 11/09/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment is mainly the removal of the causative factor. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-β has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-β and its upstream and downstream regulatory mechanisms will help to design better TGF-β based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-β signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-β on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-β. Finally, we discuss new approaches to target the TGF-β pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.
Collapse
Affiliation(s)
- Bedair Dewidar
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (B.D.); (C.M.); (S.D.)
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, 31527 Tanta, Egypt
| | - Christoph Meyer
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (B.D.); (C.M.); (S.D.)
| | - Steven Dooley
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (B.D.); (C.M.); (S.D.)
| | - Nadja Meindl-Beinker
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (B.D.); (C.M.); (S.D.)
- Correspondence: ; Tel.: +49-621-383-4983; Fax: +49-621-383-1467
| |
Collapse
|
|
19
|
Wei CY, Zhu MX, Zhang PF, Yang X, Wang L, Ying JH, Luan WJ, Chen C, Liu JQ, Zhu M, Yang YW, Feng ZH, Qi FZ, Gu JY. Elevated kindlin-2 promotes tumour progression and angiogenesis through the mTOR/VEGFA pathway in melanoma. Aging (Albany NY) 2019; 11:6273-6285. [PMID: 31427543 PMCID: PMC6738412 DOI: 10.18632/aging.102187] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 08/10/2019] [Indexed: 02/06/2023]
Abstract
Background: In our previous study, kindlin-2 promoted skin wound healing and decreased the permeability of neovascularization during angiogenesis. Herein, we explored the biological function and underlying mechanism of kindlin-2 in cutaneous melanoma. Methods and Results: Through a series of in vitro assays, we found that high levels of kindlin-2 promoted migration and invasion of melanoma cells without influencing cell proliferation. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analyses showed that upregulated kindlin-2 promoted the cellular epithelial-mesenchymal transition (EMT). Importantly, we found that melanoma cells overexpressing kindlin-2 promoted angiogenesis and VEGFA secretion in vitro and facilitated tumour growth and lung metastasis in vivo. To unveil the underlying mechanism, we conducted Next-generation sequencing (NGS) and differential expression analyses. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that overlapping differentially expressed genes (DEGs) were primarily enriched in the TGF-β, mTOR and VEGF signalling pathways. Then, we confirmed that the mTOR/VEGFA pathway was activated during the process of kindlin-2-induced melanoma progression and angiogenesis. Moreover, we demonstrated that kindlin-2 was significantly overexpressed in clinical melanoma samples and that a high level of kindlin-2 predicted a poor prognosis. Conclusions: Taken together, these findings showed that kindlin-2 promotes angiogenesis and tumour progression via the mTOR/VEGFA pathway.
Collapse
Affiliation(s)
- Chuan-Yuan Wei
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.,Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, P.R. China
| | - Meng-Xuan Zhu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, P.R. China
| | - Peng-Fei Zhang
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200032, P.R. China
| | - Xuan Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, P.R. China
| | - Lu Wang
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Jiang-Hui Ying
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Wen-Jie Luan
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Cheng Chen
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Jia-Qi Liu
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Ming Zhu
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Yan-Wen Yang
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Zi-Hao Feng
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Fa-Zhi Qi
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Jian-Ying Gu
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| |
Collapse
|