|
1
|
Huo P, Li Z, Jin S, Wang S, Luo Y, Zhu L, Jin Z. Mechanism of β‑sitosterol in treating keloids: Network pharmacology, molecular docking and experimental verification. Mol Med Rep 2025; 31:95. [PMID: 39981895 PMCID: PMC11868730 DOI: 10.3892/mmr.2025.13460] [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: 10/03/2024] [Accepted: 01/16/2025] [Indexed: 02/22/2025] Open
Abstract
β‑sitosterol (SIT) has anti‑inflammatory, anti‑tumor and anti‑fibrotic effects. However, the precise mechanisms underlying its efficacy in keloid treatment remain elusive. The present study aimed to elucidate the therapeutic effect of SIT on keloids. The active components of Fructus arctii, target molecules of these components and disease‑associated target molecules were identified and retrieved from various databases. Molecular docking was employed to evaluate the binding affinity of the active compounds for key targets. Cell viability and proliferation were evaluated via CCK‑8 and EdU assays, while cell migration capacity was assessed via wound healing assays and cell migration and invasion abilities were determined via Transwell assays. A rescue study involving YS‑49 was conducted. Western blot analysis was performed to assess the expression levels of proteins associated with EMT and proteins involved in the PI3K/AKT signaling pathway. A subcutaneous keloid fibroproliferative model was established in nude mice and immunohistochemical staining was performed on tissue sections. By intersecting the keloid targets, 29 targets were identified, with 10 core targets revealed by protein-protein interaction analysis. Molecular docking revealed a robust binding affinity between SIT and PTEN. In addition to inhibiting cell viability, invasion and migration, SIT significantly decreased the levels of phosphorylated (p‑)PI3K and p‑AKT, downregulated the protein expression of Vimentin and Snail proteins and increased the protein expression of Zonula Occludens‑1 and E‑cadherin. YS‑49 reversed the inhibitory effect of SIT on keloid in SIT‑treated cells. In vivo experiments demonstrated that SIT suppressed the growth of a keloid model in nude mice and increased PTEN expression. The present study provided the first evidence that SIT inhibits keloid proliferation, migration and invasion by modulating the PTEN/PI3K/AKT signaling pathway, suggesting its potential as a novel therapeutic approach for keloid treatment.
Collapse
Affiliation(s)
- Pingping Huo
- Keloid Research Center, Department of Dermatology, Yanbian University Hospital, Yanji, Jilin 133000, P.R. China
- Department of Medicine, Yanbian University Medical College, Yanji, Jilin 133000, P.R. China
- Department of Medical Cosmetology, Yanbian University Hospital, Yanji, Jilin 133000, P.R. China
| | - Zhouna Li
- Department of Medical Cosmetology, Yanbian University Hospital, Yanji, Jilin 133000, P.R. China
| | - Shan Jin
- Keloid Research Center, Department of Dermatology, Yanbian University Hospital, Yanji, Jilin 133000, P.R. China
| | - Sujie Wang
- Keloid Research Center, Department of Dermatology, Yanbian University Hospital, Yanji, Jilin 133000, P.R. China
- Department of Medicine, Yanbian University Medical College, Yanji, Jilin 133000, P.R. China
| | - Yinli Luo
- Keloid Research Center, Department of Dermatology, Yanbian University Hospital, Yanji, Jilin 133000, P.R. China
- Department of Medicine, Yanbian University Medical College, Yanji, Jilin 133000, P.R. China
| | - Lianhua Zhu
- Department of Medicine, Yanbian University Medical College, Yanji, Jilin 133000, P.R. China
- Department of Dermatology, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong 511518, P.R. China
| | - Zhehu Jin
- Keloid Research Center, Department of Dermatology, Yanbian University Hospital, Yanji, Jilin 133000, P.R. China
- Department of Medicine, Yanbian University Medical College, Yanji, Jilin 133000, P.R. China
- Department of Medical Cosmetology, Yanbian University Hospital, Yanji, Jilin 133000, P.R. China
| |
Collapse
|
|
2
|
Niu B, Zhang L, Chen A. Astragalin inhibits fibroblast proliferation, motion, and ECM synthesis and regulates the MAPK pathway in keloid. Arch Dermatol Res 2025; 317:599. [PMID: 40105997 DOI: 10.1007/s00403-025-04092-3] [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: 01/22/2025] [Revised: 02/14/2025] [Accepted: 02/25/2025] [Indexed: 03/22/2025]
Abstract
Keloid is a fibroproliferative skin disorder characterized by fibroblast hyperproliferation and excessive extracellular matrix (ECM) deposition. Astragalin (AST) is a bioactive natural flavonoid with multiple pharmacological properties. This study aims to investigate the effect of AST on keloid formation in vitro. Primary keloid fibroblasts (KFs) and normal fibroblasts (NFs) were isolated from human keloid tissues and normal skin tissues, respectively, and treated with or without AST. MTT, colony formation, and Transwell assays were utilized to evaluate AST's effect on fibroblast proliferation, migration, and invasiveness. Western blotting was implemented for detecting protein levels of ECM components and mitogen-activated protein kinases (MAPKs). The results showed that AST treatment hindered the proliferative, migratory, and invasive capacities of KFs and NFs, and KFs were more sensitive to AST than NFs. AST restrained ECM deposition and inactivated the MAPK signaling pathway in KFs and NFs. In conclusion, AST suppresses the invasive growth of keloid fibroblasts probably by inactivating MAPK signaling.
Collapse
Affiliation(s)
- Bin Niu
- Department of Dermatology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, No.141 Tianjin Road, Huangshi, 435000, Hubei, China
| | - Liang Zhang
- Department of Dermatology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, No.141 Tianjin Road, Huangshi, 435000, Hubei, China
| | - Anchen Chen
- Department of Dermatology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, No.141 Tianjin Road, Huangshi, 435000, Hubei, China.
| |
Collapse
|
|
3
|
Guo X, Li W, Ma W, Liu Y, Liu Z, Jiao R, Yang Z, Zhang T, Wu H, Ai X, Gu X, Wang W, Zhou H, Li X, Yang C. Daidzein alleviates skin fibrosis by suppressing TGF-β1 signaling pathway via targeting PKM2. Sci Rep 2025; 15:8649. [PMID: 40082519 PMCID: PMC11906606 DOI: 10.1038/s41598-025-93007-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 03/04/2025] [Indexed: 03/16/2025] Open
Abstract
Skin fibrosis including keloids, which are characterized including excessive deposition, abnormal proliferation, aggressiveness, and migration of the extracellular matrix of dermal fibroblasts. TGF-β signaling is a classical pro-fibrotic pathway, and it plays a crucial part in the occurrence and progression of skin fibrosis. Daidzein (Dai), an isoflavone compound, has been proved to possess anti-fibrosis effect by TGF-β signaling in various inflammatory and fibrotic diseases. However, little is known about Dai on skin fibrosis. Therefore, we further explored the potential effects and mechanisms of daidzein on skin fibrosis. As expected, Dai suppressed proliferation, migration and activation mouse primary dermal fibroblasts and keloid fibroblasts. Meanwhile, Dai also ameliorated bleomycin-induced skin fibrosis and reduced fibrotic markers of keloid tissues. In addition, Dai could target PKM2 to inhibit TGF-β1/Smad signaling in skin fibrosis. Overall, our research demonstrated that Dai might become a potential therapeutic candidate drug for skin fibrosis.
Collapse
Affiliation(s)
- Xiaowei Guo
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300353, China
| | - Wenqi Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300353, China
| | - Wei Ma
- Department of Burn and Plastic Surgery, Tianjin Fourth Hospital, Tianjin, 300222, China
| | - Yuming Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300353, China
| | - Zhigang Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300353, China
| | - Ran Jiao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300353, China
| | - Zhongyi Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300353, China
| | - Tiantian Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300353, China
| | - Hongliang Wu
- Department of Anesthesiology, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Nanli, Panjiayuan, Chaoyang District, Beijing, China
| | - Xiaoyu Ai
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300353, China
- Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, 300457, China
| | - Xiaoting Gu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300353, China
- Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, 300457, China
| | - Wendi Wang
- Department of Plastic and Burn Surgery, Tianjin First Central Hospital, No. 24 Kangfu Road, Nankai District, Tianjin, 300192, China
| | - Honggang Zhou
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300353, China.
- Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, 300457, China.
| | - Xiaohe Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300353, China.
- Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, 300457, China.
| | - Cheng Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300353, China.
- Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, 300457, China.
| |
Collapse
|
|
4
|
Zhou H, Yang P, Zhang T, Kepp O, Ren Y, Jiang N, Liu R, Li J, Li C. The role of apoptosis, immunogenic cell death, and macrophage polarization in carbon ion radiotherapy for keloids: Targeting the TGF-β1/SMADs signaling pathway. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167499. [PMID: 39245184 DOI: 10.1016/j.bbadis.2024.167499] [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: 05/04/2024] [Revised: 08/11/2024] [Accepted: 08/23/2024] [Indexed: 09/10/2024]
Abstract
Keloids, characterized by excessive extracellular matrix (ECM) deposition and aberrant fibrous tissue proliferation, present significant therapeutic challenges due to their recalcitrant and recurrent nature. This study explores the efficacy of Carbon Ion Radiotherapy (CIRT) as a novel therapeutic approach for keloids, focusing on its impact on fibroblast proliferation, apoptosis induction, immunogenic cell death (ICD), macrophage polarization, and the TGF-β/SMAD signaling pathway. Utilizing a murine model of keloid formed by subcutaneous injection of zeocin in C57BL/6 mice, we demonstrated that CIRT effectively reduces collagenous fiber synthesis and collagen production in keloid tissues. Further, CIRT was shown to inhibit keloid fibroblast proliferation and to induce apoptosis, as evidenced by increased expression of apoptosis-related proteins and confirmed through flow cytometry and TUNEL assay. Notably, CIRT induced mitochondrial stress, leading to enhanced immunogenicity of cell death, characterized by increased expression of ICD markers and secretion of interferon-γ. Additionally, CIRT promoted a shift from M2 to M1 macrophage polarization, potentially reducing TGF-β release and mitigating ECM deposition. Our findings suggest that CIRT mediates its therapeutic effects through the inhibition of the TGF-β/SMAD signaling pathway, thereby attenuating ECM formation and offering a promising avenue for keloid treatment. This study underscores the potential of CIRT as an innovative strategy for managing keloids, highlighting its multifaceted impact on key cellular processes involved in keloid pathogenesis.
Collapse
Affiliation(s)
- Heng Zhou
- School of Public Health, Yangzhou University, Yangzhou, China; Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Pengfei Yang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Tianyi Zhang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Oliver Kepp
- Centre de Recherche des Cordeliers, Université de Paris, INSERM U1138, Paris, France
| | - Yanxian Ren
- School of Public Health, Yangzhou University, Yangzhou, China; The First Hospital of Lanzhou University, Lanzhou, China
| | - Ningzu Jiang
- School of Public Health, Yangzhou University, Yangzhou, China; The First Hospital of Lanzhou University, Lanzhou, China
| | - Ruifeng Liu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China; Renmin Hospital of Wuhan Economic and Technological Development Zone, Wuhan, China
| | - Jin Li
- Renmin Hospital of Wuhan Economic and Technological Development Zone, Wuhan, China
| | - Chenghao Li
- School of Public Health, Yangzhou University, Yangzhou, China; Yangzhou University Medical College, Yangzhou, China..
| |
Collapse
|
|
5
|
Diab L, Al Kattar S, Oueini N, Hawi J, Chrabieh A, Dosh L, Jurjus R, Leone A, Jurjus A. Syndecan-1: a key player in health and disease. Immunogenetics 2024; 77:9. [PMID: 39688651 DOI: 10.1007/s00251-024-01366-4] [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: 11/04/2024] [Accepted: 11/30/2024] [Indexed: 12/18/2024]
Abstract
Syndecan-1 (SDC-1) is a transmembrane protein localized on the basolateral surface of epithelial cells, encompassing a core protein with heparin sulfate and chondroitin sulfate glycosaminoglycan side chains. SDC-1 is involved in a panoply of cellular mechanisms including cell-to-cell adhesion, extracellular matrix interactions, cell cycle modulation, and lipid clearance. Alterations in the expression and function of SDC-1 are implicated in numerous disease entities, making it an attractive diagnostic and therapeutic target. However, despite its broad involvement in several disease processes, the underlying mechanism contributing to its diverse functions, pathogenesis, and therapeutic uses remains underexplored. Therefore, this review examines the role of SDC-1 in health and disease, focusing on liver pathologies, inflammatory diseases, infectious diseases, and cancer, and sheds light on SDC-1-based therapeutic approaches. Moreover, it delves into the mechanisms through which SDC-1 contributes to these diseases, emphasizing cell-type specific mechanisms. By comprehensively summarizing the significance of SDC-1, its association with several diseases, and its underlying mechanisms of action, the findings of this review could inform future research directions toward the development of targeted therapies and early diagnosis for a multitude of disease entities.
Collapse
Affiliation(s)
- Lara Diab
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon
| | - Sahar Al Kattar
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon
| | - Naim Oueini
- Department of Agriculture and Food Engineering, School of Engineering, Holy Spirit University, Kaslik, Jounieh, Lebanon
| | - Jihad Hawi
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon
| | - Antoine Chrabieh
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon
| | - Laura Dosh
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon
| | - Rosalyn Jurjus
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon
| | - Angelo Leone
- Department of Biomedicine, Neuroscience and Advanced Diagnostic, University of Palermo, Palermo, Italy
| | - Abdo Jurjus
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon.
| |
Collapse
|
|
6
|
Zhao SY, Wu D, Cheng C, Xie JH. Advances and future directions in keloid research: Pathogenesis, diagnosis and personalized treatment strategies. World J Clin Cases 2023; 11:8094-8098. [PMID: 38130783 PMCID: PMC10731170 DOI: 10.12998/wjcc.v11.i34.8094] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 10/28/2023] [Accepted: 11/10/2023] [Indexed: 12/06/2023] Open
Abstract
Keloids, which are abnormal manifestations of wound healing, can result in significant functional impairment and aesthetic deformities. The pathogenesis of keloids is multifaceted and complex and influenced by various factors, such as genetics, the environment, and immune responses. The evolution of keloid treatment has progressed from traditional surgical excision to a contemporary combination of therapies including injection and radiation treatments, among others. This article provides a comprehensive review of keloid pathogenesis and treatment, emphasizing the latest advances in the field. Ultimately, this review underscores the necessity for continued research to enhance our understanding of keloid pathogenesis and to devise more effective treatments for this challenging condition.
Collapse
Affiliation(s)
- Song-Yun Zhao
- Department of Neurosurgery, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi 214000, Jiangsu Province, China
| | - Dan Wu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200000, China
| | - Chao Cheng
- Department of Neurosurgery, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi 214000, Jiangsu Province, China
| | - Jia-Heng Xie
- Department of Plastic Surgery, Xiangya Hospital, Central South University, Changsha 410000, Hunan Province, China
| |
Collapse
|
|
7
|
Pejšková L, Rønning SB, Kent MP, Solberg NT, Høst V, Thu-Hien T, Wold JP, Lunde M, Mosleth E, Pisconti A, Kolset SO, Carlson CR, Pedersen ME. Characterization of wooden breast myopathy: a focus on syndecans and ECM remodeling. Front Physiol 2023; 14:1301804. [PMID: 38130476 PMCID: PMC10737271 DOI: 10.3389/fphys.2023.1301804] [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: 09/25/2023] [Accepted: 11/06/2023] [Indexed: 12/23/2023] Open
Abstract
Introduction: The skeletal muscle deformity of commercial chickens (Gallus gallus), known as the wooden breast (WB), is associated with fibrotic myopathy of unknown etiology. For future breeding strategies and genetic improvements, it is essential to identify the molecular mechanisms underlying the phenotype. The pathophysiological hallmarks of WB include severe skeletal muscle fibrosis, inflammation, myofiber necrosis, and multifocal degeneration of muscle tissue. The transmembrane proteoglycans syndecans have a wide spectrum of biological functions and are master regulators of tissue homeostasis. They are upregulated and shed (cleaved) as a regulatory mechanism during tissue repair and regeneration. During the last decades, it has become clear that the syndecan family also has critical functions in skeletal muscle growth, however, their potential involvement in WB pathogenesis is unknown. Methods: In this study, we have categorized four groups of WB myopathy in broiler chickens and performed a comprehensive characterization of the molecular and histological profiles of two of them, with a special focus on the role of the syndecans and remodeling of the extracellular matrix (ECM). Results and discussion: Our findings reveal differential expression and shedding of the four syndecan family members and increased matrix metalloproteinase activity. Additionally, we identified alterations in key signaling pathways such as MAPK, AKT, and Wnt. Our work provides novel insights into a deeper understanding of WB pathogenesis and suggests potential therapeutic targets for this condition.
Collapse
Affiliation(s)
| | | | - Matthew Peter Kent
- Center for Integrative Genetics, Department of Animal and Aquacultural Sciences, Faculty of Biosciences (BIOVIT), Norwegian University of Life Sciences (NMBU), Ås, Norway
| | | | - Vibeke Høst
- Raw Materials and Optimization, Nofima AS, Ås, Norway
| | - To Thu-Hien
- Center for Integrative Genetics, Department of Animal and Aquacultural Sciences, Faculty of Biosciences (BIOVIT), Norwegian University of Life Sciences (NMBU), Ås, Norway
| | | | - Marianne Lunde
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Ellen Mosleth
- Raw Materials and Optimization, Nofima AS, Ås, Norway
| | | | - Svein Olav Kolset
- Department of Nutrition, Institute of Basic Medical Science, University of Oslo, Oslo, Norway
| | - Cathrine Rein Carlson
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
| | | |
Collapse
|
|
8
|
Zhu L, Liu L, Wang A, Liu J, Huang X, Zan T. Positive feedback loops between fibroblasts and the mechanical environment contribute to dermal fibrosis. Matrix Biol 2023; 121:1-21. [PMID: 37164179 DOI: 10.1016/j.matbio.2023.05.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 05/06/2023] [Accepted: 05/07/2023] [Indexed: 05/12/2023]
Abstract
Dermal fibrosis is characterized by excessive deposition of extracellular matrix in the dermis and affects millions of people worldwide and causes limited movement, disfigurement and psychological distress in patients. Fibroblast dysfunction of plays a central role in the pathogenesis of dermal fibrosis and is controlled by distinct factors. Recent studies support the hypothesis that fibroblasts can drive matrix deposition and stiffening, which in turn can exacerbate the functional dysregulation of fibroblasts. Ultimately, through a positive feedback loop, uncontrolled pathological fibrosis develops. This review aims to summarize the phenomenon and mechanism of the positive feedback loop in dermal fibrosis, and discuss potential therapeutic targets to help further elucidate the pathogenesis of dermal fibrosis and develop therapeutic strategies. In this review, fibroblast-derived compositional and structural changes in the ECM that lead to altered mechanical properties are briefly discussed. We focus on the mechanisms by which mechanical cues participate in dermal fibrosis progression. The mechanosensors discussed in the review include integrins, DDRs, proteoglycans, and mechanosensitive ion channels. The FAK, ERK, Akt, and Rho pathways, as well as transcription factors, including MRTF and YAP/TAZ, are also discussed. In addition, we describe stiffness-induced biological changes in the ECM on fibroblasts that contribute to the formation of a positive feedback loop. Finally, we discuss therapeutic strategies to treat the vicious cycle and present important suggestions for researchers conducting in-depth research.
Collapse
Affiliation(s)
- Liang Zhu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Lechen Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Aoli Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Jinwen Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Xin Huang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
| | - Tao Zan
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
| |
Collapse
|
|
9
|
Du Y, Liu X, Du K, Zhang W, Li R, Yang L, Cheng L, He W, Zhang W. Decorin inhibits the formation of hard nodules after microwave ablation by inhibiting the TGF-β1/SMAD and MAPK signaling pathways: in a Bama miniature pig model of mammary gland hyperplasia. Int J Hyperthermia 2023; 40:2188151. [PMID: 36919520 DOI: 10.1080/02656736.2023.2188151] [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: 03/16/2023] Open
Abstract
BACKGROUND Benign breast lesions are often associated with hard nodule formation after microwave ablation (MWA), which persists for a long time and causes problems in patients. The aim of this study was to evaluate the efficacy of decorin in the treatment of hard nodule formation and its potential mechanism of action. METHODS Using a Bama miniature pig model of mammary gland hyperplasia, immunohistochemistry, Masson's trichrome and western blotting were firstly applied to compare the extent of fibrosis and activation of key members of the TGF-β1/SMAD and MAPK signaling pathways of hard nodule in the control and MWA groups, and then the extent of fibrosis and expression of signaling pathways in hard nodule were examined after application of decorin. RESULTS The results showed that the MWA group had increased levels of TGF-β1, p-SMAD2/3, p-ERK1/2, and collagen I proteins and increased fibrosis at 2 weeks, 4 weeks, and 3 months after MWA. After decorin treatment, the expression levels of each protein were significantly downregulated, and the degree of fibrosis was reduced at 2 weeks, 4 weeks, and 3 months after MWA compared with the MWA group. CONCLUSION In conclusion, these results suggest that activation of TGF-β1 may play an important role in hard nodule formation and that decorin may reduce hard nodule formation after MWA in a model of mammary gland hyperplasia by inhibiting the TGF-β1/SMAD and MAPK signaling pathways.
Collapse
Affiliation(s)
- Yue Du
- Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xinyao Liu
- Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Kai Du
- Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wenkai Zhang
- Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Rui Li
- Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Lizhi Yang
- Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Linggang Cheng
- Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wen He
- Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wei Zhang
- Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
10
|
He L, Zhu C, Dou H, Yu X, Jia J, Shu M. Keloid Core Factor CTRP3 Overexpression Significantly Controlled TGF- β1-Induced Propagation and Migration in Keloid Fibroblasts. DISEASE MARKERS 2023; 2023:9638322. [PMID: 37091895 PMCID: PMC10115533 DOI: 10.1155/2023/9638322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/04/2022] [Accepted: 10/10/2022] [Indexed: 04/25/2023]
Abstract
Purpose Keloid is a type of benign fibrous proliferative tumor characterized by excessive scarring. C1q/TNF-related protein 3 (CTRP3) has been proven to possess antifibrotic effect. Here, we explored the role of CTRP3 in keloid. In the current research, we examined the influence of CTRP3 on keloid fibroblasts (KFs) and investigated the potential molecular mechanism. Methods KF tissue specimens and adjacent normal fibroblast (NF) tissues were collected cultured from 10 keloid participants. For the TGF-β1 stimulation group, KFs were processed with human recombinant TGF-β1. Cell transfection of pcDNA3.1-CTRP3 or pcDNA3.1 was performed. The siRNA of CTRP3 (si-CTRP3) or negative control siRNA (si-scramble) was transfected into KFs. Results CTRP3 was downregulated in keloid tissues and KFs. CTRP3 overexpression significantly controlled TGF-β1-induced propagation and migration in KFs. Col I, α-SMA, and fibronectin mRNA and protein levels were enhanced by TGF-β1 stimulation, whereas they were inhibited by CTRP3 overexpression. In contrast, CTRP3 knockdown exhibited the opposite effect. In addition, CTRP3 attenuated TGF-β receptors TRI and TRII in TGF-β1-induced KFs. Furthermore, CTRP3 prevented TGF-β1-stimulated nuclear translocation of smad2 and smad3 and suppressed the expression levels of p-smad2 and p-smad3 in KFs. Conclusion CTRP3 exerted an antifibrotic role through inhibiting proliferation, migration, and ECM accumulation of KFs via regulating TGF-β1/Smad signal path.
Collapse
Affiliation(s)
- Lin He
- Department of Plastic, Aesthetic and Maxillofacial Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Chan Zhu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Huicong Dou
- Department of Plastic, Aesthetic and Maxillofacial Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Xueyuan Yu
- Department of Plastic, Aesthetic and Maxillofacial Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Jing Jia
- Department of Plastic, Aesthetic and Maxillofacial Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Maoguo Shu
- Department of Plastic, Aesthetic and Maxillofacial Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| |
Collapse
|
|
11
|
Lee CC, Tsai CH, Chen CH, Yeh YC, Chung WH, Chen CB. An updated review of the immunological mechanisms of keloid scars. Front Immunol 2023; 14:1117630. [PMID: 37033989 PMCID: PMC10075205 DOI: 10.3389/fimmu.2023.1117630] [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: 12/06/2022] [Accepted: 03/07/2023] [Indexed: 04/11/2023] Open
Abstract
Keloid is a type of disfiguring pathological scarring unique to human skin. The disorder is characterized by excessive collagen deposition. Immune cell infiltration is a hallmark of both normal and pathological tissue repair. However, the immunopathological mechanisms of keloid remain unclear. Recent studies have uncovered the pivotal role of both innate and adaptive immunity in modulating the aberrant behavior of keloid fibroblasts. Several novel therapeutics attempting to restore regulation of the immune microenvironment have shown variable efficacy. We review the current understanding of keloid immunopathogenesis and highlight the potential roles of immune pathway-specific therapeutics.
Collapse
Affiliation(s)
- Chih-Chun Lee
- 1 Department of Medical Education, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Chia-Hsuan Tsai
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chih-Hao Chen
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yuan-Chieh Yeh
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan
- Program in Molecular Medicine, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wen-Hung Chung
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Drug Hypersensitivity Clinical and Research Center, Department of Dermatology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Drug Hypersensitivity Clinical and Research Center, Department of Dermatology, Chang Gung Memorial Hospital, Taipei, Taiwan
- Drug Hypersensitivity Clinical and Research Center, Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taiwan
- Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan
- Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Linkou, Taiwan
- Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China
- Xiamen Chang Gung Allergology Consortium, Xiamen Chang Gung Hospital, Xiamen, China
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan
- Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Chun-Bing Chen
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Drug Hypersensitivity Clinical and Research Center, Department of Dermatology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Drug Hypersensitivity Clinical and Research Center, Department of Dermatology, Chang Gung Memorial Hospital, Taipei, Taiwan
- Drug Hypersensitivity Clinical and Research Center, Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taiwan
- Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan
- Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Linkou, Taiwan
- Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China
- Xiamen Chang Gung Allergology Consortium, Xiamen Chang Gung Hospital, Xiamen, China
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan
- Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan
- *Correspondence: Chun-Bing Chen, ;
| |
Collapse
|
|
12
|
Hu H, Mao G, Zheng J, Guo F. Keloid Patient Plasma-Derived Exosomal hsa_circ_0020792 Promotes Normal Skin Fibroblasts Proliferation, Migration, and Fibrogenesis via Modulating miR-193a-5p and Activating TGF-β1/Smad2/3 Signaling. Drug Des Devel Ther 2022; 16:4223-4234. [PMID: 36524216 PMCID: PMC9744884 DOI: 10.2147/dddt.s386786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
Background Keloids are fibroproliferative disorders, which seriously affect the quality of life of patients with keloids. Additionally, circRNAs are enriched within exosomes derived from human blood samples, whereas their relationship with keloids remains largely unknown. It has been reported that hsa_circ_0020792 was abnormally upregulated in keloid tissues. However, the role of keloid patient plasma-derived exosomal hsa_circ_0020792 in the formation and development of keloids is not well understood. Methods Exosomes were isolated from the peripheral blood plasma of the patients with keloids (keloid patient-Exo) and healthy controls (Healthy control-Exo). The hsa_circ_0020792 and miR-193a-5p levels in keloid patient-Exo and healthy control-Exo, as well as in keloid fibroblasts and normal skin fibroblasts (NFs) were evaluated by RT-qPCR. Results The level of hsa_circ_0020792 was remarkably increased in keloid patient-Exo and keloid fibroblasts compared with that in Healthy control-Exo and NFs, respectively. In addition, keloid patient-Exo obviously enhanced the viability, migration, and extracellular matrix (ECM) synthesis, but reduced the apoptosis of NFs. Moreover, keloid patient-Exo notably promoted the fibrogenesis of NFs, as characterized by enhanced TGF-β signaling, increased expressions of phosphorylated Smad2/3. However, downregulation of hsa_circ_0020792 markedly reversed the promoting effects of keloid patient-Exo on cell growth, migration, and myofibroblast activation and fibrogenesis. Furthermore, downregulation of hsa_circ_0020792 significantly reduced the viability, migration, and fibrogenesis in NFs, whereas these phenomena were reversed by miR-193a-5p inhibitor. Conclusion Collectively, keloid patient plasma-derived exosomal hsa_circ_0020792 could promote the proliferation, migration, and fibrogenesis of NFs via modulating miR-193a-5p and activating TGF-β1/Smad2/3 signaling.
Collapse
Affiliation(s)
- Huan Hu
- Department of Plastic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, People’s Republic of China
| | - Guangyu Mao
- Department of Plastic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, People’s Republic of China
| | - Jianghong Zheng
- Department of Plastic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, People’s Republic of China,Correspondence: Jianghong Zheng; Feng Guo, Department of Plastic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Xuhui District, Shanghai, 200233, People’s Republic of China, Email ;
| | - Feng Guo
- Department of Plastic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, People’s Republic of China
| |
Collapse
|
|
13
|
Liu S, Yang H, Song J, Zhang Y, Abualhssain ATH, Yang B. Keloid: Genetic susceptibility and contributions of genetics and epigenetics to its pathogenesis. Exp Dermatol 2022; 31:1665-1675. [PMID: 36052657 DOI: 10.1111/exd.14671] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/29/2022] [Accepted: 08/29/2022] [Indexed: 11/30/2022]
Abstract
Keloid, characterized by fibroproliferative disorders of the skin, can be developed in people of different genders, ages, and ethnicities. Keloid can appear in any part of the body but are especially common on the earlobe, upper torso, and triangular muscle. The genetic heterogeneity and susceptibility of KD (keloid) vary among different races and ethnicities. Studies have found that multiple loci on multiple chromosomes are associated with the pathogenesis of KD, and specific gene variants may also be involved. Despite multiple investigations attempting to uncover the etiology of keloid formation, the genetic mechanism of keloid formation remains unknown. To establish a foundation for a better understanding of the genetics and epigenetics of keloids, we have evaluated and summarized current studies which are mostly related to heredity, genetic polymorphisms, predisposing gene, DNA methylation, and non-coding RNA. We also discussed the problems and potential of genetic and epigenetic investigations of keloids, with the goal of developing new therapeutic approaches to enhance the prognosis of keloid patients.
Collapse
Affiliation(s)
- Shuangfei Liu
- Dermatology Hospital of Southern Medical University, Guangzhou, China
| | - Huan Yang
- Dermatology Hospital of Southern Medical University, Guangzhou, China
| | - Jinru Song
- Dermatology Hospital of Southern Medical University, Guangzhou, China
| | - Yue Zhang
- Dermatology Hospital of Southern Medical University, Guangzhou, China
| | | | - Bin Yang
- Dermatology Hospital of Southern Medical University, Guangzhou, China
| |
Collapse
|
|
14
|
Li L, Fu H, Liu Y. The fibrogenic niche in kidney fibrosis: components and mechanisms. Nat Rev Nephrol 2022; 18:545-557. [PMID: 35788561 DOI: 10.1038/s41581-022-00590-z] [Citation(s) in RCA: 188] [Impact Index Per Article: 62.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2022] [Indexed: 02/08/2023]
Abstract
Kidney fibrosis, characterized by excessive deposition of extracellular matrix (ECM) that leads to tissue scarring, is the final common outcome of a wide variety of chronic kidney diseases. Rather than being distributed uniformly across the kidney parenchyma, renal fibrotic lesions initiate at certain focal sites in which the fibrogenic niche is formed in a spatially confined fashion. This niche provides a unique tissue microenvironment that is orchestrated by a specialized ECM network consisting of de novo-induced matricellular proteins. Other structural elements of the fibrogenic niche include kidney resident and infiltrated inflammatory cells, extracellular vesicles, soluble factors and metabolites. ECM proteins in the fibrogenic niche recruit soluble factors including WNTs and transforming growth factor-β from the extracellular milieu, creating a distinctive profibrotic microenvironment. Studies using decellularized ECM scaffolds from fibrotic kidneys show that the fibrogenic niche autonomously promotes fibroblast proliferation, tubular injury, macrophage activation and endothelial cell depletion, pathological features that recapitulate key events in the pathogenesis of chronic kidney disease. The concept of the fibrogenic niche represents a paradigm shift in understanding of the mechanism of kidney fibrosis that could lead to the development of non-invasive biomarkers and novel therapies not only for chronic kidney disease, but also for fibrotic diseases of other organs.
Collapse
Affiliation(s)
- Li Li
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haiyan Fu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Youhua Liu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| |
Collapse
|
|
15
|
Xia Y, Wang Y, Shan M, Hao Y, Liu H, Chen Q, Liang Z. Advances in the pathogenesis and clinical application prospects of tumor biomolecules in keloid. BURNS & TRAUMA 2022; 10:tkac025. [PMID: 35769828 PMCID: PMC9233200 DOI: 10.1093/burnst/tkac025] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 02/13/2022] [Indexed: 12/29/2022]
Abstract
Keloid scarring is a kind of pathological healing manifestation after skin injury and possesses various tumor properties, such as the Warburg effect, epithelial-mesenchymal transition (EMT), expression imbalances of apoptosis-related genes and the presence of stem cells. Abnormal expression of tumor signatures is critical to the initiation and operation of these effects. Although previous experimental studies have recognized the potential value of a single or several tumor biomolecules in keloids, a comprehensive evaluation system for multiple tumor signatures in keloid scarring is still lacking. This paper aims to summarize tumor biomolecules in keloids from the perspectives of liquid biopsy, genetics, proteomics and epigenetics and to investigate their mechanisms of action and feasibility from bench to bedside. Liquid biopsy is suitable for the early screening of people with keloids due to its noninvasive and accurate performance. Epigenetic biomarkers do not require changes in the gene sequence and their reversibility and tissue specificity make them ideal therapeutic targets. Nonetheless, given the ethnic specificity and genetic predisposition of keloids, more large-sample multicenter studies are indispensable for determining the prevalence of these signatures and for establishing diagnostic criteria and therapeutic efficacy estimations based on these molecules.
Collapse
Affiliation(s)
- Yijun Xia
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
| | - Youbin Wang
- Department of Plastic Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Mengjie Shan
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
| | - Yan Hao
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
| | - Hao Liu
- Department of Plastic Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Qiao Chen
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
| | - Zhengyun Liang
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
| |
Collapse
|
|
16
|
CircSLC8A1 targets miR-181a-5p/HIF1AN pathway to inhibit the growth, migration and extracellular matrix deposition of human keloid fibroblasts. Burns 2022; 49:622-632. [PMID: 35610079 DOI: 10.1016/j.burns.2022.04.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 12/28/2021] [Accepted: 04/15/2022] [Indexed: 11/20/2022]
Abstract
BACKGROUND Circular RNAs (circRNAs) are identified as important regulators in human diseases, including keloid. The purpose of this study is to reveal the role and molecular mechanism of circSLC8A1 in keloid formation. METHODS Expression of circSLC8A1, microRNA (miR)-181a-5p, and hypoxia inducible factor 1 alpha inhibitor (HIF1AN) were detected by quantitative real-time PCR. Protein expression of extracellular matrix (ECM) deposition markers and HIF1AN was detected by western blot analysis. Furthermore, the interaction between miR-181a-5p and circSLC8A1 or HIF1AN was confirmed by dual-luciferase reporter assay, RIP assay and RNA pull-down assay. RESULTS Expression of circSLC8A1 was downregulated in keloid tissues and HKFs. Overexpression of circSLC8A1 suppressed HKFs proliferation, migration, ECM deposition, and promoted apoptosis. MiR-181a-5p is targeted by circSLC8A1, and its mimic reversed the effect of circSLC8A1 on the biological function of HKFs. HIF1AN was a target of miR-181a-5p, and it was positively regulated by circSLC8A1. Knockdown of HIF1AN also reversed the negatively regulation of circSLC8A1 on the biological functions of HKFs. CONCLUSION Our data showed that circSLC8A1 regulates the miR-181a-5p/HIF1AN axis to restrain HKFs biological functions, confirming that circSLC8A1 might serve as a novel therapeutic target for keloids.
Collapse
|
|
17
|
Ntika S, Tracy LM, Franco-Cereceda A, Björck HM, Krizhanovskii C. Syndecan-1 Expression Is Increased in the Aortic Wall of Patients with Type 2 Diabetes but Is Unrelated to Elevated Fasting Plasma Glucagon-Like Peptide-1. Biomedicines 2021; 9:697. [PMID: 34203009 PMCID: PMC8233803 DOI: 10.3390/biomedicines9060697] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 06/01/2021] [Accepted: 06/17/2021] [Indexed: 11/17/2022] Open
Abstract
A reduced prevalence of a thoracic aortic aneurysm (thoracic AA) is observed in type 2 diabetes (T2D). Glucagon-like peptide-1 (GLP-1)/GLP-1-based anti-diabetic therapy has indicated protective effects in thoracic AA and regulates the processes controlling the vascular tissue expression of Syndecan-1 (Sdc-1). Sdc-1 expression on macrophages infiltrating the aortic tissue contributes to a counter-regulatory response to thoracic AA formation in animal models through the interplay with inflammation/proteolytic activity. We hypothesized that elevated fasting plasma GLP-1 (fpGLP-1) increases the aortic Sdc-1 expression in T2D, which may contribute to a reduced prevalence of thoracic AA. Consequently, we determined whether T2D/thoracic AA associates with an altered Sdc-1 expression in the aortic tissue and the possible associations with fpGLP-1 and inflammation/proteolytic activity. From a cohort of surgical patients with an aortic valve pathology, we compared different disease groups (T2D/thoracic AA) with the same sub-cohort group of controls (patients without T2D and thoracic AA). The MMP-2 activity and Sdc-1, GLP-1R and CD68 expression were analyzed in the aortic tissue. GLP-1, Sdc-1 and cytokines were analyzed in the plasma. The aortic Sdc-1 expression was increased in T2D patients but did not correlate with fpGLP-1. Thoracic AA was associated with an increased aortic expression of Sdc-1 and the macrophage marker CD68. CD68 was not detected in T2D. In conclusion, an increased aortic Sdc-1 expression may contribute to a reduced prevalence of thoracic AA in T2D.
Collapse
Affiliation(s)
- Stelia Ntika
- Department of Research, Södertälje Hospital, Södertälje, 152 86 Stockholm, Sweden; (L.M.T.); (C.K.)
- Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet & Karolinska University Hospital, 171 76 Stockholm, Sweden;
| | - Linda M. Tracy
- Department of Research, Södertälje Hospital, Södertälje, 152 86 Stockholm, Sweden; (L.M.T.); (C.K.)
| | - Anders Franco-Cereceda
- Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet & Karolinska University Hospital, 171 76 Stockholm, Sweden;
| | - Hanna M. Björck
- Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 171 76 Stockholm, Sweden;
| | - Camilla Krizhanovskii
- Department of Research, Södertälje Hospital, Södertälje, 152 86 Stockholm, Sweden; (L.M.T.); (C.K.)
- Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet & Karolinska University Hospital, 171 76 Stockholm, Sweden;
| |
Collapse
|
|
18
|
JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human Graves' Orbital Fibroblasts. Int J Mol Sci 2021; 22:ijms22062952. [PMID: 33799469 PMCID: PMC7998969 DOI: 10.3390/ijms22062952] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/08/2021] [Accepted: 03/12/2021] [Indexed: 12/12/2022] Open
Abstract
Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.
Collapse
|
|
19
|
Shen X, Wang X. The function role and synergic effect of syndecan-1 for mifepristone in uterine leiomyoma. Cytotechnology 2021; 73:179-187. [PMID: 33927475 DOI: 10.1007/s10616-021-00455-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 01/17/2021] [Indexed: 02/05/2023] Open
Abstract
The study intends to investigate the regulation of syndecan-1 in human uterine leiomyoma cells. Human syndecan-1 levels were detected by Western blot in uterus leimyoma's tissue. The efficacy of syndecan-1 silencing on the cell proliferation, metalloproteinases and extracellular matrix were determined through Cell Counting Kit (CCK8) assay and Western blot assay, respectively. We compared the respective and combined effect of mifepristone and syndecan-1 on cell proliferation and the expression of metalloproteinases and extracellular matrix (ECM) in human uterine leiomyoma cells. The inhibitory effects of Syndecan-1 silencing on proliferation, ECM and Matrix Metalloproteinase (MMP) were observed in human uterine leiomyoma cells. Furthermore, syndecan-1 inhibition enhanced the effects of mifepristone against uterine leiomyoma cell proliferation. The expression of MMPs and ECM components in human uterine leiomyoma cells was decreased dramatically after syndecan-1 silencing, which was promoted after mifepristone treatment. Altogether, syndecan-1 silencing enhanced the efficacy of mifepristone on the uterine leiomyoma cell proliferation and ECM formation. Therefore, targeting syndecan-1 represents a novel therapeutic strategy to treat uterine leiomyoma.
Collapse
Affiliation(s)
- Xiaoyan Shen
- Department of Gynecology, Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong, 226018 Jiangsu China
| | - Xiaoxu Wang
- Five Departments of Recuperation in Dalian Rehabilitation and Recuperation Center, No.30, Binhai West Road, Xigang District, Dalian City, 116013 Liaoning province China
| |
Collapse
|
|
20
|
Wang XM, Liu XM, Wang Y, Chen ZY. Activating transcription factor 3 (ATF3) regulates cell growth, apoptosis, invasion and collagen synthesis in keloid fibroblast through transforming growth factor beta (TGF-beta)/SMAD signaling pathway. Bioengineered 2020; 12:117-126. [PMID: 33315500 PMCID: PMC8806324 DOI: 10.1080/21655979.2020.1860491] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
The successful treatment of keloids is a great challenge in the plastic surgery field. Activating transcription factor 3 (ATF3) is discovered as an adaptive responsive gene, which plays a critical role in fibroblast activation. This study aimed to investigate the expression and biological role of ATF3 in the pathogenesis of keloids. ATF3 expression in normal skins and keloids was evaluated by real-time PCR, western blot and immunohistochemistry. Effects of ATF3 on cell growth, apoptosis, invasion and collagen production were evaluated in keloid fibroblast cells overexpressing or downregulating ATF3. ATF3 expression was significantly elevated in keloid tissues when compared with that of normal skins and parakeloidal skin tissues. Moreover, ATF3 promoted cell proliferation and collagen production in keloid fibroblast cells. Conversely, transfection with siRNA targeting ATF3 led to decreased cell viability and collagen synthesis via inhibiting transforming growth factor-β1 (TGF-β1) and fibroblast growth factor 2/8 (FGF2/8) production in keloid fibroblasts. ATF3 could reduce the apoptosis rate of keloid fibroblast cells. Molecularly, we found that ATF3 promoted BCL2 level and inhibit the expression of BCL2 associated agonist of cell death (Bad), Caspase3 and Caspase9 in keloid fibroblast cells. ATF3 also enhanced the invasive potential via upregulating the expression of Matrix Metalloproteinases (MMP) family members (MMP1, MMP2, MMP9 and MMP13). ATF3 could induce activation of TGF-β/Smad signaling pathway in fibroblasts. Collectively, ATF3 could promote growth and invasion, and inhibit apoptosis via TGF-β/Smad pathway in keloid fibroblast cells, suggesting that ATF3 might be considered as a novel therapeutic target for the management of keloid.
Collapse
Affiliation(s)
- Xue-Ming Wang
- Department of Plastic Surgery, Qingdao University , Qingdao, China.,Department of Plastic Surgery, Fujian Provincial Maternity and Children's Hospital , Fuzhou, China
| | - Xiu-Mei Liu
- Child Care Center, Fujian Provincial Maternity and Children's Hospital , Fuzhou, China
| | - Yuting Wang
- Department of Plastic Surgery, Yantai Yuhuangding Hospital , Yantai, China
| | - Zhen-Yu Chen
- Medical Plastic and Cosmetic Center, The Affiliated Hospital of Qingdao University , Qingdao, China
| |
Collapse
|
|
21
|
Knockdown of fibronectin extra domain B suppresses TGF-β1-mediated cell proliferation and collagen deposition in keloid fibroblasts via AKT/ERK signaling pathway. Biochem Biophys Res Commun 2020; 526:1131-1137. [PMID: 32317186 DOI: 10.1016/j.bbrc.2020.04.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 04/08/2020] [Indexed: 01/17/2023]
Abstract
Keloids represent a dermal fibrotic disease characterized by excess collagen deposition and invasion of normal skin beyond the wound boundary, similar to malignant tumor features. Fibronectin extra domain B (EDB) is highly expressed in many tumors but has not been studied in keloids. The present study aimed to investigate the expression and the influence of EDB on keloid and elucidate the putative signaling pathway. We examined expression of EDB and the effects of EDB on fibroblast proliferation, apoptosis and the expression of the related proteins and genes. The level of phosphorylation of Smad, ERK, and AKT was estimated to elucidate the signaling pathways. The results showed that EDB in human keloid tissues and fibroblasts was overexpressed. EDB knockdown suppressed the cell proliferation of keloid fibroblasts (KFs) treated by transforming growth factor-β1 (TGF-β1). Also, the phosphorylation of Smad, ERK, and AKT in TGF-β1-induced KFs was inhibited In addition, the low expression of pro-collagen-I (Col-I) and Col-III protein and mRNA level was observed in the siEDB group. EDB knockdown inhibited cell proliferation and suppressed collagen deposition in TGF-1-induced KFs. The underlying mechanism is the activation of TGF-β1/Smad, ERK, and AKT signaling pathways. Together, the results suggested that EDB is a promising therapeutic target for keloid clinical treatment.
Collapse
|