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Wang S, Li F, Feng X, Feng M, Niu X, Jiang X, Chen W, Bai R. Promoting collagen synthesis: a viable strategy to combat skin ageing. J Enzyme Inhib Med Chem 2025; 40:2488821. [PMID: 40213810 PMCID: PMC11995770 DOI: 10.1080/14756366.2025.2488821] [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: 01/20/2025] [Revised: 03/24/2025] [Accepted: 03/31/2025] [Indexed: 04/16/2025] Open
Abstract
Skin ageing is a complex physiological process primarily characterised by the deepening of wrinkles and the sagging of the skin. Collagen is essential for maintaining skin elasticity and firmness. As skin ages, it experiences structural and functional changes in collagen, including a decrease in collagen synthesis and an increase in collagen hydrolysis. Thus, promoting collagen synthesis represents a practical strategy for mitigating skin ageing. This review systematically described the functions, classifications and biosynthesis process of collagen, as well as its role in skin ageing. Additionally, the major signalling pathways and targets associated with collagen synthesis were also discussed. More importantly, the review provided a detailed summary of natural products with collagen synthesis-promoting effects and highlighted small molecule compounds with potential anti-ageing activity, especially PPARδ agonists. The relevant content offers potential targets and lead compounds for the development of anti-skin ageing therapies.
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Affiliation(s)
- Shan Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
| | - Feifan Li
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
| | - Xilong Feng
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
| | - Meiling Feng
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
| | - Xiaotian Niu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
| | - Xiaoying Jiang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
| | - Wenchao Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
| | - Renren Bai
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
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Hoseini SM, Montazeri F. Cell origin and microenvironment: The players of differentiation capacity in human mesenchymal stem cells. Tissue Cell 2025; 93:102709. [PMID: 39765135 DOI: 10.1016/j.tice.2024.102709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/12/2024] [Accepted: 12/26/2024] [Indexed: 03/05/2025]
Abstract
Mesenchymal stem cells (MSCs) have several important properties that make them desirable for regenerative medicine. These properties include immunomodulatory ability, growth factor production, and differentiation into various cell types. Despite extensive research and promising results in clinical trials, our understanding of MSC biology, their mechanism of action, and their targeted and routine use in clinics is limited. Differentiation of human MSCs (hMSCs) is a complex process influenced by various elements such as growth factors, pharmaceutical compounds, microRNAs, 3D scaffolds, and mechanical and electrical stimulation. Research has shown that different culture conditions can affect the differentiation potential of hMSCs obtained from multiple fetal and adult sources. Additionally, it seems that what affects the differentiation capacities of these cells is their secretory characteristics, which are influenced by the origin of the cells and the local microenvironment where the cells are located. The review can provide insights into the microenvironment-based mechanisms involved in MSC differentiation, which can be valuable for future therapeutic applications.
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Affiliation(s)
- Seyed Mehdi Hoseini
- Biotechnology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran; Hematology and Oncology Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fateme Montazeri
- Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran.
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Qi Y, Ma Y, Duan G. Pharmacological Mechanisms of Bile Acids Targeting the Farnesoid X Receptor. Int J Mol Sci 2024; 25:13656. [PMID: 39769418 PMCID: PMC11727972 DOI: 10.3390/ijms252413656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 12/17/2024] [Accepted: 12/17/2024] [Indexed: 01/03/2025] Open
Abstract
Bile acids (BAs), a category of amphiphilic metabolites synthesized by liver cells and released into the intestine via the bile duct, serve a vital role in the emulsification of ingested fats during the digestive process. Beyond their conventional emulsifying function, BAs, with their diverse structures, also act as significant hormones within the body. They are pivotal in facilitating nutrient absorption by interacting with the farnesoid X receptor (FXR), and they serve as key regulators of lipid and glucose metabolism, as well as immune system balance. Consequently, BAs contribute to the metabolism of glucose and lipids, enhance the digestion and absorption of lipids, and maintain the equilibrium of the bile pool. Their actions are instrumental in addressing obesity, managing cholestasis, and treating diabetes, and are involved in the onset and progression of cancer. This paper presents an updated systematic review of the pharmacological mechanisms by which BAs target the FXR, incorporating recent findings and discussing their signaling pathways in the context of novel research, including their distinct roles in various disease states and populations. The aim is to provide a theoretical foundation for the continued research and clinical application of BAs.
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Affiliation(s)
- Youchao Qi
- College of Agriculture and Animal Husbandry, Qinghai University, Xining 810016, China;
- Academy of Agriculture and Forestry Sciences, Qinghai University, Xining 810016, China
- Qinghai Plateau Key Laboratory of Tree Genetics and Breeding, Xining 810016, China
- Key Laboratory of Medicinal Animal and Plant Resources of Qinghai Tibetan Plateau, Qinghai Normal University, Xining 810008, China;
- Academy of Plateau Science and Sustainability, Qinghai Normal University, Xining 810008, China
| | - Yonggui Ma
- Key Laboratory of Medicinal Animal and Plant Resources of Qinghai Tibetan Plateau, Qinghai Normal University, Xining 810008, China;
- Academy of Plateau Science and Sustainability, Qinghai Normal University, Xining 810008, China
| | - Guozhen Duan
- Academy of Agriculture and Forestry Sciences, Qinghai University, Xining 810016, China
- Qinghai Plateau Key Laboratory of Tree Genetics and Breeding, Xining 810016, China
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4
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Son SS, Jeong HS, Lee SW, Lee ES, Lee JG, Lee JH, Yi J, Park MJ, Choi MS, Lee D, Choi SY, Ha J, Kang JS, Cho NJ, Park S, Gil HW, Chung CH, Park JS, Kim MH, Park J, Lee EY. EPRS1-mediated fibroblast activation and mitochondrial dysfunction promote kidney fibrosis. Exp Mol Med 2024; 56:2673-2689. [PMID: 39623092 DOI: 10.1038/s12276-024-01360-6] [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: 05/14/2024] [Revised: 08/30/2024] [Accepted: 09/24/2024] [Indexed: 12/28/2024] Open
Abstract
Kidney fibrosis causes irreversible structural damage in chronic kidney disease and is characterized by aberrant extracellular matrix (ECM) accumulation. Although glutamyl-prolyl-tRNA synthetase 1 (EPRS1) is a crucial enzyme involved in proline-rich protein synthesis, its role in kidney fibrosis remains unclear. The present study revealed that EPRS1 expression levels were increased in the fibrotic kidneys of patients and mice, especially in fibroblasts and proximal tubular epithelial cells, on the basis of single-cell analysis and immunostaining of fibrotic kidneys. Moreover, C57BL/6 EPRS1tm1b heterozygous knockout (Eprs1+/-) and pharmacological EPRS1 inhibition with the first-in-class EPRS1 inhibitor DWN12088 protected against kidney fibrosis and dysfunction by preventing fibroblast activation and proximal tubular injury. Interestingly, in vitro assays demonstrated that EPRS1-mediated nontranslational pathways in addition to translational pathways under transforming growth factor β-treated conditions by phosphorylating SMAD family member 3 in fibroblasts and signal transducers and activators of transcription 3 in injured proximal tubules. EPRS1 knockdown and catalytic inhibition suppressed these pathways, preventing fibroblast activation, proliferation, and subsequent collagen production. Additionally, we revealed that EPRS1 caused mitochondrial damage in proximal tubules but that this damage was attenuated by EPRS1 inhibition. Our findings suggest that the EPRS1-mediated ECM accumulation induces kidney fibrosis via fibroblast activation and mitochondrial dysfunction. Therefore, targeting EPRS1 could be a potential therapeutic target for alleviating fibrotic injury in chronic kidney disease.
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Affiliation(s)
- Seung Seob Son
- Department of Medicine, Graduate School of Soonchunhyang University, Cheonan, Korea
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Hee Seul Jeong
- Department of Medicine, Graduate School of Soonchunhyang University, Cheonan, Korea
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Seong-Woo Lee
- Department of Medicine, Graduate School of Soonchunhyang University, Cheonan, Korea
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Eun Soo Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
- Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jeong Geon Lee
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Ji-Hye Lee
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Korea
- Department of Pathology, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Jawoon Yi
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Mi Ju Park
- Department of Medicine, Graduate School of Soonchunhyang University, Cheonan, Korea
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Min Sun Choi
- Department of Medicine, Graduate School of Soonchunhyang University, Cheonan, Korea
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Donghyeong Lee
- Department of Medicine, Graduate School of Soonchunhyang University, Cheonan, Korea
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Sin Young Choi
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Jiheon Ha
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Jeong Suk Kang
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
- Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Nam-Jun Cho
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Korea
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Samel Park
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Korea
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Hyo-Wook Gil
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Korea
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Choon Hee Chung
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
- Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Joon Seok Park
- Drug Discovery Center, Daewoong Pharmaceutical Co. Ltd., Yongin, Korea
| | - Myung Hee Kim
- Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Jihwan Park
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Eun Young Lee
- Department of Medicine, Graduate School of Soonchunhyang University, Cheonan, Korea.
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan, Korea.
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Korea.
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.
- Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, Korea.
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Patidar P, Hirani N, Bharti S, Baig MS. Key regulators of hepatic stellate cell activation in alcohol liver Disease: A comprehensive review. Int Immunopharmacol 2024; 141:112938. [PMID: 39163683 DOI: 10.1016/j.intimp.2024.112938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/27/2024] [Accepted: 08/12/2024] [Indexed: 08/22/2024]
Abstract
Alcoholic liver disease (ALD) is a broad category of disorders that begin with liver injury, lead to liver fibrosis, and ultimately conclude in alcohol-induced liver cirrhosis, the most chronic and irreversible liver damage. Liver fibrosis (LF) is a common pathological characteristic observed in most chronic liver inflammatory conditions that involve prolonged inflammation. In this review, we have summarized ethanol-mediated hepatic stellate cell (HSCs) activation and its role in liver fibrosis progression. We highlight important molecular mechanisms that are modulated by ethanol, play a role in the activation of HSCs and the progression of liver fibrosis and identifying potential targets to ameliorate liver fibrosis.
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Affiliation(s)
- Pramod Patidar
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India
| | - Nik Hirani
- MRC Centre for Inflammation Research, Queen'sMedicalResearch Institute, University of Edinburgh, Edinburgh, EH164TJ, UK
| | - Shreya Bharti
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India
| | - Mirza S Baig
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India.
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Diskul-Na-Ayudthaya P, Bae SJ, Bae YU, Van NT, Kim W, Ryu S. ANKRD1 Promotes Breast Cancer Metastasis by Activating NF- κB-MAGE-A6 Pathway. Cancers (Basel) 2024; 16:3306. [PMID: 39409926 PMCID: PMC11476229 DOI: 10.3390/cancers16193306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 10/20/2024] Open
Abstract
Early detection and surgical excision of tumors have helped improve the survival rate of patients with breast cancer. However, patients with metastatic cancer typically have a poor prognosis. In this study, we propose that ANKRD1 promotes metastasis of breast cancer. ANKRD1 was found to be highly expressed in the MDA-MB-231 and MDA-LM-2 highly metastatic breast cancer cell lines compared to the non-metastatic breast cancer cell lines (MCF-7, ZR-75-30, T47D) and normal breast cancer cells (MCF-10A). Furthermore, high-grade tumors showed increased levels of ANKRD1 compared to low-grade tumors. Both in vitro and in vivo functional studies demonstrated the essential role of ANKRD1 in cancer cell migration and invasion. The previous studies have suggested a significant role of NF-κB and MAGE-A6 in breast cancer metastasis, but the upstream regulators of this axis are not well characterized. Our study suggests that ANKRD1 promotes metastasis of breast cancer by activating NF-κB as well as MAGE-A6 signaling. Our findings show that ANKRD1 is a potential therapeutic target and a diagnostic marker for breast cancer metastasis.
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Affiliation(s)
- Penchatr Diskul-Na-Ayudthaya
- Soonchunhyang Institute of Medi-bio Science (SIMS), Department of Integrated Biomedical Sciences, Soonchunhyang University, Asan-si 31151, Republic of Korea; (P.D.-N.-A.); (S.J.B.); (N.T.V.)
- Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand
| | - Seon Joo Bae
- Soonchunhyang Institute of Medi-bio Science (SIMS), Department of Integrated Biomedical Sciences, Soonchunhyang University, Asan-si 31151, Republic of Korea; (P.D.-N.-A.); (S.J.B.); (N.T.V.)
| | - Yun-Ui Bae
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Konkuk University, Seoul 05030, Republic of Korea;
| | - Ngu Trinh Van
- Soonchunhyang Institute of Medi-bio Science (SIMS), Department of Integrated Biomedical Sciences, Soonchunhyang University, Asan-si 31151, Republic of Korea; (P.D.-N.-A.); (S.J.B.); (N.T.V.)
| | - Wootae Kim
- Soonchunhyang Institute of Medi-bio Science (SIMS), Department of Integrated Biomedical Sciences, Soonchunhyang University, Asan-si 31151, Republic of Korea; (P.D.-N.-A.); (S.J.B.); (N.T.V.)
| | - Seongho Ryu
- Soonchunhyang Institute of Medi-bio Science (SIMS), Department of Integrated Biomedical Sciences, Soonchunhyang University, Asan-si 31151, Republic of Korea; (P.D.-N.-A.); (S.J.B.); (N.T.V.)
- Department of Pathology, College of Medicine, Soonchunhyang University, Asan-si 311151, Republic of Korea
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Chen W, Tan M, Zhang H, Gao T, Ren J, Cheng S, Chen J. Signaling molecules in the microenvironment of hepatocellular carcinoma. Funct Integr Genomics 2024; 24:146. [PMID: 39207523 DOI: 10.1007/s10142-024-01427-7] [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: 06/11/2024] [Revised: 08/16/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
Hepatocellular carcinoma (HCC) is a major fatal cancer that is known for its high recurrence and metastasis. An increasing number of studies have shown that the tumor microenvironment is closely related to the metastasis and invasion of HCC. The HCC microenvironment is a complex integrated system composed of cellular components, the extracellular matrix (ECM), and signaling molecules such as chemokines, growth factors, and cytokines, which are generally regarded as crucial molecules that regulate a series of important processes, such as the migration and invasion of HCC cells. Considering the crucial role of signaling molecules, this review aims to elucidate the regulatory effects of chemokines, growth factors, and cytokines on HCC cells in their microenvironment to provide important references for clarifying the development of HCC and exploring effective therapeutic targets.
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Affiliation(s)
- Wanjin Chen
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Ming Tan
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Hui Zhang
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Tingting Gao
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Jihua Ren
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Shengtao Cheng
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
| | - Juan Chen
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
- College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China.
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Miyazawa K, Itoh Y, Fu H, Miyazono K. Receptor-activated transcription factors and beyond: multiple modes of Smad2/3-dependent transmission of TGF-β signaling. J Biol Chem 2024; 300:107256. [PMID: 38569937 PMCID: PMC11063908 DOI: 10.1016/j.jbc.2024.107256] [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: 01/19/2024] [Revised: 02/28/2024] [Accepted: 03/05/2024] [Indexed: 04/05/2024] Open
Abstract
Transforming growth factor β (TGF-β) is a pleiotropic cytokine that is widely distributed throughout the body. Its receptor proteins, TGF-β type I and type II receptors, are also ubiquitously expressed. Therefore, the regulation of various signaling outputs in a context-dependent manner is a critical issue in this field. Smad proteins were originally identified as signal-activated transcription factors similar to signal transducer and activator of transcription proteins. Smads are activated by serine phosphorylation mediated by intrinsic receptor dual specificity kinases of the TGF-β family, indicating that Smads are receptor-restricted effector molecules downstream of ligands of the TGF-β family. Smad proteins have other functions in addition to transcriptional regulation, including post-transcriptional regulation of micro-RNA processing, pre-mRNA splicing, and m6A methylation. Recent technical advances have identified a novel landscape of Smad-dependent signal transduction, including regulation of mitochondrial function without involving regulation of gene expression. Therefore, Smad proteins are receptor-activated transcription factors and also act as intracellular signaling modulators with multiple modes of function. In this review, we discuss the role of Smad proteins as receptor-activated transcription factors and beyond. We also describe the functional differences between Smad2 and Smad3, two receptor-activated Smad proteins downstream of TGF-β, activin, myostatin, growth and differentiation factor (GDF) 11, and Nodal.
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Affiliation(s)
- Keiji Miyazawa
- Department of Biochemistry, Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.
| | - Yuka Itoh
- Department of Biochemistry, Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Hao Fu
- Department of Biochemistry, Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Kohei Miyazono
- Department of Applied Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Laboratory for Cancer Invasion and Metastasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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Wei Y, Wang D, Wu J, Zhang J. JAK2 inhibitors improve RA combined with pulmonary fibrosis in rats by downregulating SMAD3 phosphorylation. Int J Rheum Dis 2024; 27:e15164. [PMID: 38706209 DOI: 10.1111/1756-185x.15164] [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: 07/17/2023] [Revised: 01/01/2024] [Accepted: 04/14/2024] [Indexed: 05/07/2024]
Abstract
BACKGROUND JAK inhibitors are well known for the treatment of rheumatoid arthritis (RA), but whether they can be used to treat pulmonary fibrosis, a common extra-articular disease of RA, remains to be clarified. METHODS A jak2 inhibitor, CEP33779 (CEP), was administered to a rat model of RA-associated interstitial lung disease to observe the degree of improvement in both joint swelling and pulmonary fibrosis. HFL1 cells were stimulated with TGF-β1 to observe the expression of p-JAK2. Then, different concentrations of related gene inhibitors (JAK2, TGFβ-R1/2, and p-STAT3) or silencers (STAT3, JAK2) were administered to HFL1 cells, and the expression levels of related proteins were detected to explore the underlying mechanisms of action. RESULTS CEP not only reduced the degree of joint swelling and inflammation in rats but also improved lung function, inhibited the pro-inflammatory factors IL-1β and IL-6, reduced lung inflammation and collagen deposition, and alleviated lung fibrosis. CEP decreased the expression levels of TGFβ-R2, p-SMAD, p-STAT3, and ECM proteins in rat lung tissues. TGF-β1 induced HFL1 cells to highly express p-JAK2, with the most pronounced expression at 48 h. The levels of p-STAT3, p-SMAD3, and ECM-related proteins were significantly reduced after inhibition of either JAK2 or STAT3. CONCLUSION JAK2 inhibitors may be an important and novel immunotherapeutic drug that can improve RA symptoms while also delaying or blocking the development of associated pulmonary fibrotic disease. The mechanism may be related to the downregulation of p-STAT3 protein via inhibition of the JAK2/STAT signaling pathway, which affects the phosphorylation of SMAD3.
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Affiliation(s)
- Yimei Wei
- Department of Geriatrics, Chongqing Medical University, Chongqing, China
- Department Geriatrics, Chongqing General Hospital, Chongqing, China
| | - Dandan Wang
- Department Geriatrics, Chongqing General Hospital, Chongqing, China
- Department of Pulmonary Department of Respiratory and Critical Care Medicine, Southwest Medical University, Luzhou, China
| | - Juan Wu
- Department Geriatrics, Chongqing General Hospital, Chongqing, China
| | - Jie Zhang
- Department Geriatrics, Chongqing General Hospital, Chongqing, China
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Reid SE, Pantaleo J, Bolivar P, Bocci M, Sjölund J, Morsing M, Cordero E, Larsson S, Malmberg M, Seashore-Ludlow B, Pietras K. Cancer-associated fibroblasts rewire the estrogen receptor response in luminal breast cancer, enabling estrogen independence. Oncogene 2024; 43:1113-1126. [PMID: 38388711 PMCID: PMC10997519 DOI: 10.1038/s41388-024-02973-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 02/05/2024] [Accepted: 02/07/2024] [Indexed: 02/24/2024]
Abstract
Advanced breast cancers represent a major therapeutic challenge due to their refractoriness to treatment. Cancer-associated fibroblasts (CAFs) are the most abundant constituents of the tumor microenvironment and have been linked to most hallmarks of cancer. However, the influence of CAFs on therapeutic outcome remains largely unchartered. Here, we reveal that spatial coincidence of abundant CAF infiltration with malignant cells was associated with reduced estrogen receptor (ER)-α expression and activity in luminal breast tumors. Notably, CAFs mediated estrogen-independent tumor growth by selectively regulating ER-α signaling. Whereas most prototypical estrogen-responsive genes were suppressed, CAFs maintained gene expression related to therapeutic resistance, basal-like differentiation, and invasion. A functional drug screen in co-cultures identified effector pathways involved in the CAF-induced regulation of ER-α signaling. Among these, the Transforming Growth Factor-β and the Janus kinase signaling cascades were validated as actionable targets to counteract the CAF-induced modulation of ER-α activity. Finally, genes that were downregulated in cancer cells by CAFs were predictive of poor response to endocrine treatment. In conclusion, our work reveals that CAFs directly control the luminal breast cancer phenotype by selectively modulating ER-α expression and transcriptional function, and further proposes novel targets to disrupt the crosstalk between CAFs and tumor cells to reinstate treatment response to endocrine therapy in patients.
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Affiliation(s)
- Steven E Reid
- Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, Lund, Sweden
| | - Jessica Pantaleo
- Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, Lund, Sweden
| | - Paulina Bolivar
- Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, Lund, Sweden
| | - Matteo Bocci
- Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, Lund, Sweden
| | - Jonas Sjölund
- Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, Lund, Sweden
| | - Mikkel Morsing
- Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, Lund, Sweden
| | - Eugenia Cordero
- Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, Lund, Sweden
| | - Sara Larsson
- Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, Lund, Sweden
| | - Maria Malmberg
- Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, Lund, Sweden
| | - Brinton Seashore-Ludlow
- Department of Oncology-Pathology, SciLifeLab, Stockholm, Sweden
- Chemical Biology Consortium Sweden (CBCS), Karolinska Institute, Stockholm, Sweden
| | - Kristian Pietras
- Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, Lund, Sweden.
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11
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Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, He J. TGF-β signaling in health, disease, and therapeutics. Signal Transduct Target Ther 2024; 9:61. [PMID: 38514615 PMCID: PMC10958066 DOI: 10.1038/s41392-024-01764-w] [Citation(s) in RCA: 217] [Impact Index Per Article: 217.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 08/31/2023] [Accepted: 01/31/2024] [Indexed: 03/23/2024] Open
Abstract
Transforming growth factor (TGF)-β is a multifunctional cytokine expressed by almost every tissue and cell type. The signal transduction of TGF-β can stimulate diverse cellular responses and is particularly critical to embryonic development, wound healing, tissue homeostasis, and immune homeostasis in health. The dysfunction of TGF-β can play key roles in many diseases, and numerous targeted therapies have been developed to rectify its pathogenic activity. In the past decades, a large number of studies on TGF-β signaling have been carried out, covering a broad spectrum of topics in health, disease, and therapeutics. Thus, a comprehensive overview of TGF-β signaling is required for a general picture of the studies in this field. In this review, we retrace the research history of TGF-β and introduce the molecular mechanisms regarding its biosynthesis, activation, and signal transduction. We also provide deep insights into the functions of TGF-β signaling in physiological conditions as well as in pathological processes. TGF-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are highlighted. Through the summary of previous knowledge and recent updates, this review aims to provide a systematic understanding of TGF-β signaling and to attract more attention and interest to this research area.
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Affiliation(s)
- Ziqin Deng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tao Fan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chu Xiao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - He Tian
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yujia Zheng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chunxiang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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12
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Jiang H, Yang J, Li T, Wang X, Fan Z, Ye Q, Du Y. JAK/STAT3 signaling in cardiac fibrosis: a promising therapeutic target. Front Pharmacol 2024; 15:1336102. [PMID: 38495094 PMCID: PMC10940489 DOI: 10.3389/fphar.2024.1336102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/18/2024] [Indexed: 03/19/2024] Open
Abstract
Cardiac fibrosis is a serious health problem because it is a common pathological change in almost all forms of cardiovascular diseases. Cardiac fibrosis is characterized by the transdifferentiation of cardiac fibroblasts (CFs) into cardiac myofibroblasts and the excessive deposition of extracellular matrix (ECM) components produced by activated myofibroblasts, which leads to fibrotic scar formation and subsequent cardiac dysfunction. However, there are currently few effective therapeutic strategies protecting against fibrogenesis. This lack is largely because the molecular mechanisms of cardiac fibrosis remain unclear despite extensive research. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascade is an extensively present intracellular signal transduction pathway and can regulate a wide range of biological processes, including cell proliferation, migration, differentiation, apoptosis, and immune response. Various upstream mediators such as cytokines, growth factors and hormones can initiate signal transmission via this pathway and play corresponding regulatory roles. STAT3 is a crucial player of the JAK/STAT pathway and its activation is related to inflammation, malignant tumors and autoimmune illnesses. Recently, the JAK/STAT3 signaling has been in the spotlight for its role in the occurrence and development of cardiac fibrosis and its activation can promote the proliferation and activation of CFs and the production of ECM proteins, thus leading to cardiac fibrosis. In this manuscript, we discuss the structure, transactivation and regulation of the JAK/STAT3 signaling pathway and review recent progress on the role of this pathway in cardiac fibrosis. Moreover, we summarize the current challenges and opportunities of targeting the JAK/STAT3 signaling for the treatment of fibrosis. In summary, the information presented in this article is critical for comprehending the role of the JAK/STAT3 pathway in cardiac fibrosis, and will also contribute to future research aimed at the development of effective anti-fibrotic therapeutic strategies targeting the JAK/STAT3 signaling.
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Affiliation(s)
- Heng Jiang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Junjie Yang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Tao Li
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Xinyu Wang
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Zhongcai Fan
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Qiang Ye
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yanfei Du
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
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13
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Dai X, Du Z, Jin C, Tang B, Chen X, Jing X, Shen Y, He F, Wang S, Li J, Ding K, Zang Y. Inulin-like polysaccharide ABWW may impede CCl 4 induced hepatic stellate cell activation through mediating the FAK/PI3K/AKT signaling pathway in vitro & in vivo. Carbohydr Polym 2024; 326:121637. [PMID: 38142102 DOI: 10.1016/j.carbpol.2023.121637] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 11/17/2023] [Accepted: 11/22/2023] [Indexed: 12/25/2023]
Abstract
Studies have shown that terrestrial acidic polysaccharides containing carboxyl groups and seaweed sulfated polysaccharides have strong potential in anti-liver fibrosis. However, there is no investigation on the anti-liver fibrosis of fructan, a ubiquitous natural polysaccharide. The present study aimed to understand the effect of fructan in ameliorating carbon tetrachloride (CCl4)-induced liver fibrosis in mice. Here, an inulin-like fructan ABWW from Achyranthes bidentata Bl. was characterized by fructose enzymatic hydrolysis, methylation analysis, ESI-MS, and NMR. It was composed of →2)-β-d-Fruf-(1→ and →2)-β-d-Fruf-(1, 6→, terminated with →1)-α-d-Glcp and →2)-β-d-Fruf residues. The biological studies showed that ABWW could improve liver damage and liver fibrosis induced by CCl4in vivo and inhibit hepatic stellate cell (HSC) activation and migration in vitro. We further demonstrated that ABWW inhibited LX2 activation via suppressing the FAK/PI3K/AKT signaling pathway. Hence, ABWW might be a potential novel active compound for anti-fibrosis new drug development.
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Affiliation(s)
- Xiaolan Dai
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhenyun Du
- Glycochemistry and Glycobiology Lab, Carbohydrate Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Can Jin
- Glycochemistry and Glycobiology Lab, Carbohydrate Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Nanjing University of Traditional Chinese Medicine, Nanjing 563003, China
| | - Bixi Tang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Xia Chen
- Glycochemistry and Glycobiology Lab, Carbohydrate Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xiaoqi Jing
- Glycochemistry and Glycobiology Lab, Carbohydrate Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yumei Shen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Fei He
- Glycochemistry and Glycobiology Lab, Carbohydrate Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Shunchun Wang
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Jia Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China; ZhongShan Institute for Drug Discovery, Zhongshan Tsuihang New District, Guangdong 528400, China.
| | - Kan Ding
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Glycochemistry and Glycobiology Lab, Carbohydrate Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; ZhongShan Institute for Drug Discovery, Zhongshan Tsuihang New District, Guangdong 528400, China.
| | - Yi Zang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Lingang Laboratory, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
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14
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Nipper M, Xu Y, Liu J, Yin X, Liu Z, Ye Z, Zhang J, Chen Y, Wang P. TGFβ and Hippo Signaling Pathways Coordinate to Promote Acinar to Ductal Metaplasia in Human Pancreas. Cells 2024; 13:186. [PMID: 38247878 PMCID: PMC10813953 DOI: 10.3390/cells13020186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/04/2023] [Accepted: 12/09/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND & AIMS Acinar-to-ductal metaplasia (ADM) serves as a precursor event in the development of pancreatic ductal adenocarcinoma (PDAC) upon constitutive environmental and genetical stress. While the role of ADM in PDAC progression has been established, the molecular mechanisms underlying human ADM remain elusive. We previously demonstrated the induction of ADM in human acinar cells through the transforming growth factor beta (TGFβ) signaling pathway. We aim to investigate the interaction between TGFβ and Hippo pathways in mediating ADM. METHODS RNA-sequencing was conducted on sorted normal primary human acinar, ductal, and AD (acinar cells that have undergone ADM) cells. ATAC-seq analysis was utilized to reveal the chromatin accessibility in these three cell types. ChIP-Seq of YAP1, SMAD4, and H3K27ac was performed to identify the gene targets of YAP1 and SMAD4. The role of YAP1/TAZ in ADM-driven cell proliferation, as well as in oncogenic KRAS driven proliferation, was assessed using sphere formation assay. RESULTS AD cells have a unique transcription profile, with upregulated genes in open chromatin states in acinar cells. YAP1 and SMAD4 co-occupy the loci of ADM-related genes, including PROM1, HES1, and MMP7, co-regulating biological functions such as cell adhesion, cell migration, and inflammation. Overexpression of YAP1/TAZ promoted acinar cell proliferation but still required the TGFβ pathway. YAP1/TAZ were also crucial for TGFβ-induced sphere formation and were necessary for KRAS-induced proliferation. CONCLUSIONS Our study reveals the intricate transition between acinar and AD states in human pancreatic tissues. It unveils the complex interaction between the Hippo and TGF-β pathways during ADM, highlighting the pivotal role of YAP1/TAZ and SMAD4 in PDAC initiation.
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Affiliation(s)
- Michael Nipper
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (M.N.); (Y.X.); (J.L.); (X.Y.)
| | - Yi Xu
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (M.N.); (Y.X.); (J.L.); (X.Y.)
| | - Jun Liu
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (M.N.); (Y.X.); (J.L.); (X.Y.)
| | - Xue Yin
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (M.N.); (Y.X.); (J.L.); (X.Y.)
| | - Zhijie Liu
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA;
| | - Zhengqing Ye
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (Z.Y.); (Y.C.)
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Jianmin Zhang
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Yidong Chen
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (Z.Y.); (Y.C.)
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Pei Wang
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (M.N.); (Y.X.); (J.L.); (X.Y.)
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15
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Arvanitakis K, Papadakos SP, Lekakis V, Koufakis T, Lempesis IG, Papantoniou E, Kalopitas G, Georgakopoulou VE, Stergiou IE, Theocharis S, Germanidis G. Meeting at the Crossroad between Obesity and Hepatic Carcinogenesis: Unique Pathophysiological Pathways Raise Expectations for Innovative Therapeutic Approaches. Int J Mol Sci 2023; 24:14704. [PMID: 37834153 PMCID: PMC10572430 DOI: 10.3390/ijms241914704] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/21/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
The escalating global prevalence of obesity and its intricate association with the development of hepatocellular carcinoma (HCC) pose a substantial challenge to public health. Obesity, acknowledged as a pervasive epidemic, is linked to an array of chronic diseases, including HCC, catalyzing the need for a comprehensive understanding of its molecular underpinnings. Notably, HCC has emerged as a leading malignancy with rising incidence and mortality. The transition from viral etiologies to the prominence of metabolic dysfunction-associated fatty liver disease (MAFLD)-related HCC underscores the urgent need to explore the intricate molecular pathways linking obesity and hepatic carcinogenesis. This review delves into the interwoven landscape of molecular carcinogenesis in the context of obesity-driven HCC while also navigating using the current therapeutic strategies and future prospects for combating obesity-related HCC. We underscore the pivotal role of obesity as a risk factor and propose an integrated approach encompassing lifestyle interventions, pharmacotherapy, and the exploration of emerging targeted therapies. As the obesity-HCC nexus continues to challenge healthcare systems globally, a comprehensive understanding of the intricate molecular mechanisms and innovative therapeutic strategies is imperative to alleviate the rising burden of this dual menace.
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Affiliation(s)
- Konstantinos Arvanitakis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (K.A.); (E.P.); (G.K.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Stavros P. Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.P.P.); (S.T.)
| | - Vasileios Lekakis
- Department of Gastroenterology, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece;
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece;
| | - Ioannis G. Lempesis
- Institute of Metabolism and Systems Research (IMSR), College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK;
| | - Eleni Papantoniou
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (K.A.); (E.P.); (G.K.)
| | - Georgios Kalopitas
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (K.A.); (E.P.); (G.K.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | | | - Ioanna E. Stergiou
- Pathophysiology Department, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Stamatios Theocharis
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.P.P.); (S.T.)
| | - Georgios Germanidis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (K.A.); (E.P.); (G.K.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
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16
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Nicholas SE, Choi AJ, Lam TN, Basu SK, Mandal N, Karamichos D. Potentiation of Sphingolipids and TGF-β in the human corneal stroma reveals intricate signaling pathway crosstalks. Exp Eye Res 2023; 231:109487. [PMID: 37084874 DOI: 10.1016/j.exer.2023.109487] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 04/11/2023] [Accepted: 04/18/2023] [Indexed: 04/23/2023]
Abstract
Corneal haze brought on by fibrosis due to insult can lead to partial or complete vision loss. Currently, corneal transplantation is the gold standard for treating severe corneal fibrosis, which comes with the risk of rejection and the issue of donor tissue shortages. Sphingolipids (SPLs) are known to be associated with fibrosis in various tissues and organs, including the cornea. We previously reported that SPLs are tightly related to Transforming Growth Factor β (TGF-β) signaling and corneal fibrogenesis. This study aimed to elucidate the interplay of SPLs, specifically sphingosine-1-phosphate (S1P) signaling, and its' interactions with TGF-β signaling through detailed analyses of the corresponding downstream signaling targets in the context of corneal fibrosis, in vitro. Healthy human corneal fibroblasts (HCFs) were isolated, plated on polycarbonate membranes, and stimulated with a stable Vitamin C derivative. The 3D constructs were treated with either 5 μM sphingosine-1-phosphate (S1P), 5 μM SPHK I2 (I2; inhibitor of sphingosine kinase 1, one of the two enzymes responsible for generating S1P in mammalian cells), 0.1 ng/mL TGF-β1, or 0.1 ng/mL TGF-β3. Cultures with control medium-only served as controls. All 3D constructs were examined for protein expression of fibrotic markers, SPLs, TGF-βs, and relevant downstream signaling pathways. This data revealed no significant changes in any LTBP (latent TGF-β binding proteins) expression when stimulated with S1P or I2. However, LTBP1 was significantly upregulated via stimulation of TGF-β1 and TGF-β3, whereas LTBP2 was significantly upregulated only with TGF-β3 stimulation. Significant downregulation of TGF-β receptor II (TGF-βRII) following S1P stimulation but significant upregulation following I2 stimulation was observed. Following TGF-β1, S1P, and I2 stimulation, phospho-SMAD2 (pSMAD2) was significantly downregulated. Furthermore, I2 stimulation led to significant downregulation of SMAD4. Adhesion/proliferation/transcription regulation targets, SRC, FAK, and pERK 1/2 were all significantly downregulated by exogenous S1P, whereas I2 only significantly downregulated FAK. Exogenous TGF-β3 caused significant upregulation of AKT. Interestingly, both I2 and TGF-β3 caused significant downregulation of JNK expression. Lastly, TGF-β1 led to significant upregulation of sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate receptor 3 (S1PR3), whereas TGF-β3 caused significant upregulation of only SphK1. Together with previously published work from our group and others, S1P inhibition exhibits great potential as an efficacious anti-fibrotic modality in human corneal stromal ECM. The current findings shed further light on a very complex and rather incompletely investigated mechanism, and cement the intricate crosstalk between SPLs and TGF-β in corneal fibrogenesis. Future studies will dictate the potential of utilizing SPLs/TGF-β signaling modulators as novel therapeutics in corneal fibrosis.
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Affiliation(s)
- Sarah E Nicholas
- North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA; Department of Pharmaceutical Sciences, University of North Texas HSC, Fort Worth, TX, 76107, USA
| | - Alexander J Choi
- North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA; Department of Pharmaceutical Sciences, University of North Texas HSC, Fort Worth, TX, 76107, USA
| | - Thi N Lam
- Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Sandip K Basu
- Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Nawajes Mandal
- Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA; Department of Anatomy and Neurobiology, University of Tennessee HSC, Memphis, TN, 38163, USA
| | - Dimitrios Karamichos
- North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA; Department of Pharmaceutical Sciences, University of North Texas HSC, Fort Worth, TX, 76107, USA; Department of Pharmacology and Neuroscience, University of North Texas HSC, Fort Worth, TX, 76107, USA.
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17
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Expression and Function of BMP and Activin Membrane-Bound Inhibitor (BAMBI) in Chronic Liver Diseases and Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:ijms24043473. [PMID: 36834884 PMCID: PMC9964332 DOI: 10.3390/ijms24043473] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) is a transmembrane pseudoreceptor structurally related to transforming growth factor (TGF)-β type 1 receptors (TGF-β1Rs). BAMBI lacks a kinase domain and functions as a TGF-β1R antagonist. Essential processes such as cell differentiation and proliferation are regulated by TGF-β1R signaling. TGF-β is the best-studied ligand of TGF-βRs and has an eminent role in inflammation and fibrogenesis. Liver fibrosis is the end stage of almost all chronic liver diseases, such as non-alcoholic fatty liver disease, and at the moment, there is no effective anti-fibrotic therapy available. Hepatic BAMBI is downregulated in rodent models of liver injury and in the fibrotic liver of patients, suggesting that low BAMBI has a role in liver fibrosis. Experimental evidence convincingly demonstrated that BAMBI overexpression is able to protect against liver fibrosis. Chronic liver diseases have a high risk of hepatocellular carcinoma (HCC), and BAMBI was shown to exert tumor-promoting as well as tumor-protective functions. This review article aims to summarize relevant studies on hepatic BAMBI expression and its role in chronic liver diseases and HCC.
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Jiao J, Sanchez JI, Saldarriaga OA, Solis LM, Tweardy DJ, Maru DM, Stevenson HL, Beretta L. Spatial molecular and cellular determinants of STAT3 activation in liver fibrosis progression in non-alcoholic fatty liver disease. JHEP Rep 2023; 5:100628. [PMID: 36687470 PMCID: PMC9850198 DOI: 10.1016/j.jhepr.2022.100628] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 11/03/2022] [Accepted: 11/05/2022] [Indexed: 11/23/2022] Open
Abstract
Background & Aims The prevalence of non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), is increasing. Individuals with NASH often develop liver fibrosis and advanced liver fibrosis is the main determinant of mortality in individuals with NASH. We and others have reported that STAT3 contributes to liver fibrosis and hepatocellular carcinoma in mice. Methods Here, we explored whether STAT3 activation in hepatocyte and non-hepatocyte areas, measured by phospho-STAT3 (pSTAT3), is associated with liver fibrosis progression in 133 patients with NAFLD. We further characterized the molecular and cellular determinants of STAT3 activation by integrating spatial distribution and transcriptomic changes in fibrotic NAFLD livers.Results: pSTAT3 scores in non-hepatocyte areas progressively increased with fibrosis severity (r = 0.53, p <0.001). Correlation analyses between pSTAT3 scores and expression of 1,540 immune- and cancer-associated genes revealed a large effect of STAT3 activation on gene expression changes in non-hepatocyte areas and confirmed a major role for STAT3 activation in fibrogenesis. Digital spatial transcriptomic profiling was also performed on 13 regions selected in hepatocyte and non-hepatocyte areas from four NAFLD liver biopsies with advanced fibrosis, using a customized panel of markers including pSTAT3, PanCK+CK8/18, and CD45. The regions were further segmented based on positive or negative pSTAT3 staining. Cell deconvolution analysis revealed that activated STAT3 was enriched in hepatic progenitor cells (HPCs) and sinusoidal endothelial cells. Regression of liver fibrosis upon STAT3 inhibition in mice with NASH resulted in a reduction of HPCs, demonstrating a direct role for STAT3 in HPC expansion. Conclusion Increased understanding of the spatial dependence of STAT3 signaling in NASH and liver fibrosis progression could lead to novel targeted treatment approaches. Impact and implications Advanced liver fibrosis is the main determinant of mortality in patients with NASH. This study showed using liver biopsies from 133 patients with NAFLD, that STAT3 activation in non-hepatocyte areas is strongly associated with fibrosis severity, inflammation, and progression to NASH. STAT3 activation was enriched in hepatic progenitor cells (HPCs) and sinusoidal endothelial cells (SECs), as determined by innovative technologies interrogating the spatial distribution of pSTAT3. Finally, STAT3 inhibition in mice resulted in reduced liver fibrosis and depletion of HPCs, suggesting that STAT3 activation in HPCs contributes to their expansion and fibrogenesis in NAFLD.
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Key Words
- DSP, digital spatial profiler
- FC, fold change
- HCC, hepatocellular carcinoma
- HFD, high-fat diet
- HPCs, hepatic progenitor cells
- HSCs, hepatic stellate cells
- IPA, Ingenuity® Pathway Analysis
- LSECs, liver sinusoidal endothelial cells
- NAFLD
- NAFLD, non-alcoholic fatty liver disease
- NAS, NAFLD activity score
- NASH
- NASH, non-alcoholic steatohepatitis
- SECs, sinusoidal endothelial cells
- STAT, signal transducer and activator of transcription
- STAT3
- cirrhosis
- fibrosis
- liver cancer
- pSTAT3, phospho-STAT3
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Affiliation(s)
- Jingjing Jiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jessica I. Sanchez
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Omar A. Saldarriaga
- Department of Pathology, The University of Texas Medical Branch, Galveston TX, USA
| | - Luisa M. Solis
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David J. Tweardy
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dipen M. Maru
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Heather L. Stevenson
- Department of Pathology, The University of Texas Medical Branch, Galveston TX, USA
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Proteomic Analysis of Dupuytren's Contracture-Derived Sweat Glands Revealed the Synthesis of Connective Tissue Growth Factor and Initiation of Epithelial-Mesenchymal Transition as Major Pathogenetic Events. Int J Mol Sci 2023; 24:ijms24021081. [PMID: 36674597 PMCID: PMC9866571 DOI: 10.3390/ijms24021081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 01/03/2023] [Accepted: 01/03/2023] [Indexed: 01/09/2023] Open
Abstract
Dupuytren's contracture (DC) is a chronic and progressive fibroproliferative disorder restricted to the palmar fascia of the hands. Previously, we discovered the presence of high levels of connective tissue growth factor in sweat glands in the vicinity of DC nodules and hypothesized that sweat glands have an important role in the formation of DC lesions. Here, we shed light on the role of sweat glands in the DC pathogenesis by proteomic analysis and immunofluorescence microscopy. We demonstrated that a fraction of sweat gland epithelium underwent epithelial-mesenchymal transition illustrated by negative regulation of E-cadherin. We hypothesized that the increase in connective tissue growth factor expression in DC sweat glands has both autocrine and paracrine effects in sustaining the DC formation and inducing pathological changes in DC-associated sweat glands.
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20
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Hu Q, Bian Q, Rong D, Wang L, Song J, Huang HS, Zeng J, Mei J, Wang PY. JAK/STAT pathway: Extracellular signals, diseases, immunity, and therapeutic regimens. Front Bioeng Biotechnol 2023; 11:1110765. [PMID: 36911202 PMCID: PMC9995824 DOI: 10.3389/fbioe.2023.1110765] [Citation(s) in RCA: 125] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 02/13/2023] [Indexed: 02/25/2023] Open
Abstract
Janus kinase/signal transduction and transcription activation (JAK/STAT) pathways were originally thought to be intracellular signaling pathways that mediate cytokine signals in mammals. Existing studies show that the JAK/STAT pathway regulates the downstream signaling of numerous membrane proteins such as such as G-protein-associated receptors, integrins and so on. Mounting evidence shows that the JAK/STAT pathways play an important role in human disease pathology and pharmacological mechanism. The JAK/STAT pathways are related to aspects of all aspects of the immune system function, such as fighting infection, maintaining immune tolerance, strengthening barrier function, and cancer prevention, which are all important factors involved in immune response. In addition, the JAK/STAT pathways play an important role in extracellular mechanistic signaling and might be an important mediator of mechanistic signals that influence disease progression, immune environment. Therefore, it is important to understand the mechanism of the JAK/STAT pathways, which provides ideas for us to design more drugs targeting diseases based on the JAK/STAT pathway. In this review, we discuss the role of the JAK/STAT pathway in mechanistic signaling, disease progression, immune environment, and therapeutic targets.
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Affiliation(s)
- Qian Hu
- Department of Pharmacy, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.,Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China.,Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Qihui Bian
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China
| | - Dingchao Rong
- Department of Orthopaedic Surgery, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Leiyun Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Department of Pharmacy, Wuhan First Hospital, Wuhan, China
| | - Jianan Song
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China
| | - Hsuan-Shun Huang
- Department of Research, Center for Prevention and Therapy of Gynecological Cancers, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
| | - Jun Zeng
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Jie Mei
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China.,Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Peng-Yuan Wang
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China
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21
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Embryonic organizer formation disorder leads to multiorgan dysplasia in Down syndrome. Cell Death Dis 2022; 13:1054. [PMID: 36535930 PMCID: PMC9763398 DOI: 10.1038/s41419-022-05517-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 12/08/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
Despite the high prevalence of Down syndrome (DS) and early identification of the cause (trisomy 21), its molecular pathogenesis has been poorly understood and specific treatments have consequently been practically unavailable. A number of medical conditions throughout the body associated with DS have prompted us to investigate its molecular etiology from the viewpoint of the embryonic organizer, which can steer the development of surrounding cells into specific organs and tissues. We established a DS zebrafish model by overexpressing the human DYRK1A gene, a highly haploinsufficient gene located at the "critical region" within 21q22. We found that both embryonic organizer and body axis were significantly impaired during early embryogenesis, producing abnormalities of the nervous, heart, visceral, and blood systems, similar to those observed with DS. Quantitative phosphoproteome analysis and related assays demonstrated that the DYRK1A-overexpressed zebrafish embryos had anomalous phosphorylation of β-catenin and Hsp90ab1, resulting in Wnt signaling enhancement and TGF-β inhibition. We found an uncovered ectopic molecular mechanism present in amniocytes from fetuses diagnosed with DS and isolated hematopoietic stem cells (HSCs) of DS patients. Importantly, the abnormal proliferation of DS HSCs could be recovered by switching the balance between Wnt and TGF-β signaling in vitro. Our findings provide a novel molecular pathogenic mechanism in which ectopic Wnt and TGF-β lead to DS physical dysplasia, suggesting potential targeted therapies for DS.
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22
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Liu J, Gong W, Liu P, Li Y, Jiang H, Wu X, Zhao Y, Ren J. Macrophages-microenvironment crosstalk in fibrostenotic inflammatory bowel disease: from basic mechanisms to clinical applications. Expert Opin Ther Targets 2022; 26:1011-1026. [PMID: 36573664 DOI: 10.1080/14728222.2022.2161889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Intestinal fibrosis is a common complication of Inflammatory Bowel Disease (IBD) with no available drugs. The current therapeutic principle is surgical intervention as the core. Intestinal macrophages contribute to both the progression of inflammation and fibrosis. Understanding the role of macrophages in the intestinal microenvironment could bring new hope for fibrosis prevention or even reversal. AREAS COVERED This article reviewed the most relevant reports on macrophage in the field of intestinal fibrosis. The authors discussed current opinions about how intestinal macrophages function and interact with surrounding mediators during inflammation resolution and fibrostenotic IBD. Based on biological mechanisms findings, authors summarized related clinical trial outcomes. EXPERT OPINION The plasticity of intestinal macrophages allows them to undergo dramatic alterations in their phenotypes or functions when exposed to gastrointestinal environmental stimuli. They exhibit distinct metabolic characteristics, secrete various cytokines, express unique surface markers, and transmit different signals. Nevertheless, the specific mechanism through which the intestinal macrophages contribute to intestinal fibrosis remains unclear. It should further elucidate a novel therapeutic approach by targeting macrophages, especially distinct mechanisms in specific subgroups of macrophages involved in the progression of fibrogenesis in IBD.
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Affiliation(s)
- Juanhan Liu
- Department of General Surgery, Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, 210002, Nanjing, P. R. China
| | - Wenbin Gong
- Department of General Surgery, Southeast University, 210096, Nanjing, P. R. China
| | - Peizhao Liu
- Department of General Surgery, Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, 210002, Nanjing, P. R. China
| | - Yangguang Li
- Department of General Surgery, Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, 210002, Nanjing, P. R. China
| | - Haiyang Jiang
- Department of General Surgery, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, 210019, Nanjing, P. R. China
| | - Xiuwen Wu
- Department of General Surgery, Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, 210002, Nanjing, P. R. China
| | - Yun Zhao
- Department of General Surgery, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, 210019, Nanjing, P. R. China
| | - Jianan Ren
- Department of General Surgery, Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, 210002, Nanjing, P. R. China
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23
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Hung CT, Su TH, Chen YT, Wu YF, Chen YT, Lin SJ, Lin SL, Yang KC. Targeting ER protein TXNDC5 in hepatic stellate cell mitigates liver fibrosis by repressing non-canonical TGFβ signalling. Gut 2022; 71:1876-1891. [PMID: 34933915 DOI: 10.1136/gutjnl-2021-325065] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 12/05/2021] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND OBJECTIVES Liver fibrosis (LF) occurs following chronic liver injuries. Currently, there is no effective therapy for LF. Recently, we identified thioredoxin domain containing 5 (TXNDC5), an ER protein disulfide isomerase (PDI), as a critical mediator of cardiac and lung fibrosis. We aimed to determine if TXNDC5 also contributes to LF and its potential as a therapeutic target for LF. DESIGN Histological and transcriptome analyses on human cirrhotic livers were performed. Col1a1-GFPTg , Alb-Cre;Rosa26-tdTomato and Tie2-Cre/ERT2;Rosa26-tdTomato mice were used to determine the cell type(s) where TXNDC5 was induced following liver injury. In vitro investigations were conducted in human hepatic stellate cells (HSCs). Col1a2-Cre/ERT2;Txndc5fl/fl (Txndc5cKO ) and Alb-Cre;Txndc5fl/fl (Txndc5Hep-cKO ) mice were generated to delete TXNDC5 in HSCs and hepatocytes, respectively. Carbon tetrachloride treatment and bile duct ligation surgery were employed to induce liver injury/fibrosis in mice. The extent of LF was quantified using histological, imaging and biochemical analyses. RESULTS TXNDC5 was upregulated markedly in human and mouse fibrotic livers, particularly in activated HSC at the fibrotic foci. TXNDC5 was induced by transforming growth factor β1 (TGFβ1) in HSCs and it was both required and sufficient for the activation, proliferation, survival and extracellular matrix production of HSC. Mechanistically, TGFβ1 induces TXNDC5 expression through increased ER stress and ATF6-mediated transcriptional regulation. In addition, TXNDC5 promotes LF by redox-dependent JNK and signal transducer and activator of transcription 3 activation in HSCs through its PDI activity, activating HSCs and making them resistant to apoptosis. HSC-specific deletion of Txndc5 reverted established LF in mice. CONCLUSIONS ER protein TXNDC5 promotes LF through redox-dependent HSC activation, proliferation and excessive extracellular matrix production. Targeting TXNDC5, therefore, could be a potential novel therapeutic strategy to ameliorate LF.
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Affiliation(s)
- Chen-Ting Hung
- Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tung-Hung Su
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Ting Chen
- Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yueh-Feng Wu
- Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan
| | - You-Tzung Chen
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Sung-Jan Lin
- Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan.,Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.,Research Center for Developmental Biology & Regenerative Medicine, National Taiwan University, Taipei, Taiwan.,Center for Frontier Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Shuei-Liong Lin
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Research Center for Developmental Biology & Regenerative Medicine, National Taiwan University, Taipei, Taiwan.,Graduate Institute and Department of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei, Taiwan
| | - Kai-Chien Yang
- Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan .,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Research Center for Developmental Biology & Regenerative Medicine, National Taiwan University, Taipei, Taiwan.,Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
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24
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Liu Y, Hu M, Fan G, Xing N, Zhang R. Effect of Baricitinib on the epithelial-mesenchymal transition of alveolar epithelial cells induced by IL-6. Int Immunopharmacol 2022; 110:109044. [PMID: 35850052 DOI: 10.1016/j.intimp.2022.109044] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 06/27/2022] [Accepted: 07/07/2022] [Indexed: 11/05/2022]
Abstract
OBJECTIVE Interstitial lung disease (ILD) is one of the common complications of Connective tissue disease (CTD). Epithelial-mesenchymal transition (EMT) is one of the main pathological mechanisms of ILD. IL-6 may induce ILD through the JAK/STAT pathway. Therefore, exploring the mechanism of IL-6 on the EMT of alveolar epithelial cells and inhibition JAK/STAT pathway with Baricitinib on the EMT of alveolar epithelial cells is helpful in revealing the pathogenesis of CTD-ILD and guiding treatment. METHODS Electrochemiluminescence was applied to detect the changes in serum IL-6 levels before and after treatment in 37 patients with anti-synthetase syndrome-associated ILD; A549 cells (a human AEC cell line) were incubated with IL-6, Baricitinib, or both IL-6 and Baricitinib, and changes in EMT-related markers levels were measured using real-time PCR, western blotting and fluorescence microscopy. The related proteins in the JAK/STAT signaling pathways were examined by western blot. The level of Connective tissue growth factor (CTGF) and Hydroxyproline (Hyp) in cell supernatants was measured by ELISA. RESULTS Serum IL-6 level in patients with anti-synthetase syndrome-associated ILD was significantly higher than that in health (6.78(4.19, 16.14)pg/ml vs. 2.10(1.43, 5.18)pg/ml, p < 0.01). The level of IL-6 in the improvement group of ASS-ILD was considerably decreased than that before treatment(before(7.48(4.54, 22.76) pg/mL vs. 5.00(3.46, 11.32)pg/mL, p < 0.01), p < 0.01), and the level of IL-6 in the progressive group of ASS-ILD was significantly higher than that before treatment(before(7.49(6.77, 35.80) pg/mL vs. 30.02(8.01, 82.98) pg/mL, p < 0.05). IL-6 increased the expression of epithelial phenotypic marker E-cadherin and inhibited mesenchymal phenotypic markers, including vimentin and N-cadherin in A549 cells. Moreover, IL-6-induced EMT was attenuated by Baricitinib. Furthermore, we found that IL-6 activated the phosphorylation of JAK1/2, STAT3, and Baricitinib, partially inhibiting these changes in this process. Baricitinib reduced the secretion of CTGF and Hyp in A549 cells. CONCLUSION The significant higher level of IL-6 in patients with anti-synthase syndrome-associated ILD may be related to disease activity and recurrence. Our results suggest that Baricitinib attenuates epithelial-mesenchymal transition in alveolar epithelial cells in the presence of IL-6 through the JAK/STAT signaling pathway.
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Affiliation(s)
- Yiping Liu
- Department of Rheumatology, The First Affiliated Hospital of China Medical University, China
| | - Ming Hu
- Department of Rheumatology, The First Affiliated Hospital of China Medical University, China
| | - Guanzhi Fan
- Department of Pathology, Shengjing Hospital Affiliated to China Medical University, China
| | - Nanshu Xing
- Department of Infectious Disease, The First Affiliated Hospital of China Medical University, China
| | - Rong Zhang
- Department of Rheumatology, The First Affiliated Hospital of China Medical University, China.
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25
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Targeting fibrosis, mechanisms and cilinical trials. Signal Transduct Target Ther 2022; 7:206. [PMID: 35773269 PMCID: PMC9247101 DOI: 10.1038/s41392-022-01070-3] [Citation(s) in RCA: 222] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/17/2022] [Accepted: 06/20/2022] [Indexed: 02/05/2023] Open
Abstract
Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response. Multiple organs can develop fibrosis, including the liver, kidney, heart, and lung. Fibrosis such as liver cirrhosis, idiopathic pulmonary fibrosis, and cystic fibrosis caused substantial disease burden. Persistent abnormal activation of myofibroblasts mediated by various signals, such as transforming growth factor, platelet-derived growth factor, and fibroblast growh factor, has been recongized as a major event in the occurrence and progression of fibrosis. Although the mechanisms driving organ-specific fibrosis have not been fully elucidated, drugs targeting these identified aberrant signals have achieved potent anti-fibrotic efficacy in clinical trials. In this review, we briefly introduce the aetiology and epidemiology of several fibrosis diseases, including liver fibrosis, kidney fibrosis, cardiac fibrosis, and pulmonary fibrosis. Then, we summarise the abnormal cells (epithelial cells, endothelial cells, immune cells, and fibroblasts) and their interactions in fibrosis. In addition, we also focus on the aberrant signaling pathways and therapeutic targets that regulate myofibroblast activation, extracellular matrix cross-linking, metabolism, and inflammation in fibrosis. Finally, we discuss the anti-fibrotic drugs based on their targets and clinical trials. This review provides reference for further research on fibrosis mechanism, drug development, and clinical trials.
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26
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Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis: Breaking the Bridge. Int J Mol Sci 2022; 23:ijms23116064. [PMID: 35682743 PMCID: PMC9181498 DOI: 10.3390/ijms23116064] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 05/24/2022] [Accepted: 05/26/2022] [Indexed: 12/23/2022] Open
Abstract
CTGF is upregulated in patients with idiopathic pulmonary fibrosis (IPF), characterized by the deposition of a pathological extracellular matrix (ECM). Additionally, many omics studies confirmed that aberrant cellular senescence-associated mitochondria dysfunction and metabolic reprogramming had been identified in different IPF lung cells (alveolar epithelial cells, alveolar endothelial cells, fibroblasts, and macrophages). Here, we reviewed the role of the CTGF in IPF lung cells to mediate anomalous senescence-related metabolic mechanisms that support the fibrotic environment in IPF.
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27
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Lua I, Balog S, Asahina K. TAZ/WWTR1 mediates liver mesothelial-mesenchymal transition induced by stiff extracellular environment, TGF-β1, and lysophosphatidic acid. J Cell Physiol 2022; 237:2561-2573. [PMID: 35445400 DOI: 10.1002/jcp.30750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 02/14/2022] [Accepted: 03/04/2022] [Indexed: 11/08/2022]
Abstract
Mesothelial cells cover the surface of the internal organs and the walls of body cavities, facilitating the movement between organs by secretion of a lubricating fluid. Upon injury, mesothelial cells undergo a mesothelial-mesenchymal transition (MMT) and give rise to myofibroblasts during organ fibrosis, including in the liver. Although transforming growth factor-β1 (TGF-β1) was shown to induce MMT, molecular and cellular mechanisms underlying MMT remain to be clarified. In the present study, we examined how the extracellular environment, soluble factors, and cell density control the phenotype of liver mesothelial cells by culturing them at different cell densities or on hydrogels of different stiffness. We found that TGF-β1 does not fully induce MMT in mesothelial cells cultured at high cell density or in the absence of fetal bovine serum. Extracellular lysophosphatidic acid (LPA) synergistically induced MMT in the presence of TGF-β1 in mesothelial cells. LPA induced nuclear localization of WW domain-containing transcription regulator1 (WWTR1/TAZ) and knockdown of Taz, which suppressed LPA-induced MMT. Mesothelial cells cultured on stiff hydrogels upregulated nuclear localization of TAZ and myofibroblastic differentiation. Knockdown of Taz suppressed MMT of mesothelial cells cultured on stiff hydrogels, but inhibition of TGF-β1 signaling failed to suppress MMT. Our data indicate that TAZ mediates MMT induced by TGF-β1, LPA, and a stiff matrix. The microenvironment of a stiff extracellular matrix is a strong inducer of MMT.
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Affiliation(s)
- Ingrid Lua
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Steven Balog
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Kinji Asahina
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.,Central Research Laboratory, Shiga University of Medical Science, Shiga, Japan
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28
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Zhang J, Zhang Z, Holst S, Blöchl C, Madunic K, Wuhrer M, Ten Dijke P, Zhang T. Transforming growth factor-β challenge alters the N-, O-, and glycosphingolipid glycomes in PaTu-S pancreatic adenocarcinoma cells. J Biol Chem 2022; 298:101717. [PMID: 35151689 PMCID: PMC8914387 DOI: 10.1016/j.jbc.2022.101717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 11/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and high mortality. Transforming growth factor-β (TGF-β) plays a key role in PDAC tumor progression, which is often associated with aberrant glycosylation. However, how PDAC cells respond to TGF-β and the role of glycosylation therein is not well known. Here, we investigated the TGF-β-mediated response and glycosylation changes in the PaTu-8955S (PaTu-S) cell line deficient in SMA-related and MAD-related protein 4 (SMAD4), a signal transducer of the TGF-β signaling. PaTu-S cells responded to TGF-β by upregulating SMAD2 phosphorylation and target gene expression. We found that TGF-β induced expression of the mesenchymal marker N-cadherin but did not significantly affect epithelial marker E-cadherin expression. We also examined differences in N-glycans, O-glycans, and glycosphingolipid-linked glycans in PaTu-S cells upon TGF-β stimulation. TGF-β treatment primarily induced N-glycome aberrations involving elevated levels of branching, core fucosylation, and sialylation in PaTu-S cells, in agreement with TGF-β-induced changes in the expression of glycosylation-associated genes. In addition, we observed differences in O glycosylation and glycosphingolipid glycosylation profiles after TGF-β treatment, including lower levels of sialylated Tn antigen and neoexpression of globosides. Furthermore, the expression of transcription factor sex-determining region Y-related high-mobility group box 4 was upregulated upon TGF-β stimulation, and its depletion blocked TGF-β-induced N-glycomic changes. Thus, TGF-β-induced N-glycosylation changes can occur in a sex-determining region Y-related high-mobility group box 4–dependent and SMAD4-independent manner in the pancreatic PaTu-S cancer cell line. Our results open up avenues to study the relevance of glycosylation in TGF-β signaling in SMAD4-inactivated PDAC.
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Affiliation(s)
- Jing Zhang
- Oncode Institute and Department of Cell Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Zejian Zhang
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Stephanie Holst
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Constantin Blöchl
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands; Department of Biosciences, University of Salzburg, Salzburg, Austria
| | - Katarina Madunic
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Peter Ten Dijke
- Oncode Institute and Department of Cell Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.
| | - Tao Zhang
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
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Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms. Exp Mol Med 2022; 54:273-284. [PMID: 35288649 PMCID: PMC8980093 DOI: 10.1038/s12276-022-00742-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 11/04/2021] [Accepted: 12/21/2021] [Indexed: 12/03/2022] Open
Abstract
Although bone marrow-derived mesenchymal stromal cells (BM-MSCs) have been identified as a major cellular source of fibrosis, the exact molecular mechanism and signaling pathways involved have not been identified thus far. Here, we show that BM-MSCs contribute to fibrosis in myeloproliferative neoplasms (MPNs) by differentiating into αSMA-positive myofibroblasts. These cells display a dysregulated extracellular matrix with increased FN1 production and secretion of profibrotic MMP9 compared to healthy donor cells. Fibrogenic TGFβ and inflammatory JAK2/STAT3 and NFκB signaling pathway activity is increased in BM-MSCs of MPN patients. Moreover, coculture with mononuclear cells from MPN patients was sufficient to induce fibrosis in healthy BM-MSCs. Inhibition of JAK1/2, SMAD3 or NFκB significantly reduced the fibrotic phenotype of MPN BM-MSCs and was able to prevent the development of fibrosis induced by coculture of healthy BM-MSCs and MPN mononuclear cells with overly active JAK/STAT signaling, underlining their involvement in fibrosis. Combined treatment with JAK1/2 and SMAD3 inhibitors showed synergistic and the most favorable effects on αSMA and FN1 expression in BM-MSCs. These results support the combined inhibition of TGFβ and inflammatory signaling to extenuate fibrosis in MPN. The treatment of fibrosis in patients with rare bone marrow disorders could be improved with a combined therapy that targets inflammatory pathways. Myeloproliferative neoplasms (MPN) are a group of bone marrow disorders characterized by the over-production of blood cells, which can lead to fibrosis in the bone marrow. Vladan Čokić at the University of Belgrade, Serbia, and co-workers examined how stem cells known as mesenchymal stromal cells from the bone marrow contribute to MPN fibrosis. They found an increase in three pro-inflammatory signaling pathways in MPN patients, resulting in the stromal cells differentiating into cells with dysregulated extracellular matrices. The differentiated cells did not behave correctly nor degrade properly, triggering fibrosis. The team combined two drugs that target the inflammatory signaling pathways, and successfully inhibited the development of fibrosis in MPN cell cultures.
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Cho K, Kim NH, Seo SH, Song SH, Jeong CH, Kim HS, Um JE, Ku M, Yang J, Park JY, Ahn SH, Yook JI, Kim SU. A micellized bone morphogenetic protein-7 prodrug ameliorates liver fibrosis by suppressing transforming growth factor- β signaling. Am J Cancer Res 2022; 12:763-778. [PMID: 35261800 PMCID: PMC8900005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 01/07/2022] [Indexed: 06/14/2023] Open
Abstract
Bone morphogenetic protein-7 (BMP-7) antagonizes transforming growth factor-β (TGF-β), which is critically involved in liver fibrogenesis. Here, we designed a micelle formulation consisting of a protein transduction domain (PTD) fused BMP-7 polypeptide (mPTD-BMP-7) to enhance endocytic delivery, and investigated its ability to ameliorate liver fibrosis. The mPTD-BMP-7 formulation was efficiently delivered into cells via endocytosis, where it inhibited TGF-β mediated epithelial-mesenchymal transition. After successfully demonstrating delivery of fluorescently labeled mPTD-BMP-7 into the murine liver in vivo, we tested the mPTD-BMP-7 formulation in a murine liver fibrosis model, developed by repeated intraperitoneal injection of hepatotoxic carbon tetrachloride, twice weekly from 4 to 16 weeks. mPTD-BMP-7 effects were tested by injecting the mPTD-BMP-7 formulation (or vehicle control) into the lateral tail at a dose of 50 (n=8) or 500 μg/kg (n=10), also twice per week from 4 to 16 weeks. Vehicle-treated control mice developed fibrous septa surrounding the liver parenchyma and marked portal-to-portal bridging with occasional nodules, whereas mice treated with mPTD-BMP-7 showed only fibrous expansion of some portal areas, with or without short fibrous septa. Using the Ishak scoring system, we found that the fibrotic burden was significantly lower in mPTD-BMP-7 treated mice than in control mice (all P<0.001). Treatment with mPTD-BMP-7 protected tight junctions between hepatocytes and reduced extracellular matrix protein levels. It also significantly decreased mRNA levels of collagen 1A, smooth muscle α-actin, and connective tissue growth factor compared with that in control mice (all P<0.001). Collectively, out results indicate that mPTD-BMP-7, a prodrug formulation of BMP-7, ameliorates liver fibrosis by suppressing the TGF-β signaling pathway in a murine liver fibrosis model.
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Affiliation(s)
- Kyungjoo Cho
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of MedicineSeoul, Korea
- Yonsei Liver Center, Severance HospitalSeoul, Korea
| | - Nam Hee Kim
- Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of DentistrySeoul, Korea
| | - Sang Hyun Seo
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of MedicineSeoul, Korea
- Yonsei Liver Center, Severance HospitalSeoul, Korea
| | - Sang Hyun Song
- Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of DentistrySeoul, Korea
| | - Chul Hee Jeong
- Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of DentistrySeoul, Korea
| | - Hyun Sil Kim
- Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of DentistrySeoul, Korea
| | | | - Minhee Ku
- Department of Radiology, Yonsei University College of MedicineSeoul, Korea
- Convergence Research Center for Systems Molecular Radiological Science, Yonsei UniversitySeoul, Korea
| | - Jaemoon Yang
- Department of Radiology, Yonsei University College of MedicineSeoul, Korea
- Convergence Research Center for Systems Molecular Radiological Science, Yonsei UniversitySeoul, Korea
| | - Jun Yong Park
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of MedicineSeoul, Korea
- Yonsei Liver Center, Severance HospitalSeoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of MedicineSeoul, Korea
| | - Sang Hoon Ahn
- Yonsei Liver Center, Severance HospitalSeoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of MedicineSeoul, Korea
| | - Jong In Yook
- Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of DentistrySeoul, Korea
- MET Life Sciences LtdSeoul, Korea
| | - Seung Up Kim
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of MedicineSeoul, Korea
- Yonsei Liver Center, Severance HospitalSeoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of MedicineSeoul, Korea
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31
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Wang L, Zhu W, Sun R, Liu J, Ma Q, Zhang B, Shi Y. Network Pharmacology Prediction and Molecular Docking-Based Strategy to Discover the Potential Pharmacological Mechanism of Wen-Yu-Jin against Pulmonary Fibrosis in a Mouse Model. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:7753508. [PMID: 35186103 PMCID: PMC8853792 DOI: 10.1155/2022/7753508] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/16/2022]
Abstract
BACKGROUND Pulmonary fibrosis (PF) is a devastating lung disease, resulting in gas exchange dysfunction until death. The two drugs approved by the FDA, pirfenidone and nintedanib, have obvious side effects. Wen-yu-jin (WYJ), one of the commonly used herbs in China, can treat respiratory diseases. The potential effects and the underlying mechanism of WYJ against PF are unclear. PURPOSE Employing network pharmacology, molecular docking, and in vivo and in vitro experiments to explore the potential effects and underlying mechanisms of WYJ in the treatment of PF. METHODS Ultra-high pressure liquid chromatography combined with linear ion trap-orbital tandem mass spectrometry (UHPLC-LTQ-orbital trap) was used to identify compounds of WYJ. We got PF-related targets and WYJ compounds-related targets from public databases and further completed critical targets exploration, network construction, and pathway analysis by network pharmacology. Molecular docking predicted binding activity of WYJ compounds and critical targets. Based on the above results, in vivo and in vitro experiments validated the potential effects and mechanisms of WYJ against PF. RESULTS 23 major compositions of WYJ were identified based on UHPLC-LTQ-Orbitrap. According to the results of network pharmacology, STAT3, SRC, IL6, MAPK1, AKT1, EGFR, MAPK8, MAPK14, and IL1B are critical therapeutic targets. Molecular docking results showed that most of the compounds have good binding activities with critical targets. The results of in vivo and in vitro experiments showed that WYJ alleviated the process of fibrosis by targeting MAPK and STAT3 pathways. CONCLUSION Network pharmacology, molecular docking, and in vivo and in vitro experiments showed the potential effects and mechanisms of WYJ against PF, which provides a theoretical basis for the treatment of WYJ with PF.
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Affiliation(s)
- Lu Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Wenxiang Zhu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
- Shenzhen Research Institute, Beijing University of Chinese Medicine, Shenzhen, China
| | - Rui Sun
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Jing Liu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Qihong Ma
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Binbin Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yuanyuan Shi
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
- Shenzhen Research Institute, Beijing University of Chinese Medicine, Shenzhen, China
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32
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Zhang YZ, Zeb A, Cheng LF. Exploring the molecular mechanism of hepatitis virus inducing hepatocellular carcinoma by microarray data and immune infiltrates analysis. Front Immunol 2022; 13:1032819. [PMID: 36439183 PMCID: PMC9697180 DOI: 10.3389/fimmu.2022.1032819] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 10/27/2022] [Indexed: 11/12/2022] Open
Abstract
The number of new cases of hepatocellular carcinoma (HCC) worldwide reached 910,000, ranking the sixth, 80% HCC is associated with viruses, so exploring the molecular mechanism of viral carcinogenicity is imperative. The study showed that both HBV and HCV associated HCC and non-viral HCC have the same molecular phenotype (low gene expression and inhibition of immune pathways), but in the tumor immune micro-environment, there is excessive M2-type macrophage polarization in virus-associated hepatocellular carcinoma. To address this phenomenon, the data sets were analyzed and identified five hub genes (POLR2A, POLR2B, RPL5, RPS6, RPL23A) involved in viral gene expression and associated with PI3K-Akt-mTOR pathway activation by six algorithms. In addition, numerous studies have reported that M2-type macrophages participate in the hepatic fibro-pathological process of the development of HCC and are regulated by the PI3K-Akt-mTOR pathway. On this basis, the study showed that hepatitis virus causes abnormal expression of hub genes, leading to the activation of the pathway, which in turn promote the differentiation of M2-type macrophages and eventually promote the formation of liver fibrosis, leading to the occurrence of HCC. In addition, these hub genes are regulated by transcription factors and m6A enzyme, and have good prognosis and diagnostic value. With regard to drug reuse, the results suggest that patients with virus-related HCC for whom Cytidine triphosphate disodium salt and Guanosine-5'-Triphosphate are used as supplementary therapy, and may have a better prognosis. In conclusion, the study has identified novel molecules that are carcinogenic to hepatitis viruses and are expected to serve as molecular markers and targets for diagnosis and treatment.
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Affiliation(s)
- Yong-Zheng Zhang
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi, China
| | - Amir Zeb
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi, China
| | - Lu-Feng Cheng
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi, China
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33
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Baghaei K, Mazhari S, Tokhanbigli S, Parsamanesh G, Alavifard H, Schaafsma D, Ghavami S. Therapeutic potential of targeting regulatory mechanisms of hepatic stellate cell activation in liver fibrosis. Drug Discov Today 2021; 27:1044-1061. [PMID: 34952225 DOI: 10.1016/j.drudis.2021.12.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/11/2021] [Accepted: 12/17/2021] [Indexed: 11/03/2022]
Abstract
Hepatic fibrosis is a manifestation of different etiologies of liver disease with the involvement of multiple mediators in complex network interactions. Activated hepatic stellate cells (aHSCs) are the central driver of hepatic fibrosis, given their potential to induce connective tissue formation and extracellular matrix (ECM) protein accumulation. Therefore, identifying the cellular and molecular pathways involved in the activation of HSCs is crucial in gaining mechanistic and therapeutic perspectives to more effectively target the disease. In addition to a comprehensive summary of our current understanding of the role of HSCs in liver fibrosis, we also discuss here the proposed therapeutic strategies based on targeting HSCs.
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Affiliation(s)
- Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Sogol Mazhari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Samaneh Tokhanbigli
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Gilda Parsamanesh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Helia Alavifard
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | | | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
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34
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Lu ZN, Shan Q, Hu SJ, Zhao Y, Zhang GN, Zhu M, Yu DK, Wang JX, He HW. Discovery of 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents via repressing PI3K/AKT/Smad and JAK2/STAT3 pathways. Bioorg Med Chem 2021; 49:116438. [PMID: 34610571 DOI: 10.1016/j.bmc.2021.116438] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/09/2021] [Accepted: 09/18/2021] [Indexed: 11/19/2022]
Abstract
Liver fibrosis is one of the most common pathological consequences of chronic liver diseases (CLD). To develop effective antifibrotic strategies, a novel class of 1-(substituted phenyl)-1,8-naphthalidine-3-carboxamide derivatives were designed and synthesized. By means of the collagen type I α 1 (COL1A1)-based screening and cytotoxicity assay in human hepatic stellate cell (HSC) line LX-2, seven compounds were screened out from total 60 derivatives with high inhibitory effect and relatively low cytotoxicity for further COL1A1 mRNA expression analysis. It was found that compound 17f and 19g dose-dependently inhibited the expression of fibrogenic markers, including α-smooth muscle actin (α-SMA), matrix metalloprotein 2 (MMP-2), connective tissue growth factor (CTGF) and transforming growth factor β1 (TGFβ1) on both mRNA and protein levels. Further mechanism studies indicated that they might suppress the hepatic fibrogenesis via inhibiting both PI3K/AKT/Smad and non-Smad JAK2/STAT3 signaling pathways. Furthermore, 19g administration attenuated hepatic histopathological injury and collagen accumulation, and reduced fibrogenesis-associated protein expression in liver tissues of bile duct ligation (BDL) rats, showing significant antifibrotic effect in vivo. These findings identified 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents, and provided valuable information for further structure optimization.
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Affiliation(s)
- Zhen-Ning Lu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Qi Shan
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Shang-Jiu Hu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Yue Zhao
- Beijing Changping Technology Innodevelop Group, Beijing 102200, China
| | - Guo-Ning Zhang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Mei Zhu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Dong-Ke Yu
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Ju-Xian Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
| | - Hong-Wei He
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
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35
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Hoffman KA, Villar MJ, Poveda C, Bottazzi ME, Hotez PJ, Tweardy DJ, Jones KM. Signal Transducer and Activator of Transcription-3 Modulation of Cardiac Pathology in Chronic Chagasic Cardiomyopathy. Front Cell Infect Microbiol 2021; 11:708325. [PMID: 34504808 PMCID: PMC8421853 DOI: 10.3389/fcimb.2021.708325] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/23/2021] [Indexed: 01/31/2023] Open
Abstract
Chronic Chagasic cardiomyopathy (CCC) is a severe clinical manifestation that develops in 30%–40% of individuals chronically infected with the protozoal parasite Trypanosoma cruzi and is thus an important public health problem. Parasite persistence during chronic infection drives pathologic changes in the heart, including myocardial inflammation and progressive fibrosis, that contribute to clinical disease. Clinical manifestations of CCC span a range of symptoms, including cardiac arrhythmias, thromboembolic disease, dilated cardiomyopathy, and heart failure. This study aimed to investigate the role of signal transducer and activator of transcription-3 (STAT3) in cardiac pathology in a mouse model of CCC. STAT3 is a known cellular mediator of collagen deposition and fibrosis. Mice were infected with T. cruzi and then treated daily from 70 to 91 days post infection (DPI) with TTI-101, a small molecule inhibitor of STAT3; benznidazole; a combination of benznidazole and TTI-101; or vehicle alone. Cardiac function was evaluated at the beginning and end of treatment by echocardiography. By the end of treatment, STAT3 inhibition with TTI-101 eliminated cardiac fibrosis and fibrosis biomarkers but increased cardiac inflammation; serum levels of interleukin-6 (IL-6), and IFN−γ; cardiac gene expression of STAT1 and nuclear factor-κB (NF-κB); and upregulation of IL-6 and Type I and Type II IFN responses. Concurrently, decreased heart function was measured by echocardiography and myocardial strain. These results indicate that STAT3 plays a critical role in the cardiac inflammatory–fibrotic axis during CCC.
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Affiliation(s)
- Kristyn A Hoffman
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States.,Department of Pediatrics, Section of Tropical Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Maria Jose Villar
- Department of Pediatrics, Section of Tropical Medicine, Baylor College of Medicine, Houston, TX, United States.,Texas Children's Hospital Center for Vaccine Development, Houston, TX, United States
| | - Cristina Poveda
- Department of Pediatrics, Section of Tropical Medicine, Baylor College of Medicine, Houston, TX, United States.,Texas Children's Hospital Center for Vaccine Development, Houston, TX, United States
| | - Maria Elena Bottazzi
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States.,Department of Pediatrics, Section of Tropical Medicine, Baylor College of Medicine, Houston, TX, United States.,Texas Children's Hospital Center for Vaccine Development, Houston, TX, United States.,Department of Biology, Baylor University, Waco, TX, United States
| | - Peter J Hotez
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States.,Department of Pediatrics, Section of Tropical Medicine, Baylor College of Medicine, Houston, TX, United States.,Texas Children's Hospital Center for Vaccine Development, Houston, TX, United States.,Department of Biology, Baylor University, Waco, TX, United States
| | - David J Tweardy
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine and Department of Molecular & Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Kathryn M Jones
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States.,Department of Pediatrics, Section of Tropical Medicine, Baylor College of Medicine, Houston, TX, United States.,Texas Children's Hospital Center for Vaccine Development, Houston, TX, United States
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Perilipin 5 Ameliorates Hepatic Stellate Cell Activation via SMAD2/3 and SNAIL Signaling Pathways and Suppresses STAT3 Activation. Cells 2021; 10:cells10092184. [PMID: 34571833 PMCID: PMC8467115 DOI: 10.3390/cells10092184] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/18/2021] [Accepted: 08/21/2021] [Indexed: 12/12/2022] Open
Abstract
Comprehending the molecular mechanisms underlying hepatic fibrogenesis is essential to the development of treatment. The hallmark of hepatic fibrosis is the development and deposition of excess fibrous connective tissue forcing tissue remodeling. Hepatic stellate cells (HSC) play a major role in the pathogenesis of liver fibrosis. Their activation via the transforming growth factor-β1 (TGF-β1) as a key mediator is considered the crucial event in the pathophysiology of hepatic fibrogenesis. It has been shown that Perilipin 5 (PLIN5), known as a lipid droplet structural protein that is highly expressed in oxidative tissue, can inhibit such activation through various mechanisms associated with lipid metabolism. This study aimed to investigate the possible influence of PLIN5 on TGF-β1 signaling. Our findings confirm the importance of PLIN5 in maintaining HSC quiescence in vivo and in vitro. PLIN5 overexpression suppresses the TGF-β1-SMAD2/3 and SNAIL signaling pathways as well as the activation of the signal transducers and activators of transcription 3 (STAT3). These findings derived from experiments in hepatic cell lines LX-2 and Col-GFP, in which overexpression of PLIN5 was able to downregulate the signaling pathways SMAD2/3 and SNAIL activated previously by TGF-β1 treatment. Furthermore, TGF-β1-mediatedinduction of extracellular matrix proteins, such as collagen type I (COL1), Fibronectin, and α-smooth muscle actin (α-SMA), was suppressed by PLIN5. Moreover, STAT3, which is interrelated with TGF-β1 was already basally activated in the cell lines and inhibited by PLIN5 overexpression, leading to a further reduction in HSC activity shown by lowered α-SMA expression. This extension of the intervening mechanisms presents PLIN5 as a potent and pleiotropic target in HSC activation.
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37
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Aashaq S, Batool A, Mir SA, Beigh MA, Andrabi KI, Shah ZA. TGF-β signaling: A recap of SMAD-independent and SMAD-dependent pathways. J Cell Physiol 2021; 237:59-85. [PMID: 34286853 DOI: 10.1002/jcp.30529] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 06/06/2021] [Accepted: 07/06/2021] [Indexed: 12/20/2022]
Abstract
Transforming growth factor-β (TGF-β) is a proinflammatory cytokine known to control a diverse array of pathological and physiological conditions during normal development and tumorigenesis. TGF-β-mediated physiological effects are heterogeneous and vary among different types of cells and environmental conditions. TGF-β serves as an antiproliferative agent and inhibits tumor development during primary stages of tumor progression; however, during the later stages, it encourages tumor development and mediates metastatic progression and chemoresistance. The fundamental elements of TGF-β signaling have been divulged more than a decade ago; however, the process by which the signals are relayed from cell surface to nucleus is very complex with additional layers added in tumor cell niches. Although the intricate understanding of TGF-β-mediated signaling pathways and their regulation are still evolving, we tried to make an attempt to summarize the TGF-β-mediated SMAD-dependent andSMAD-independent pathways. This manuscript emphasizes the functions of TGF-β as a metastatic promoter and tumor suppressor during the later and initial phases of tumor progression respectively.
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Affiliation(s)
- Sabreena Aashaq
- Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, JK, India
| | - Asiya Batool
- Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, Srinagar, JK, India
| | | | | | | | - Zaffar Amin Shah
- Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, JK, India
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The TGF-β Pathway: A Pharmacological Target in Hepatocellular Carcinoma? Cancers (Basel) 2021; 13:cancers13133248. [PMID: 34209646 PMCID: PMC8268320 DOI: 10.3390/cancers13133248] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 02/07/2023] Open
Abstract
Transforming Growth Factor-beta (TGF-β) superfamily members are essential for tissue homeostasis and consequently, dysregulation of their signaling pathways contributes to the development of human diseases. In the liver, TGF-β signaling participates in all the stages of disease progression from initial liver injury to hepatocellular carcinoma (HCC). During liver carcinogenesis, TGF-β plays a dual role on the malignant cell, behaving as a suppressor factor at early stages, but contributing to later tumor progression once cells escape from its cytostatic effects. Moreover, TGF-β can modulate the response of the cells forming the tumor microenvironment that may also contribute to HCC progression, and drive immune evasion of cancer cells. Thus, targeting the TGF-β pathway may constitute an effective therapeutic option for HCC treatment. However, it is crucial to identify biomarkers that allow to predict the response of the tumors and appropriately select the patients that could benefit from TGF-β inhibitory therapies. Here we review the functions of TGF-β on HCC malignant and tumor microenvironment cells, and the current strategies targeting TGF-β signaling for cancer therapy. We also summarize the clinical impact of TGF-β inhibitors in HCC patients and provide a perspective on its future use alone or in combinatorial strategies for HCC treatment.
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39
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Integrin αVβ1 regulates procollagen I production through a non-canonical transforming growth factor β signaling pathway in human hepatic stellate cells. Biochem J 2021; 478:1689-1703. [PMID: 33876829 DOI: 10.1042/bcj20200749] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 04/14/2021] [Accepted: 04/19/2021] [Indexed: 11/17/2022]
Abstract
Hepatic stellate cells (HSCs) are thought to play key roles in the development of liver fibrosis. Extensive evidence has established the concept that αV integrins are involved in the activation of latent transforming growth factor β (TGF-β), a master regulator of the fibrotic signaling cascade. Based on mRNA and protein expression profiling data, we found that αVβ1 integrin is the most abundant member of the αV integrin family in either quiescent or TGF-β1-activated primary human HSCs. Unexpectedly, either a selective αVβ1 inhibitor, Compound 8 (C8), or a pan-αV integrin inhibitor, GSK3008348, decreased TGF-β1-activated procollagen I production in primary human HSCs, in which the role of β1 integrin was confirmed by ITGB1 siRNA. In contrast with an Activin receptor-like kinase 5 (Alk5) inhibitor, C8 and GSK3008348 failed to inhibit TGF-β1 induced SMAD3 and SMAD2 phosphorylation, but inhibited TGF-β-induced phosphorylation of ERK1/2 and STAT3, suggesting that αVβ1 integrin is involved in non-canonical TGF-β signaling pathways. Consistently, ITGB1 siRNA significantly decreased phosphorylation of ERK1/2. Furthermore, a selective inhibitor of MEK1/2 blocked TGF-β1 induced phosphorylation of ERK1/2 and decreased TGF-β1 induced procollagen I production, while a specific inhibitor of STAT3 had no effect on TGF-β1 induced procollagen I production. Taken together, current data indicate that αVβ1 integrin can regulate TGF-β signaling independent of its reported role in activating latent TGF-β. Our data further support that αVβ1 inhibition is a promising therapeutic target for the treatment of liver fibrosis.
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Yang H, Tan S, Chen S, Wu Y, Yang Y, Li H, Yu H. Effects of fermented Yupingfeng on intramuscular fatty acids and ruminal microbiota in Qingyuan black goats. Anim Sci J 2021; 92:e13554. [PMID: 33938087 DOI: 10.1111/asj.13554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 03/05/2021] [Accepted: 03/15/2021] [Indexed: 11/29/2022]
Abstract
Our previous work has demonstrated that Yupingfeng, a Chinese herb medicine, considered as prebiotic showed beneficial properties in poultry health and disease prevention and regulated intestinal microbiota. The effects of Yupingfeng on fatty acids related to meat flavor and ruminal microbiota are not yet known in Qingyuan black goat. In this study, we supplemented fermented (FYP) and unfermented (UYP) Yupingfeng in different combinations to 90 goats. Compared with the normal control group, FYP and UYP significantly increased the concentration of palmitic acid, octadecanoic acid, and arachidonate acid (related to meat flavor) in the longissimus dorsi muscle (p < .05). In addition, the significant upregulation of peroxisome proliferator-activated receptor gamma (PPARγ) and fatty acid translocase (CD36) was observed in the FYP and UYP groups (p < .05). In addition, Firmicutes and Bacteroidetes were the most abundance in goat rumen. At the genus level, FYP and UYP significantly increased Ruminococcus related to fiber degradation, and Alistipes related to short-chain fatty acids production. In summary, Yupingfeng could improve fatty acids of goat meat, which is probably triggered by the increase of PPARγ and CD36, and microbial activity. Besides, FYP showed more beneficial effects than UYP, with increased flavor fatty acids and beneficial microbes.
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Affiliation(s)
- Hong Yang
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Foshan University, Foshan, China
| | - Shuwen Tan
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Foshan University, Foshan, China
| | - Siyu Chen
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Foshan University, Foshan, China
| | - Yongliang Wu
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Foshan University, Foshan, China
| | - Ying Yang
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Foshan University, Foshan, China
| | - Hua Li
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Foshan University, Foshan, China
| | - Hui Yu
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Foshan University, Foshan, China
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Zhuang H, Zheng NX, Lin L, Zhang WZ, Zhang WY, Yu QQ, Xu W. Fluorofenidone inhibits epithelial-mesenchymal transition in human lens epithelial cell line FHL 124: a promising therapeutic strategy against posterior capsular opacification. Arq Bras Oftalmol 2021; 84:258-266. [PMID: 33567029 PMCID: PMC11826781 DOI: 10.5935/0004-2749.20210040] [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: 01/29/2020] [Accepted: 04/16/2020] [Indexed: 11/20/2022] Open
Abstract
PURPOSE The present study aimed to investigate the inhibitory effect of fluorofenidone against transforming growth factor β2-induced proliferation and epithelial-mesenchymal transition in human lens epithelial cell line FHL 124 and its potential mechanism. METHODS We evaluated the effect of fluorofenidone on proliferation and epithelial-mesenchymal transition of human lens epithelial cell line FHL 124 in vitro. After treatment with 0, 0.1, 0.2, 0.4, 0.6, and 1.0 mg/mL fluorofenidone, cell proliferation was measured via MTT assay. Cell viability was evaluated by lactate dehydrogenase activity from damaged cells. FHL 124 cells were treated with different transforming growth factor β2 concentrations (0-10 ng/mL) for 24 h and the expression of CTGF, α-SMA, COL-I, E-cadherin, and Fn were detected via quantitative polymerase chain reaction and Western blot analysis. After treatment with 0, 0.2, and 0.4 mg/ml fluorofenidone, the expressions of transforming growth factor β2 and SMADs were detected with real-time polymerase chain reaction and Western blot analysis. Expressions of CTGF, α-SMA, COL-I, and Fn were analyzed by immunocytochemistry assay. RESULTS The viability of FHL 124 cells was not inhibited when the fluorofenidone concentration was ≤0.4 mg/mL after the 24h treatment. Cytotoxicity was not detected via lactate dehydrogenase assay after the 24h and 36h treatment with 0.2 and 0.4 mg/mL fluorofenidone. Transforming growth factor β2 increased mRNA and protein expression of CTGF, α-SMA, COL-I, and Fn. However, fluorofenidone significantly suppressed expression of SMADs, CTGF, α-SMA, COL-I, and Fn in the absence or presence of transforming growth factor β2 stimulation. CONCLUSIONS Fluorofenidone significantly inhibited expression of SMADs, CTGF, α-SMA, COL-I, and Fn in FHL 124 cells. Due to noncompliance in infants, fluorofenidone may become a novel therapeutic drug against posterior capsular opacification in infants.
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Affiliation(s)
- Hua Zhuang
- Fuzhou Aier eye Hospital, Fuzhou, China
- Aier School of Ophthalmology, Central South University, Changsha,
Hunan Province, China
| | - Ning-Xuan Zheng
- Fujian Center for Disease Control and Prevention, Fu Zhou, Fujian
Province, China
| | - Lin Lin
- Women and Children’s Hospital Affiliated to Xiamen University,
Xiamen, Fujian Province, China
| | - Wu-Zhen Zhang
- Xianyou maternal and Child Health Hospital, Putian, 351200, Fujian
Province, China
| | - Wan-Yu Zhang
- Fujian Children’s Hospital, Fu Zhou, Fujian Province, China
| | - Qin-Qi Yu
- Yongzhou First People’s Hospital, Hunan Province, China
| | - Wei Xu
- The 1st affiliated hospital of Fujian Medical University, Fu Zhou,
Fujian Province, China
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Wilson SE. TGF beta -1, -2 and -3 in the modulation of fibrosis in the cornea and other organs. Exp Eye Res 2021; 207:108594. [PMID: 33894227 DOI: 10.1016/j.exer.2021.108594] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/10/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023]
Abstract
The TGF beta-1, -2 and -3 isoforms are transcribed from different genes but bind to the same receptors and signal through the same canonical and non-canonical signal transduction pathways. There are numerous regulatory mechanisms controlling the action of each isoform that include the organ-specific cells producing latent TGF beta growth factors, multiple effectors that activate the isoforms, ECM-associated SLRPs and basement membrane components that modulate the activity and localization of the isoforms, other interactive cytokine-growth factor receptor systems, such as PDGF and CTGF, TGF beta receptor expression on target cells, including myofibroblast precursors, receptor binding competition, positive and negative signal transduction effectors, and transcription and translational regulatory mechanisms. While there has long been the view that TGF beta-1and TGF beta-2 are pro-fibrotic, while TGF beta-3 is anti-fibrotic, this review suggests that view is too simplistic, at least in adult tissues, since TGF beta-3 shares far more similarities in its modulation of fibrotic gene expression with TGF beta-1 and TGF beta-2, than it does differences, and often the differences are subtle. Rather, TGF beta-3 should be seen as a fibro-modulatory partner to the other two isoforms that modulates a nuanced and better controlled response to injury. The complex interplay between the three isoforms and numerous interactive proteins, in the context of the cellular milieu, controls regenerative non-fibrotic vs. fibrotic healing in a response to injury in a particular organ, as well as the resolution of fibrosis, when that occurs.
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Affiliation(s)
- Steven E Wilson
- The Cole Eye Institute, The Cleveland Clinic, Cleveland, OH, USA.
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Park YJ, Jeon MS, Lee S, Kim JK, Jang TS, Chung KH, Kim KH. Anti-fibrotic effects of brevilin A in hepatic fibrosis via inhibiting the STAT3 signaling pathway. Bioorg Med Chem Lett 2021; 41:127989. [PMID: 33794317 DOI: 10.1016/j.bmcl.2021.127989] [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] [Received: 12/15/2020] [Revised: 03/14/2021] [Accepted: 03/20/2021] [Indexed: 12/15/2022]
Abstract
Hepatic fibrosis is a chronic liver disease characterized by the accumulation of extracellular matrix (ECM). Activation of hepatic stellate cells (HSCs) after repetitive liver damage is a key event in hepatic fibrogenesis. As part of ongoing research projects to identify pharmacologically effective natural products, the phytochemical investigation of a MeOH extract of Centipeda minima led to the isolation of a sesquiterpene lactone, brevilin A, which was explored to elucidate potential anti-fibrotic effects by reversing HSC activation. First, we observed that transforming growth factor (TGF)-β1 treatment significantly increased the expression levels of HSC activation marker, α-smooth muscle actin (α-SMA), and ECM protein such as collagen and fibronectin. Then, we demonstrated that brevilin A reversed the TGF-β1-induced increase in protein and mRNA expression levels of α-SMA and collagen. To investigate the underlying molecular mechanism of brevilin A, we evaluated the effects of brevilin A on the STAT3 signaling pathway. STAT3 phosphorylation, increased by TGF-β1 treatment, was strongly inhibited by brevilin A; the expression levels of fibronectin and connective tissue growth factor were also significantly decreased by brevilin A. The present study indicated that brevilin A has a preventive and therapeutic potential against hepatic fibrosis.
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Affiliation(s)
- Yong Joo Park
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea; College of Pharmacy, Kyungsung University, Busan 48434, Republic of Korea
| | - Mi Seon Jeon
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Seulah Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea; Division of Life Sciences, Korea Polar Research Institute, KIOST, Incheon 21990, Republic of Korea
| | - Jung Kyu Kim
- School of Chemical Engineering, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Tae Su Jang
- Department of Medicine, Dankook University, Cheonan, Chungnam 31116, Republic of Korea
| | - Kyu Hyuck Chung
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Ki Hyun Kim
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
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Sisto M, Ribatti D, Lisi S. Organ Fibrosis and Autoimmunity: The Role of Inflammation in TGFβ-Dependent EMT. Biomolecules 2021; 11:biom11020310. [PMID: 33670735 PMCID: PMC7922523 DOI: 10.3390/biom11020310] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/09/2021] [Accepted: 02/16/2021] [Indexed: 02/07/2023] Open
Abstract
Recent advances in our understanding of the molecular pathways that control the link of inflammation with organ fibrosis and autoimmune diseases point to the epithelial to mesenchymal transition (EMT) as the common association in the progression of these diseases characterized by an intense inflammatory response. EMT, a process in which epithelial cells are gradually transformed to mesenchymal cells, is a major contributor to the pathogenesis of fibrosis. Importantly, the chronic inflammatory microenvironment has emerged as a decisive factor in the induction of pathological EMT. Transforming growth factor-β (TGF-β), a multifunctional cytokine, plays a crucial role in the induction of fibrosis, often associated with chronic phases of inflammatory diseases, contributing to marked fibrotic changes that severely impair normal tissue architecture and function. The understanding of molecular mechanisms underlying EMT-dependent fibrosis has both a basic and a translational relevance, since it may be useful to design therapies aimed at counteracting organ deterioration and failure. To this end, we reviewed the recent literature to better elucidate the molecular response to inflammatory/fibrogenic signals in autoimmune diseases in order to further the specific regulation of EMT-dependent fibrosis in more targeted therapies.
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Park E, Lee SJ, Moon H, Park J, Jeon H, Hwang JS, Hwang H, Hong KB, Han SH, Choi S, Kang S. Discovery and Biological Evaluation of N-Methyl-pyrrolo[2,3- b]pyridine-5-carboxamide Derivatives as JAK1-Selective Inhibitors. J Med Chem 2021; 64:958-979. [PMID: 33428419 DOI: 10.1021/acs.jmedchem.0c01026] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Janus kinase 1 (JAK1) plays a key role in most cytokine-mediated inflammatory and autoimmune responses through JAK/STAT signaling; thus, JAK1 inhibition is a promising therapeutic strategy for several diseases. Analysis of the binding modes of current JAK inhibitors to JAK isoforms allowed the design of N-alkyl-substituted 1-H-pyrrolo[2,3-b] pyridine carboxamide as a JAK1-selective scaffold, and the synthesis of various methyl amide derivatives provided 4-((cis-1-(4-chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31g) as a potent JAK1-selective inhibitor. In particular, the (S,S)-enantiomer of 31g (38a) exhibited excellent potency for JAK1 and selectivity over JAK2, JAK3, and TYK2. On investigating the effect of 31g on hepatic fibrosis, it was found that it reduces the proliferation and fibrogenic gene expression of TGF-β-induced hepatic stellate cells (HSCs). Specifically, 31g significantly inhibited TGF-β-induced migration of HSCs at 0.25 μM in wound-healing assays.
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Affiliation(s)
- Eunsun Park
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Sun Joo Lee
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea
| | - Heegyum Moon
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea
| | - Jongmi Park
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Hyeonho Jeon
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea
| | - Ji Sun Hwang
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea
| | - Hayoung Hwang
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea
| | - Ki Bum Hong
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea
| | - Seung-Hee Han
- Central Research Laboratory, KOREA PHARMA Co. Ltd, jeyakgongdan 3-gil, Hyangnam-eup, Hwaseong-si, Gyeonggi-do 18622, Republic of Korea
| | - Sun Choi
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Soosung Kang
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
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Han M, Liao Z, Liu F, Chen X, Zhang B. Modulation of the TGF-β signaling pathway by long noncoding RNA in hepatocellular carcinoma. Biomark Res 2020; 8:70. [PMID: 33292618 PMCID: PMC7709261 DOI: 10.1186/s40364-020-00252-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 11/24/2020] [Indexed: 12/21/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of liver cancer with poor prognosis. There have been demonstrated to exist many possible mechanisms in HCC tumorigenesis, and recent investigations have provided some promising therapy targets. However, further mechanisms remain to be researched to improve the therapeutic strategy and diagnosis of HCC. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine which plays critical roles in networks of different cellular processes, and TGF-β signaling has been found to participate in tumor initiation and development of HCC in recent years. Moreover, among the molecules and signaling pathways, researchers paid more attention to lncRNAs (long non-coding RNAs), but the connection between lncRNAs and TGF-βremain poorly understood. In this review, we conclude the malignant procedure which lncRNAs and TGF-β involved in, and summarize the mechanisms of lncRNAs and TGF-βin HCC initiation and development. Furthermore, the interaction between lncRNA and TGF-β are paid more attention, and the potential therapy targets are mentioned.
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Affiliation(s)
- Mengzhen Han
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China
| | - Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China
| | - Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China. .,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China.
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China. .,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China.
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Hepatoprotective Potency of Chrysophanol 8- O-Glucoside from Rheum palmatum L. against Hepatic Fibrosis via Regulation of the STAT3 Signaling Pathway. Int J Mol Sci 2020; 21:ijms21239044. [PMID: 33261209 PMCID: PMC7730872 DOI: 10.3390/ijms21239044] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/25/2020] [Accepted: 11/25/2020] [Indexed: 02/07/2023] Open
Abstract
Rhubarb is a well-known herb worldwide and includes approximately 60 species of the Rheum genus. One of the representative plants is Rheum palmatum, which is prescribed as official rhubarb due to its pharmacological potential in the Korean and Chinese pharmacopoeia. In our bioactive screening, we found out that the EtOH extract of R. palmatum inhibited hepatic stellate cell (HSC) activation by transforming growth factor β1 (TGF-β1). Chemical investigation of the EtOH extract led to the isolation of chrysophanol 8-O-glucoside, which was determined by structural analysis using NMR spectroscopic techniques and electrospray ionization mass spectrometry (ESIMS). To elucidate the effects of chrysophanol 8-O-glucoside on HSC activation, activated LX-2 cells were treated for 48 h with chrysophanol 8-O-glucoside, and α-SMA and collagen, HSC activation markers, were measured by comparative quantitative real-time PCR (qPCR) and western blotting analysis. Chrysophanol 8-O-glucoside significantly inhibited the protein and mRNA expression of α-SMA and collagen compared with that in TGF-β1-treated LX-2 cells. Next, the expression of phosphorylated SMAD2 (p-SMAD2) and p-STAT3 was measured and the translocation of p-STAT3 to the nucleus was analyzed by western blotting analysis. The expression of p-SMAD2 and p-STAT3 showed that chrysophanol 8-O-glucoside strongly downregulated STAT3 phosphorylation by inhibiting the nuclear translocation of p-STAT3, which is an important mechanism in HSC activation. Moreover, chrysophanol 8-O-glucoside suppressed the expression of p-p38, not that of p-JNK or p-Erk, which can activate STAT3 phosphorylation and inhibit MMP2 expression, the downstream target of STAT3 signaling. These findings provided experimental evidence concerning the hepatoprotective effects of chrysophanol 8-O-glucoside against liver damage and revealed the molecular basis underlying its anti-fibrotic effects through the blocking of HSC activation.
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Chen Q, Jiang N, Zhang Y, Ye S, Liang X, Wang X, Lin X, Zong R, Chen H, Liu Z. Fenofibrate Inhibits Subretinal Fibrosis Through Suppressing TGF-β-Smad2/3 signaling and Wnt signaling in Neovascular Age-Related Macular Degeneration. Front Pharmacol 2020; 11:580884. [PMID: 33442383 PMCID: PMC7797782 DOI: 10.3389/fphar.2020.580884] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 10/13/2020] [Indexed: 12/29/2022] Open
Abstract
Subretinal fibrosis is a common pathological change that causes vision loss in neovascular age-related macular degeneration (nAMD). Treatment modalities for subretinal fibrosis are limited. In the present study, the effects of fenofibrate, a specific peroxisome proliferator-activated receptor alpha agonist, on subretinal fibrosis of nAMD were tested, and its molecular mechanisms of action were delineated. Collagen deposition and protein expression of fibrotic markers, such as vimentin, collagen-1, alpha-smooth muscle actin, and fibronectin, were increased in very low-density lipoprotein receptor (VLDLR) knockout mouse, indicating Vldlr -/- mice can be used as a model for subretinal fibrosis. Fenofibrate suppressed subretinal fibrosis of Vldlr -/- mice by reducing collagen deposition and protein expression of fibrotic markers. Two fibrotic pathways, TGF-β-Smad2/3 signaling and Wnt signaling, were significantly up-regulated, while inhibited by fenofibrate in Vldlr -/- retinas. Moreover, fenofibrate significantly reduced the downstream connective tissue growth factor (CTGF) expression of these two pathways. Müller cells were a major source of CTGF in Vldlr -/- retinas. Fenofibrate was capable of suppressing Müller cell activation and thus reducing the release of CTGF in Vldlr -/- retinas. In cultured Müller cells, fenofibrate reversed TGF-β2-induced up-regulation of Wnt signaling and CTGF expression. These findings suggested that fenofibrate inhibits subretinal fibrosis by suppressing TGF-β-Smad2/3 signaling and Wnt signaling and reducing CTGF expression, and thus, fenofibrate could be a potential treatment for nAMD with subretinal fibrosis.
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Affiliation(s)
- Qian Chen
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.,Xiamen University affiliated Xiamen Eye Center, Xiamen, China
| | - Nan Jiang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Yuhan Zhang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Sihao Ye
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xu Liang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xin Wang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xiang Lin
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Rongrong Zong
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Haoyu Chen
- Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, China
| | - Zuguo Liu
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.,Xiamen University affiliated Xiamen Eye Center, Xiamen, China
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Endoglin Promotes Myofibroblast Differentiation and Extracellular Matrix Production in Diabetic Nephropathy. Int J Mol Sci 2020; 21:ijms21207713. [PMID: 33081058 PMCID: PMC7589772 DOI: 10.3390/ijms21207713] [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: 08/21/2020] [Revised: 10/07/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023] Open
Abstract
Diabetic nephropathy (DN) is a complication of diabetes mellitus that can lead to proteinuria and a progressive decline in renal function. Endoglin, a co-receptor of TGF-β, is known primarily for regulating endothelial cell function; however, endoglin is also associated with hepatic, cardiac, and intestinal fibrosis. This study investigates whether endoglin contributes to the development of interstitial fibrosis in DN. Kidney autopsy material from 80 diabetic patients was stained for endoglin and Sirius Red and scored semi-quantitatively. Interstitial endoglin expression was increased in samples with DN and was correlated with Sirius Red staining (p < 0.001). Endoglin expression was also correlated with reduced eGFR (p = 0.001), increased creatinine (p < 0.01), increased systolic blood pressure (p < 0.05), hypertension (p < 0.05), and higher IFTA scores (p < 0.001). Biopsy samples from DN patients were also co-immunostained for endoglin together with CD31, CD68, vimentin, or α-SMA Endoglin co-localized with both the endothelial marker CD31 and the myofibroblast marker α-SMA. Finally, we used shRNA to knockdown endoglin expression in a human kidney fibroblast cell line. We found that TGF-β1 stimulation upregulated SERPINE1, CTGF, and ACTA2 mRNA and α-SMA protein, and that these effects were significantly reduced in fibroblasts after endoglin knockdown. Taken together, these data suggest that endoglin plays a role in the pathogenesis of interstitial fibrosis in DN.
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Lv L, Liu FR, Na D, Xu HM, Wang ZN, Jiang CG. Transforming growth factor-β1 induces connective tissue growth factor expression and promotes peritoneal metastasis of gastric cancer. Biosci Rep 2020; 40:BSR20201501. [PMID: 32885819 PMCID: PMC7502695 DOI: 10.1042/bsr20201501] [Citation(s) in RCA: 7] [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: 05/04/2020] [Revised: 08/26/2020] [Accepted: 09/02/2020] [Indexed: 12/14/2022] Open
Abstract
Transforming growth factor-β1 (TGF-β1) is involved in human cancer development and progression. Nonetheless, the role of TGF-β1 as regards peritoneal metastasis of gastric cancer has not been completely characterized. In the present study, we investigated the exact role of TGF-β1 on peritoneal metastasis of gastric cancer. The results indicated that human peritoneal mesothelial cells (HPMCs) exposed to TGF-β1 or serum-free conditional medium (SF-CM) of SGC7901 that produced a large amount of TGF-β1 became exfoliated, apoptosis and exhibited signs of injury, and the tumor-mesothelial cell adhesion significantly increased. Connective tissue growth factor (CTGF) expression was also increased when HPMCs were exposed to TGF-β1 or SF-CM of SGC7901. However, these effects were significantly decreased when HPMCs were exposed to SF-CM of SGC7901-TGFβS, a TGF-β1 knockdown stable cell line. Animal studies revealed that nude mice injected with SGC7901-TGFβS cells featured a smaller number of peritoneal seeding nodules and lower expression of CTGF in ascites than the control cell lines. These findings suggest that TGF-β1 promotes peritoneal metastasis of gastric cancer and induces CTGF expression. Therefore, blockage of TGF-β1 or TGF-β1 signaling pathway might prevent and treat peritoneal metastasis of gastric cancer.
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Affiliation(s)
- Ling Lv
- Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Fu-Rong Liu
- Department of Cell Biology, China Medical University, Shenyang, Liaoning Province, China
| | - Di Na
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Hui-Mian Xu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Zhen-Ning Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Cheng-Gang Jiang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
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