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1
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Siquier-Dameto G, Iguaran-Pérez A, Gimeno-Beltrán J, Bellia G, Giori AM, Boadas-Vaello P, Verdú E. Subcutaneous Injection and Brush Application of Ovalbumin-Aluminum Salt Solution Induces Dermatitis-like Changes in Mice. J Clin Med 2025; 14:1701. [PMID: 40095628 PMCID: PMC11900249 DOI: 10.3390/jcm14051701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 02/27/2025] [Accepted: 02/28/2025] [Indexed: 03/19/2025] Open
Abstract
Background: Intraperitoneal sensitization combined with topical and/or epicutaneous treatment using an ovalbumin (OVA)-aluminum salt solution (OVA-AL) represents a model for inducing atopic dermatitis (AD). However, the combination of sensitization with subcutaneous treatment and cutaneous application of OVA-AL via a brush has not been explored as a method for inducing AD. Methods: Adult mice were subcutaneously injected with OVA-AL following sensitization on days 0, 7, and 14 and were treated with OVA-AL via brush application to the dorsal skin fortnightly until days 35 and 49. Concomitant alloknesis and skin changes were assessed. Mice of the Balb/c and ICR-CD1 strains were treated with OVA-AL until day 35, with only the ICR-CD1 strain continuing treatment until day 49. Control animals received saline. At 35 and 49 days, dorsal skin was harvested and processed for histological analysis. Results: Mice treated with OVA-AL developed dry skin, with no scratching or alloknesis. Histological examination of dorsal skin revealed an increase in mast cells and collagen deposition. Conclusions: Dermatitis-like symptoms were observed in mice treated with OVA-AL using this administration method.
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Affiliation(s)
- Gabriel Siquier-Dameto
- Research Group of Clinical Anatomy, Embryology and Neuroscience (NEOMA), Department of Medical Sciences, University of Girona, 17003 Girona, Spain; (G.S.-D.); (A.I.-P.); (P.B.-V.)
- Dameto Clinics International, 07310 Campanet, Spain
| | - Ainhoa Iguaran-Pérez
- Research Group of Clinical Anatomy, Embryology and Neuroscience (NEOMA), Department of Medical Sciences, University of Girona, 17003 Girona, Spain; (G.S.-D.); (A.I.-P.); (P.B.-V.)
| | | | | | | | - Pere Boadas-Vaello
- Research Group of Clinical Anatomy, Embryology and Neuroscience (NEOMA), Department of Medical Sciences, University of Girona, 17003 Girona, Spain; (G.S.-D.); (A.I.-P.); (P.B.-V.)
| | - Enrique Verdú
- Research Group of Clinical Anatomy, Embryology and Neuroscience (NEOMA), Department of Medical Sciences, University of Girona, 17003 Girona, Spain; (G.S.-D.); (A.I.-P.); (P.B.-V.)
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2
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Lu KC, Tsai KW, Hu WC. Role of TGFβ-producing regulatory T cells in scleroderma and end-stage organ failure. Heliyon 2024; 10:e35590. [PMID: 39170360 PMCID: PMC11336735 DOI: 10.1016/j.heliyon.2024.e35590] [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: 04/09/2024] [Revised: 07/31/2024] [Accepted: 07/31/2024] [Indexed: 08/23/2024] Open
Abstract
Regulatory T cells (Tregs) are crucial immune cells that initiate a tolerable immune response. Transforming growth factor-beta (TGFβ) is a key cytokine produced by Tregs and plays a significant role in stimulating tissue fibrosis. Systemic sclerosis, an autoimmune disease characterized by organ fibrosis, is associated with an overrepresentation of regulatory T cells. This review aims to identify Treg-dominant tolerable host immune reactions and discuss their association with scleroderma and end-stage organ failure. End-stage organ failures, including heart failure, liver cirrhosis, uremia, and pulmonary fibrosis, are frequently linked to tissue fibrosis. This suggests that TGFβ-producing Tregs are involved in the pathogenesis of these conditions. However, the exact significance of TGFβ and the mechanisms through which it induces tolerable immune reactions during end-stage organ failure remain unclear. A deeper understanding of these mechanisms could lead to improved preventive and therapeutic strategies for these severe diseases.
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Affiliation(s)
- Kuo-Cheng Lu
- Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
- Division of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Kuo-Wang Tsai
- Department of Medical Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, 231, Taiwan
| | - Wan-Chung Hu
- Department of Medical Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, 231, Taiwan
- Department of Clinical Pathology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, 231, Taiwan
- Department of Biotechnology, Ming Chuan University, Taoyuan City, 333, Taiwan
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3
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Fei H, Qian Y, Pan T, Wei Y, Hu Y. Curcumin alleviates hypertrophic scarring by inhibiting fibroblast activation and regulating tissue inflammation. J Cosmet Dermatol 2024; 23:227-235. [PMID: 37400988 DOI: 10.1111/jocd.15905] [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: 02/26/2023] [Revised: 04/12/2023] [Accepted: 06/21/2023] [Indexed: 07/05/2023]
Abstract
BACKGROUND Hypertrophic scar (HS) that can lead to defects in appearance and function is often characterized by uncontrolled fibroblast proliferation and excessive inflammation. Curcumin has been shown to have anti-inflammatory and anti-oxidative effects and to play an anti-fibrotic role by interfering transforming growth factor-β1 (TGF-β1)/Smads signaling pathways. AIM To study the effect and mechanism of curcumin on HS from the perspective of fibroblast activity and inflammation regulation. METHODS Cell proliferation, migration and the expression of α-smooth muscle actin (α-SMA) of TGF-β1-induced human dermal fibroblasts (HDFs) treated by curcumin were evaluated using Cell Counting Kit-8 assay, 5-ethynyl-2'-deoxyuridine staining, Transwell assay, Western blotting and immunofluorescence, respectively. The expression of TGF-β1/Smad3 pathway-related molecules (TGF-β1, TGFβ-R1/2, p-Smad3, Smad4) was detected by Western blotting. In a rabbit ear model, hematoxylin and eosin and Masson's staining were conducted to assess scar elevation and collagen deposition, and immunohistochemistry was performed to detect the activation of fibroblasts and infiltration of inflammatory cells. RESULTS Curcumin inhibited proliferation, migration and α-SMA expression of HDFs in a dose-dependent manner. Curcumin (25 μm mol/L) did not regulate the expression of endogenous TGF-β1, but suppressed Smad3 phosphorylation and nuclear translocation, leading to lower α-SMA expression. Curcumin also reduced hypertrophic scarring of rabbit ear, accompanied by the inhibited TGF-β1/Smad3 pathway, inflammatory infiltration and M2 macrophage polarization. CONCLUSION Curcumin plays an anti-scar role through regulating fibroblast activation and tissue inflammation. Our findings provide scientific reference for the clinical use of curcumin in the treatment of HS.
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Affiliation(s)
- Huanhuan Fei
- Department of Pathology, Huzhou Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Huzhou, China
| | - Yao Qian
- Department of Plastic Surgery, Huzhou Central Hospital, Affiliated to Huzhou University, Huzhou, China
- Department of Plastic Surgery, Jiahui Medical Beauty Clinic Co.Ltd, Huzhou, China
| | - Tianyun Pan
- Department of Pathology, Huzhou Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Huzhou, China
| | - Ying Wei
- Department of Plastic Surgery, Huzhou Central Hospital, Affiliated to Huzhou University, Huzhou, China
| | - Yun Hu
- Department of Pathology, Huzhou Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Huzhou, China
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4
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Wang L, Li T, Ma X, Li Y, Li Z, Li Z, Yu N, Huang J, Han Q, Long X. Exosomes from human adipose-derived mesenchymal stem cells attenuate localized scleroderma fibrosis by the let-7a-5p/TGF-βR1/Smad axis. J Dermatol Sci 2023; 112:31-38. [PMID: 37743142 DOI: 10.1016/j.jdermsci.2023.09.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 07/21/2023] [Accepted: 09/05/2023] [Indexed: 09/26/2023]
Abstract
BACKGROUND Inflammation and fibrosis of the skin are characteristics of localized scleroderma (LS). Emerging evidence has demonstrated that exosomes from human adipose tissue-derived mesenchymal stem cells (ADSC-Exo) could alleviate skin fibrosis. OBJECTIVE The impact and potential mechanism of ADSC-Exo on LS fibrosis was examined. METHODS ADSC-Exo was isolated and identified. The effects of ADSC-Exo on the abilities of proliferation and migration of LS-derived fibroblasts (LSFs) were assessed by CCK-8 and scratch assays, respectively. qRT-PCR, western blot, and immunofluorescence were conducted to detect LSFs stimulated with ADSC-Exo, ADSC-ExoAnti-let-7a-5p, let-7a-5p mimic/TGF-βR1 shRNA virus, and negative controls. The impact of ADSC-Exo on C57BL/6j LS mice was evaluated by photographic morphology, hematoxylin-eosin (H&E), Masson's trichrome, and immunohistochemical staining. RESULTS The verified ADSC-Exo limited the proliferation and migration of LSFs and reduced the expression of COL1, COL3, α-SMA, TGF-βR1, and p-Smad2/ 3 in vitro and in vivo. TGF-βR1 knockdown and let-7a-5p mimic in LSFs reduced the expression of COL1, COL3, α-SMA, and p-Smad2/3. However, compared with the ADSC-ExoNC group, the dermal thickness was increased, collagen arrangement was disordered, and α-SMA and TGF-βR1 levels were increased after exposure to ADSC-ExoAnti-let-7a-5p. CONCLUSIONS In this study, it might show that ADSC-Exo may successfully prevent LSF bioactivity, collagen deposition, and myofibroblast trans-differentiation. Additionally, we confirmed that let-7a-5p in ADSC-Exo could directly target TGF-R1 to control the Smad pathway and reduce fibrosis in LSFs. Our work offered a brand-new therapeutic approach and clarified the unique mechanism for the clinical management of LS.
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Affiliation(s)
- Liquan Wang
- Department of Plastic and Aesthetic Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Tianhao Li
- Department of Plastic and Aesthetic Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Xuda Ma
- Department of Plastic and Aesthetic Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Yunzhu Li
- Department of Plastic and Aesthetic Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Zhujun Li
- Department of Plastic and Aesthetic Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Ziming Li
- Department of Plastic and Aesthetic Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Nanze Yu
- Department of Plastic and Aesthetic Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Jiuzuo Huang
- Department of Plastic and Aesthetic Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Qin Han
- Beijing Key Laboratory (No.BZO381), Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Beijing, China.
| | - Xiao Long
- Department of Plastic and Aesthetic Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.
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Osuna-Gómez R, Castellví I, Mulet M, Ortiz MÀ, Brough DE, Sabzevari H, Semnani RT, Vidal S. Impaired Regulation by IL-35 in Systemic Sclerosis. Int J Mol Sci 2023; 24:10567. [PMID: 37445745 PMCID: PMC10341604 DOI: 10.3390/ijms241310567] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/20/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
This study investigated the role of IL-35 in systemic sclerosis (SSc) patients, focusing on CD4+ T cell response and immunomodulatory cytokine production. By comparing the cytokine levels in healthy donors (HD) and SSc patients using ELISAs, we found a significantly lower plasma IL-35 concentration in the SSc patients (52.1 ± 5.6 vs. 143 ± 11.1, p < 0.001). Notably, the IL-35 levels showed a negative correlation with TGF-β (p < 0.001) and IL-17 (p = 0.04). Assessing the IL-35R expression across cell types in the SSc patients and HDs via flow cytometry, we found higher levels on monocytes (40.7 + 5.7 vs. 20.3 ± 1.9, p < 0.001) and lower levels on CD8+ T cells (61.8 ± 9.2 vs. 83.4 ± 0.8, p < 0.05) in the SSc patients. The addition of recombinant IL-35 to stimulated peripheral blood mononuclear cells reduced the IL-17+CD4+ T cell percentage (9.0 ± 1.5 vs. 4.8 ± 0.7, p < 0.05) and increased the IL-35+CD4+ T percentage (4.1 ± 2.3 vs. 10.2 ± 0.8, p < 0.001). In a Treg:Tresponder cell Sco-culture assay with HD and SSc samples, rIL35 decreased the cell proliferation and levels of IL-17A (178.2 ± 30.5 pg/mL vs. 37.4 ± 6.4 pg/mL, p < 0.001) and TGF-β (4194 ± 777 pg/mL vs. 2413 ± 608 pg/mL, p < 0.01). Furthermore, we observed a positive correlation between the modified Rodnan skin score (mRSS) and TGF-β (p < 0.001), while there was a negative correlation between mRSS and IL-35 (p = 0.004). Interestingly, higher levels of plasmatic IL-35 were detected in individuals with limited disease compared to those with diffuse disease (60.1 ± 8.0 vs. 832.3 ± 4.1, p < 0.05). These findings suggest that IL-35 exhibits anti-inflammatory properties in SSc and it may serve as a marker for disease severity and a therapeutic target.
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Affiliation(s)
- Rubén Osuna-Gómez
- Inflammatory Diseases, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (R.O.-G.); (M.M.); (M.À.O.)
| | - Ivan Castellví
- Department of Rheumatology and Systemic Autoimmune Diseases, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain;
| | - Maria Mulet
- Inflammatory Diseases, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (R.O.-G.); (M.M.); (M.À.O.)
| | - Mª Àngels Ortiz
- Inflammatory Diseases, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (R.O.-G.); (M.M.); (M.À.O.)
| | - Douglas E. Brough
- Precigen, Inc., Germantown, MD 20876, USA; (D.E.B.); (H.S.); (R.T.S.)
| | - Helen Sabzevari
- Precigen, Inc., Germantown, MD 20876, USA; (D.E.B.); (H.S.); (R.T.S.)
| | | | - Silvia Vidal
- Inflammatory Diseases, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (R.O.-G.); (M.M.); (M.À.O.)
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6
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Vorstandlechner V, Copic D, Klas K, Direder M, Golabi B, Radtke C, Ankersmit HJ, Mildner M. The Secretome of Irradiated Peripheral Mononuclear Cells Attenuates Hypertrophic Skin Scarring. Pharmaceutics 2023; 15:pharmaceutics15041065. [PMID: 37111549 PMCID: PMC10143262 DOI: 10.3390/pharmaceutics15041065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 03/15/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023] Open
Abstract
Hypertrophic scars can cause pain, movement restrictions, and reduction in the quality of life. Despite numerous options to treat hypertrophic scarring, efficient therapies are still scarce, and cellular mechanisms are not well understood. Factors secreted by peripheral blood mononuclear cells (PBMCsec) have been previously described for their beneficial effects on tissue regeneration. In this study, we investigated the effects of PBMCsec on skin scarring in mouse models and human scar explant cultures at single-cell resolution (scRNAseq). Mouse wounds and scars, and human mature scars were treated with PBMCsec intradermally and topically. The topical and intradermal application of PBMCsec regulated the expression of various genes involved in pro-fibrotic processes and tissue remodeling. We identified elastin as a common linchpin of anti-fibrotic action in both mouse and human scars. In vitro, we found that PBMCsec prevents TGFβ-mediated myofibroblast differentiation and attenuates abundant elastin expression with non-canonical signaling inhibition. Furthermore, the TGFβ-induced breakdown of elastic fibers was strongly inhibited by the addition of PBMCsec. In conclusion, we conducted an extensive study with multiple experimental approaches and ample scRNAseq data demonstrating the anti-fibrotic effect of PBMCsec on cutaneous scars in mouse and human experimental settings. These findings point at PBMCsec as a novel therapeutic option to treat skin scarring.
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Affiliation(s)
- Vera Vorstandlechner
- Laboratory for Cardiac and Thoracic Diagnosis, Regeneration and Applied Immunology, Department of Thoracic Surgery, Medical University of Vienna, 1090 Vienna, Austria
- Aposcience AG, 1200 Vienna, Austria
- Department of Plastic and Reconstructive Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Dragan Copic
- Laboratory for Cardiac and Thoracic Diagnosis, Regeneration and Applied Immunology, Department of Thoracic Surgery, Medical University of Vienna, 1090 Vienna, Austria
- Aposcience AG, 1200 Vienna, Austria
- Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, 1090 Vienna, Austria
| | - Katharina Klas
- Laboratory for Cardiac and Thoracic Diagnosis, Regeneration and Applied Immunology, Department of Thoracic Surgery, Medical University of Vienna, 1090 Vienna, Austria
- Aposcience AG, 1200 Vienna, Austria
| | - Martin Direder
- Laboratory for Cardiac and Thoracic Diagnosis, Regeneration and Applied Immunology, Department of Thoracic Surgery, Medical University of Vienna, 1090 Vienna, Austria
- Aposcience AG, 1200 Vienna, Austria
- Department of Orthopedics and Trauma-Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Bahar Golabi
- Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria
| | - Christine Radtke
- Department of Plastic and Reconstructive Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Hendrik J. Ankersmit
- Laboratory for Cardiac and Thoracic Diagnosis, Regeneration and Applied Immunology, Department of Thoracic Surgery, Medical University of Vienna, 1090 Vienna, Austria
- Aposcience AG, 1200 Vienna, Austria
| | - Michael Mildner
- Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria
- Correspondence:
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LaChance AH, Goldman N, Kassamali B, Vleugels RA. Immunologic underpinnings and treatment of morphea. Expert Rev Clin Immunol 2022; 18:461-483. [DOI: 10.1080/1744666x.2022.2063841] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Avery H. LaChance
- Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Nathaniel Goldman
- Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts
- New York Medical College School of Medicine, Valhalla, NY
| | - Bina Kassamali
- Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Ruth Ann Vleugels
- Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts
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8
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Zhang X, Alanazi YF, Jowitt TA, Roseman AM, Baldock C. Elastic Fibre Proteins in Elastogenesis and Wound Healing. Int J Mol Sci 2022; 23:4087. [PMID: 35456902 PMCID: PMC9027394 DOI: 10.3390/ijms23084087] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/31/2022] [Accepted: 04/03/2022] [Indexed: 12/30/2022] Open
Abstract
As essential components of our connective tissues, elastic fibres give tissues such as major blood vessels, skin and the lungs their elasticity. Their formation is complex and co-ordinately regulated by multiple factors. In this review, we describe key players in elastogenesis: fibrillin-1, tropoelastin, latent TGFβ binding protein-4, and fibulin-4 and -5. We summarise their roles in elastogenesis, discuss the effect of their mutations on relevant diseases, and describe their interactions involved in forming the elastic fibre network. Moreover, we look into their roles in wound repair for a better understanding of their potential application in tissue regeneration.
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Affiliation(s)
- Xinyang Zhang
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK; (X.Z.); (T.A.J.)
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK;
| | - Yasmene F. Alanazi
- Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Thomas A. Jowitt
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK; (X.Z.); (T.A.J.)
| | - Alan M. Roseman
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK;
| | - Clair Baldock
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK; (X.Z.); (T.A.J.)
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK;
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9
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Cassisa A, Vannucchi M. Morphea Profunda with Tertiary Lymphoid Follicles: Description of Two Cases and Review of the Literature. Dermatopathology (Basel) 2022; 9:17-22. [PMID: 35076471 PMCID: PMC8788542 DOI: 10.3390/dermatopathology9010003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/30/2021] [Accepted: 12/31/2021] [Indexed: 02/05/2023] Open
Abstract
Morphea profunda or subcutaneous (deep) morphea is a variant of localized morphea, characterized by one or more ill-defined, deep sclerotic plaque. Preferential sites are the abdomen, trunk, sacral area, or extremities. The presence of hyperplastic lymphoid follicles in the context of the sclerotic bands of morphea is rarely described. Localized scleroderma is sustained by a profibrotic inflammatory profile. Transforming growth factor-β (TGF-β), an imbalance between functional subclasses of T-lymphocytes (innate immune cells) has a role in activate collagen deposition. In this case report, we present two cases of morphea profunda with lymphoid follicular hyperplasia. A systematic review of the literature on the pathophysiology of localized scleroderma is also presented, with particular reference to the presence of lymphoid structures.
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Affiliation(s)
- Angelo Cassisa
- Section of Pathology, Department of Oncology, San Giovanni di Dio Hospital, USL Centro Toscana, 50143 Florence, Italy
- Correspondence:
| | - Margherita Vannucchi
- Section of Pathology, Department of Medical Biotechnology, University of Siena, 53100 Siena, Italy;
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10
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Modulation by 17,20S(OH) 2pD of Fibrosis-Related Mediators in Dermal Fibroblast Lines from Healthy Donors and from Patients with Systemic Sclerosis. Int J Mol Sci 2021; 23:ijms23010367. [PMID: 35008794 PMCID: PMC8745512 DOI: 10.3390/ijms23010367] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/16/2021] [Accepted: 12/27/2021] [Indexed: 12/15/2022] Open
Abstract
We previously demonstrated that the non-calcemic pregnacalciferol (pD) analog 17,20S (OH)2pD suppressed TGF-β1-induced type I collagen production in cultured normal human dermal fibroblasts. In the present studies, we examined fibroblasts cultured from the lesional skin of patients with systemic sclerosis (scleroderma (SSc)) and assessed the effects of 17,20S(OH)2pD on fibrosis-related mediators. Dermal fibroblast lines were established from skin biopsies from patients with SSc and healthy controls. Fibroblasts were cultured with either 17,20S(OH)2pD or 1,25(OH)2D3 (positive control) with/without TGF-β1 stimulation and extracted for protein and/or mRNA for collagen synthesis and mediators of fibrosis (MMP-1, TIMP-1, PAI-1, BMP-7, PGES, GLI1, and GLI2). 1 7,20S(OH)2pD (similar to 1,25(OH)2D3) significantly suppressed net total collagen production in TGF-β1-stimulated normal donor fibroblast cultures and in cultures of SSc dermal fibroblasts. 17,20S(OH)2pD (similar to 1,25(OH)2D3) also increased MMP-1, BMP-7, and PGES and decreased TIMP-1 and PAI1 expression in SSc fibroblasts. Although 17,20S(OH)2pD had no effect on Gli1 or Gli2 in SSc fibroblasts, it increased Gli2 expression when cultured with TGF-β1 in normal fibroblasts. These studies demonstrated that 17,20S(OH)2pD modulates mediators of fibrosis to favor the reduction of fibrosis and may offer new noncalcemic secosteroidal therapeutic approaches for treating SSc and fibrosis.
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11
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Griffin MF, Borrelli MR, Garcia JT, Januszyk M, King M, Lerbs T, Cui L, Moore AL, Shen AH, Mascharak S, Diaz Deleon NM, Adem S, Taylor WL, desJardins-Park HE, Gastou M, Patel RA, Duoto BA, Sokol J, Wei Y, Foster D, Chen K, Wan DC, Gurtner GC, Lorenz HP, Chang HY, Wernig G, Longaker MT. JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models. Sci Transl Med 2021; 13:eabb3312. [PMID: 34516825 DOI: 10.1126/scitranslmed.abb3312] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Michelle F Griffin
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Mimi R Borrelli
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Julia T Garcia
- Center for Personal Dynamics Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Genetics, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Michael Januszyk
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Megan King
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.,CIRM Scholars Program, Humboldt State University, Arcata, CA 95521, USA
| | - Tristan Lerbs
- Department of Pathology, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Lu Cui
- Department of Pathology, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Alessandra L Moore
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Abra H Shen
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Shamik Mascharak
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Pathology, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Nestor M Diaz Deleon
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Sandeep Adem
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Walter L Taylor
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Heather E desJardins-Park
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.,Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Marc Gastou
- Department of Pathology, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Ronak A Patel
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Bryan A Duoto
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Jan Sokol
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Yuning Wei
- Center for Personal Dynamics Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Deshka Foster
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Pathology, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Kellen Chen
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Derrick C Wan
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Geoffrey C Gurtner
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Hermann P Lorenz
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Howard Y Chang
- Center for Personal Dynamics Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Genetics, Stanford School of Medicine, Stanford, CA 94305, USA.,Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA
| | - Gerlinde Wernig
- Department of Pathology, Stanford School of Medicine, Stanford, CA 94305, USA.,Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Michael T Longaker
- Hagey Laboratory of Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.,Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305, USA
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12
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Licandro SA, Crippa L, Pomarico R, Perego R, Fossati G, Leoni F, Steinkühler C. The pan HDAC inhibitor Givinostat improves muscle function and histological parameters in two Duchenne muscular dystrophy murine models expressing different haplotypes of the LTBP4 gene. Skelet Muscle 2021; 11:19. [PMID: 34294164 PMCID: PMC8296708 DOI: 10.1186/s13395-021-00273-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/27/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND In the search of genetic determinants of Duchenne muscular dystrophy (DMD) severity, LTBP4, a member of the latent TGF-β binding protein family, emerged as an important predictor of functional outcome trajectories in mice and humans. Nonsynonymous single-nucleotide polymorphisms in LTBP4 gene associate with prolonged ambulation in DMD patients, whereas an in-frame insertion polymorphism in the mouse LTBP4 locus modulates disease severity in mice by altering proteolytic stability of the Ltbp4 protein and release of transforming growth factor-β (TGF-β). Givinostat, a pan-histone deacetylase inhibitor currently in phase III clinical trials for DMD treatment, significantly reduces fibrosis in muscle tissue and promotes the increase of the cross-sectional area (CSA) of muscles in mdx mice. In this study, we investigated the activity of Givinostat in mdx and in D2.B10 mice, two mouse models expressing different Ltbp4 variants and developing mild or more severe disease as a function of Ltbp4 polymorphism. METHODS Givinostat and steroids were administrated for 15 weeks in both DMD murine models and their efficacy was evaluated by grip strength and run to exhaustion functional tests. Histological examinations of skeletal muscles were also performed to assess the percentage of fibrotic area and CSA increase. RESULTS Givinostat treatment increased maximal normalized strength to levels that were comparable to those of healthy mice in both DMD models. The effect of Givinostat in both grip strength and exhaustion tests was dose-dependent in both strains, and in D2.B10 mice, Givinostat outperformed steroids at its highest dose. The in vivo treatment with Givinostat was effective in improving muscle morphology in both mdx and D2.B10 mice by reducing fibrosis. CONCLUSION Our study provides evidence that Givinostat has a significant effect in ameliorating both muscle function and histological parameters in mdx and D2.B10 murine models suggesting a potential benefit also for patients with a poor prognosis LTBP4 genotype.
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Affiliation(s)
| | - Luca Crippa
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | | | | | | | - Flavio Leoni
- Preclinical Development, Italfarmaco S.p.A., Milan, Italy
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13
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Voulgaris TA, Karamanolis GP. Esophageal manifestation in patients with scleroderma. World J Clin Cases 2021; 9:5408-5419. [PMID: 34307594 PMCID: PMC8281422 DOI: 10.12998/wjcc.v9.i20.5408] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/22/2021] [Accepted: 05/10/2021] [Indexed: 02/06/2023] Open
Abstract
The esophagus is the most commonly affected part of the gastrointestinal system in patients with systemic sclerosis (SSc). Esophageal involvement may lead to a significant reduction in patient quality of life. The exact pathophysiology is complex and not yet fully elucidated. Ultimately, esophageal smooth muscle becomes atrophied and replaced by fibrous tissue leading to severe motility disturbance of the distal esophagus. Symptoms are mainly attributed to gastroesophageal reflux disease and to esophageal dysmotility. Compelling evidence has correlated esophageal involvement to the severity of pulmonary disease. No formed guidelines exist about the diagnostic modalities used to assess esophageal disease in patients with SSc, though upper gastrointestinal endoscopy is the first and most important modality used as it can reveal alterations commonly observed in patients with SSc. Further exploration can be made by high resolution manometry and pH-impedance study. Proton pump inhibitors remain the mainstay of treatment, while prokinetic agents are commonly used as add-on therapy in patients with symptoms attributed to gastroesophageal reflux disease not responding to standard therapy as well as to motility disturbances. Gastroesophageal reflux disease symptoms in patients with SSc are frequently difficult to manage, and new therapeutic modalities are emerging. The role of surgical treatment is restricted and should only be preserved for resistant cases.
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Affiliation(s)
- Theodoros A Voulgaris
- Department of Gastroenterology and Hepatology, Laiko General Hospital, National and Kapodistian University of Athens, Athens 11527, Greece
| | - Georgios P Karamanolis
- Department of Gastroenterology and Hepatology, Laiko General Hospital, National and Kapodistian University of Athens, Athens 11527, Greece
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14
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Su CT, Urban Z. LTBP4 in Health and Disease. Genes (Basel) 2021; 12:genes12060795. [PMID: 34071145 PMCID: PMC8224675 DOI: 10.3390/genes12060795] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/14/2021] [Accepted: 05/21/2021] [Indexed: 12/20/2022] Open
Abstract
Latent transforming growth factor β (TGFβ)-binding protein (LTBP) 4, a member of the LTBP family, shows structural homology with fibrillins. Both these protein types are characterized by calcium-binding epidermal growth factor-like repeats interspersed with 8-cysteine domains. Based on its domain composition and distribution, LTBP4 is thought to adopt an extended structure, facilitating the linear deposition of tropoelastin onto microfibrils. In humans, mutations in LTBP4 result in autosomal recessive cutis laxa type 1C, characterized by redundant skin, pulmonary emphysema, and valvular heart disease. LTBP4 is an essential regulator of TGFβ signaling and is related to development, immunity, injury repair, and diseases, playing a central role in regulating inflammation, fibrosis, and cancer progression. In this review, we focus on medical disorders or diseases that may be manipulated by LTBP4 in order to enhance the understanding of this protein.
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Affiliation(s)
- Chi-Ting Su
- Department of Internal Medicine, Renal Division, National Taiwan University Hospital Yunlin Branch, Douliu 640, Taiwan;
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Medicine, National Taiwan University Cancer Center Hospital, Taipei 106, Taiwan
| | - Zsolt Urban
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Correspondence: ; Tel.: +1-412-648-8269
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15
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Luo Y, Wadhawan S, Greenfield A, Decato BE, Oseini AM, Collen R, Shevell DE, Thompson J, Jarai G, Charles ED, Sanyal AJ. SOMAscan Proteomics Identifies Serum Biomarkers Associated With Liver Fibrosis in Patients With NASH. Hepatol Commun 2021; 5:760-773. [PMID: 34027267 PMCID: PMC8122380 DOI: 10.1002/hep4.1670] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/24/2020] [Accepted: 12/17/2020] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a major cause of liver-related morbidity and mortality worldwide. Liver fibrosis stage, a key component of NASH, has been linked to the risk of mortality and liver-related clinical outcomes. Currently there are no validated noninvasive diagnostics that can differentiate between fibrosis stages in patients with NASH; many existing tests do not reflect underlying disease pathophysiology. Noninvasive biomarkers are needed to identify patients at high-risk of NASH with advanced fibrosis. This was a retrospective study of patients with histologically proven NASH with fibrosis stages 0-4. The SOMAscan proteomics platform was used to quantify 1,305 serum proteins in a discovery cohort (n = 113). In patients with advanced (stages 3-4) versus early fibrosis (stages 0-2), 97 proteins with diverse biological functions were differentially expressed. Next, fibrosis-stage classification models were explored using a machine learning-based approach to prioritize the biomarkers for further evaluation. A four-protein model differentiated patients with stage 0-1 versus stage 2-4 fibrosis (area under the receiver operating characteristic curve [AUROC] = 0.74), while a 12-protein classifier differentiated advanced versus early fibrosis (AUROC = 0.83). Subsequently, the model's performance was validated in two independent cohorts (n = 71 and n = 32) with similar results (AUROC = 0.74-0.78). Our advanced fibrosis model performed similarly to or better than Fibrosis-4 index, aspartate aminotransferase-to-platelet ratio index, and nonalcoholic fatty liver disease (NAFLD) fibrosis score-based models for all three cohorts. Conclusion: A SOMAscan proteomics-based exploratory classifier for advanced fibrosis, consisting of biomarkers that reflect the complexity of NASH pathophysiology, demonstrated similar performance in independent validation cohorts and performed similarly or better than Fibrosis-4 index, aspartate aminotransferase-to-platelet ratio index, and NAFLD fibrosis score. Further studies are warranted to evaluate the clinical utility of these biomarker panels in patients with NAFLD.
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Affiliation(s)
- Yi Luo
- Bristol Myers SquibbPrincetonNJUSA
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16
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Li Y, Wu G, Shang Y, Qi Y, Wang X, Ning S, Chen H. ILDGDB: a manually curated database of genomics, transcriptomics, proteomics and drug information for interstitial lung diseases. BMC Pulm Med 2020; 20:323. [PMID: 33308175 PMCID: PMC7731518 DOI: 10.1186/s12890-020-01350-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 11/12/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Interstitial lung diseases (ILDs), a diverse group of diffuse lung diseases, mainly affect the lung parenchyma. The low-throughput 'omics' technologies (genomics, transcriptomics, proteomics) and relative drug information have begun to reshaped our understanding of ILDs, whereas, these data are scattered among massive references and are difficult to be fully exploited. Therefore, we manually mined and summarized these data at a database (ILDGDB, http://ildgdb.org/ ) and will continue to update it in the future. MAIN BODY The current version of ILDGDB incorporates 2018 entries representing 20 ILDs and over 600 genes obtained from over 3000 articles in four species. Each entry contains detailed information, including species, disease type, detailed description of gene (e.g. official symbol of gene), and the original reference etc. ILDGDB is free, and provides a user-friendly web page. Users can easily search for genes of interest, view their expression pattern and detailed information, manage genes sets and submit novel ILDs-gene association. CONCLUSION The main principle behind ILDGDB's design is to provide an exploratory platform, with minimum filtering and interpretation, while making the presentation of the data very accessible, which will provide great help for researchers to decipher gene mechanisms and improve the prevention, diagnosis and therapy of ILDs.
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Affiliation(s)
- Yupeng Li
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Gangao Wu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Yu Shang
- Department of Respiration, Harbin First Hospital, Harbin, 150081, China
| | - Yue Qi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Xue Wang
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Shangwei Ning
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
| | - Hong Chen
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China.
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17
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Ali EMT, Abdallah HI, El-Sayed SM. Histomorphological, VEGF and TGF-β immunoexpression changes in the diabetic rats' ovary and the potential amelioration following treatment with metformin and insulin. J Mol Histol 2020; 51:287-305. [PMID: 32399705 DOI: 10.1007/s10735-020-09880-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/05/2020] [Indexed: 12/29/2022]
Abstract
Diabetes mellitus (DM) affects the ovary by reducing the number and diameters of ovarian follicles and increasing atretic follicles. Follicular growth and diameters depend on VEGF production. Hyperglycemia causes ovarian stromal and follicular degeneration then fibrosis by activating TGF-β. Insulin and metformin promote development of ovarian follicles and reduce atretic follicles. Therefore, the present study investigates the ovarian VEGF and TGF-β immune-expression and its variations in diabetic, insulin and metformin-treated rats. Forty adult female albino rats were divided equally into four groups: control, diabetic (STZ-induced diabetes), diabetic metformin-treated group (100 mg/kg/day orally/eight weeks) and diabetic insulin-treated group (5 U insulin /day). Ovarian sections were stained with hematoxylin and eosin, Masson's trichrome, immunohistochemistry for VEGF and TGF-β. The diabetic group showed noticeable atrophic and degenerative changes in cortex and medulla as well as increased density and distribution of the collagenous fibers. The number and diameter of primary, secondary and tertiary follicles were decreased. However, the number of atretic follicles and corpus luteum was increased. Significant decrease in the surface area percentage of VEGF immuno-expression and significant increase in TGF-β immuno-expression surface area percentage were detected. By treating animals with metformin and insulin, there was restoration of the ovarian histological structure more or less as in control. DM negatively affects the histological and morphometric parameters of ovaries. Furthermore, insulin showed more beneficial effects than metformin in hindering these complications by modifying the expression of VEGF and TGF-β.
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Affiliation(s)
- Eyad M T Ali
- Department of Anatomy, Faculty of medicine, Taibah University, Madinah, Kingdom of Saudi Arabia. .,Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt.
| | - Hesham I Abdallah
- Department of Anatomy, Faculty of medicine, Taibah University, Madinah, Kingdom of Saudi Arabia.,Department of Anatomy, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Sayed M El-Sayed
- Department of Anatomy, Faculty of medicine, Taibah University, Madinah, Kingdom of Saudi Arabia.,Department of Anatomy, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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18
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van Caam A, Aarts J, van Ee T, Vitters E, Koenders M, van de Loo F, van Lent P, van den Hoogen F, Thurlings R, Vonk MC, van der Kraan PM. TGFβ-mediated expression of TGFβ-activating integrins in SSc monocytes: disturbed activation of latent TGFβ? Arthritis Res Ther 2020; 22:42. [PMID: 32143707 PMCID: PMC7059334 DOI: 10.1186/s13075-020-2130-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 02/12/2020] [Indexed: 12/26/2022] Open
Abstract
Introduction The pathophysiology of systemic sclerosis (SSc) is closely linked to overactive TGFβ signaling. TGFβ is produced and circulates in latent form, making its activation crucial for signaling. This activation can be mediated via integrins. We investigated the balance between active and latent TGFβ in serum of SSc patients and investigated if this correlates with integrin expression on monocytes. Methods A TGFβ/SMAD3- or BMP/SMAD1/5-luciferase reporter construct was expressed in primary human skin fibroblasts. Both acidified and non-acidified sera of ten SSc patients and ten healthy controls were tested on these cells to determine total and active TGFβ and BMP levels respectively. A pan-specific TGFβ1/2/3 neutralizing antibody was used to confirm TGFβ signaling. Monocytes of 20 SSc patients were isolated using CD14+ positive selection, and integrin gene expression was measured using qPCR. Integrin expression was modulated using rhTGFβ1 or a small molecule inhibitor of TGFBR1: SB-505124. Results SSc sera induced 50% less SMAD3-reporter activity than control sera. Serum acidification increased reporter activity, but a difference between healthy control and SSc serum was no longer observed, indicating that total TGFβ levels were not different. Addition of a pan-specific TGFβ1/2/3 neutralizing antibody fully inhibited SMAD3-reporter activity of both acidified and not-acidified control and SSc sera. Both HC and SSc sera induced similar SMAD1/5-reporter activity, and acidification increased this, but not differently between groups. Interestingly, expression of two integrin alpha subunits ITGA5 and ITGAV was significantly reduced in monocytes obtained from SSc patients. Furthermore, ITGB3, ITGB5, and ITGB8 expression was also reduced in SSc monocytes. Stimulation of monocytes with TGFβ1 induced ITGA5 and ITGAV but lowered ITGB8 expression, whereas the use of the TGFβ receptor inhibitor SB-505124 had the opposite effect. Conclusion Total TGFβ serum levels are not different between SSc patients and controls, but TGFβ activity is. This coincides with a reduced expression of TGFβ-activating integrins in monocytes of SSc patients. Because TGFβ regulates expression of these integrins in monocytes, a negative feedback mechanism possibly underlies these observations.
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Affiliation(s)
- A van Caam
- Experimental Rheumatology, Radboudumc, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands
| | - J Aarts
- Experimental Rheumatology, Radboudumc, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands
| | - T van Ee
- Experimental Rheumatology, Radboudumc, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands
| | - E Vitters
- Experimental Rheumatology, Radboudumc, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands
| | - M Koenders
- Experimental Rheumatology, Radboudumc, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands
| | - F van de Loo
- Experimental Rheumatology, Radboudumc, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands
| | - P van Lent
- Experimental Rheumatology, Radboudumc, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands
| | - F van den Hoogen
- Department of Rheumatology, Radboudumc, Nijmegen, The Netherlands
| | - R Thurlings
- Department of Rheumatology, Radboudumc, Nijmegen, The Netherlands
| | - M C Vonk
- Department of Rheumatology, Radboudumc, Nijmegen, The Netherlands
| | - P M van der Kraan
- Experimental Rheumatology, Radboudumc, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
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19
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Yi X, Yang Y, Wu P, Xu X, Li W. Alternative splicing events during adipogenesis from hMSCs. J Cell Physiol 2019; 235:304-316. [PMID: 31206189 DOI: 10.1002/jcp.28970] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 05/28/2019] [Accepted: 05/29/2019] [Indexed: 12/22/2022]
Abstract
Adipogenesis, the developmental process of progenitor-cell differentiating into adipocytes, leads to fat metabolic disorders. Alternative splicing (AS), a ubiquitous regulatory mechanism of gene expression, allows the generation of more than one unique messenger RNA (mRNA) species from a single gene. Till now, alternative splicing events during adipogenesis from human mesenchymal stem cells (hMSCs) are not yet fully elucidated. We performed RNA-Seq coupled with bioinformatics analysis to identify the differentially expressed AS genes and events during adipogenesis from hMSCs. A global survey separately identified 1262, 1181, 1167, and 1227 ASE involved in the most common types of AS including cassette exon, alt3, and alt5, especially with cassette exon the most prevalent, at 7, 14, 21, and 28 days during adipogenesis. Interestingly, 122 differentially expressed ASE referred to 118 genes, and the three genes including ACTN1 (alt3 and cassette), LRP1 (alt3 and alt5), and LTBP4 (cassette, cassette_multi, and unknown), appeared in multiple AS types of ASE during adipogenesis. Except for all the identified ASE of LRP1 occurred in the extracellular topological domain, alt3 (84) in transmembrane domain significantly differentially expressed was the potential key event during adipogenesis. Overall, we have, for the first time, conducted the global transcriptional profiling during adipogenesis of hMSCs to identify differentially expressed ASE and ASE-related genes. This finding would provide extensive ASE as the regulator of adipogenesis and the potential targets for future molecular research into adipogenesis-related metabolic disorders.
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Affiliation(s)
- Xia Yi
- Jiangxi Provincial Key Laboratory of Systems Biomedicine, Jiujiang University, Jiujiang, China
| | - Yunzhong Yang
- Beijing Yuanchuangzhilian Techonlogy Development Co., Ltd, Beijing, China
| | - Ping Wu
- Jiangxi Provincial Key Laboratory of Systems Biomedicine, Jiujiang University, Jiujiang, China
| | - Xiaoyuan Xu
- Jiangxi Provincial Key Laboratory of Systems Biomedicine, Jiujiang University, Jiujiang, China
| | - Weidong Li
- Jiangxi Provincial Key Laboratory of Systems Biomedicine, Jiujiang University, Jiujiang, China
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20
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Liu Q, Lu J, Lin J, Tang Y, Pu W, Shi X, Jiang S, Liu J, Ma Y, Li Y, Xu J, Jin L, Wang J, Wu W. Salvianolic acid B attenuates experimental skin fibrosis of systemic sclerosis. Biomed Pharmacother 2018; 110:546-553. [PMID: 30530290 DOI: 10.1016/j.biopha.2018.12.016] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Revised: 11/28/2018] [Accepted: 12/02/2018] [Indexed: 02/02/2023] Open
Abstract
Systemic sclerosis (SSc) is a connective tissue disease characterized mainly by fibrosis of skin and internal organs. Our previous study has shown that salvianolic acid B (SAB), a bioactive component extracted from Salvia miltiorrhiza (SM), was one of the essential ingredients in the traditional Chinese medicine Yiqihuoxue formula, which has been used to treat SSc-related dermal and pulmonary fibrosis. The aim of the present study was to evaluate the effect of SAB on skin fibrosis and explore its underlying anti-fibrotic mechanism. We found that SAB was capable of alleviating skin fibrosis in a bleomycin-induced SSc mouse model, alleviating skin thickness and reducing collagen deposition. in vitro studies indicated that SAB reduced SSc skin fibroblast proliferation and downregulated extracellular matrix gene transcription and collagen protein expression. TGF-β/SMAD and MAPK/ERK pathway activation were also shown to be suppressed in SAB treated fibroblasts. Moreover, RNA-seq revealed that the anti-fibrotic effect of SAB might be related to antioxidant activity, the cell cycle, and the p53 signaling pathway. Taken together, our results suggest that SAB has the ability to alleviate SSc-related skin fibrosis both in vivo and in vitro.
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Affiliation(s)
- Qingmei Liu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China; State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Jiaying Lu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jinran Lin
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yulong Tang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Weilin Pu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Xiangguang Shi
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China; State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Shuai Jiang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Jing Liu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Yanyun Ma
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Yuan Li
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Jinhua Xu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Li Jin
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China; Human Phenome Institute, Fudan University, Shanghai, China
| | - Jiucun Wang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China; Human Phenome Institute, Fudan University, Shanghai, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China.
| | - Wenyu Wu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China; Department of dermatology, Jing'an District Central Hospital, Shanghai, China.
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21
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Shi X, Liu Q, Li N, Tu W, Luo R, Mei X, Ma Y, Xu W, Chu H, Jiang S, Du Z, Zhao H, Zhao L, Jin L, Wu W, Wang J. MiR-3606-3p inhibits systemic sclerosis through targeting TGF-β type II receptor. Cell Cycle 2018; 17:1967-1978. [PMID: 30145936 PMCID: PMC6224271 DOI: 10.1080/15384101.2018.1509621] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 07/26/2018] [Accepted: 07/28/2018] [Indexed: 12/24/2022] Open
Abstract
Systemic sclerosis (SSc) is a multisystemic fibrotic disease characterized by excessive collagen deposition and extracellular matrix synthesis. Though transforming growth factor-β (TGF-β) plays a fundamental role in the pathogenesis of SSc, the mechanism by which TGF-β signaling acts in SSc remains largely unclear. Here, we showed that TGF-β type II receptor (TGFBR2) was significantly upregulated in both human SSc dermal tissues and primary fibroblasts. In fibroblasts, siRNA-induced knockdown of TGFBR2 resulted in a reduction of p-SMAD2/3 levels and reduced production of type I collagen. Additionally, functional experiments revealed that downregulation of TGFBR2 yielded an anti-growth effect on fibroblasts through inhibiting cell cycle progression. Further studies showed that miR-3606-3p could directly target the 3'-UTR of TGFBR2 and significantly decrease the levels of both TGFBR2 mRNA and protein. Furthermore, SSc dermal tissues and primary fibroblasts contain significantly reduced amounts of miR-3606-3p, and the overexpression of miR-3606-3p in fibroblasts replicates the phenotype of TGFBR2 downregulation. Collectively, our findings demonstrated that increased TGFBR2 could be responsible for the hyperactive TGF-β signaling observed in SSc. Moreover, we identified a pivotal role for miR-3606-3p in SSc, which acts, at least partly, through the attenuation of TGF-β signaling via TGFBR2 repression, suggesting that the regulation of miR-3606-3p/TGFBR2 could be a promising therapeutic target that could improve the treatment strategy for fibrosis.
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Affiliation(s)
- Xiangguang Shi
- State Key Laboratory of Genetic Engineering, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, P. R. China
- Human Phenome Institute, Fudan University, Shanghai, China
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Qingmei Liu
- State Key Laboratory of Genetic Engineering, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, P. R. China
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Na Li
- State Key Laboratory of Genetic Engineering, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, P. R. China
| | - Wenzhen Tu
- Division of Rheumatology, Shanghai TCM-Integrated Hospital, Shanghai, China
| | - Ruoyu Luo
- State Key Laboratory of Genetic Engineering, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, P. R. China
- Human Phenome Institute, Fudan University, Shanghai, China
| | - Xueqian Mei
- State Key Laboratory of Genetic Engineering, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, P. R. China
| | - Yanyun Ma
- Human Phenome Institute, Fudan University, Shanghai, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, P. R. China
| | - Weihong Xu
- The Clinical Laboratory of Shanghai Tongren Hosipital, Jiaotong University, Shanghai, China
| | - Haiyan Chu
- State Key Laboratory of Genetic Engineering, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, P. R. China
| | - Shuai Jiang
- State Key Laboratory of Genetic Engineering, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, P. R. China
| | - Zhimin Du
- State Key Laboratory of Genetic Engineering, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, P. R. China
| | - Han Zhao
- State Key Laboratory of Genetic Engineering, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, P. R. China
| | - Liang Zhao
- State Key Laboratory of Genetic Engineering, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, P. R. China
| | - Li Jin
- State Key Laboratory of Genetic Engineering, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, P. R. China
- Human Phenome Institute, Fudan University, Shanghai, China
| | - Wenyu Wu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
- Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China
| | - Jiucun Wang
- State Key Laboratory of Genetic Engineering, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, P. R. China
- Human Phenome Institute, Fudan University, Shanghai, China
- Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China
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A Profibrotic Phenotype in Naïve and in Fibrotic Lung Myofibroblasts Is Governed by Modulations in Thy-1 Expression and Activation. Mediators Inflamm 2018; 2018:4638437. [PMID: 30002599 PMCID: PMC5996423 DOI: 10.1155/2018/4638437] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 03/05/2018] [Accepted: 04/12/2018] [Indexed: 01/27/2023] Open
Abstract
Lung fibrosis is characterized by abnormal accumulation of Thy-deficient fibroblasts in the interstitium of the alveolar space. We have previously shown in bleomycin-treated chimeric Thy1-deficient mice with wild-type lymphocytes that Thy1-deficient fibroblasts accumulate and promote fibrosis and an “inflammation-free” environment. Here, we aimed to identify the critical effects of Thy1, or the absence of Thy1, in lung myofibroblast profibrotic functions, particularly proliferation and collagen deposition. Using specific Thy1 siRNA in Thy1-positive cells, Thy1 knockout cells, Thy1 cDNA expression vector in Thy1-deficient cells, and Thy1 cross-linking, we evaluated cell proliferation (assessed by cell mass and BrdU uptake), differentiation (using immunofluorescence), and collagen deposition (using Sircol assay). We found that myofibroblast Thy1 cross-linking and genetic manipulation modulate cell proliferation and expression of Fgf (fibroblast growth factor) and Angtl (angiotensin) receptors (using qPCR) that are involved in myofibroblast proliferation, differentiation, and collagen deposition. In conclusion, lung myofibroblast downregulation of Thy1 expression is critical to increase proliferation, differentiation, and collagen deposition.
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23
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Jannic A, Maillet J, Rossi B, Guedj N, Descamps V, Fantin B, Le Bozec P. Flagellate erythema in systemic sclerosis: A case report. JAAD Case Rep 2018; 4:239-241. [PMID: 29687059 PMCID: PMC5909470 DOI: 10.1016/j.jdcr.2017.09.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Affiliation(s)
- Arnaud Jannic
- Department of Dermatology, Beaujon Hospital, Hôpitaux Universitaires Paris Nord Val de Seine, APHP, Clichy, France.,Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France
| | - Jérémy Maillet
- Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France.,Department of Internal Medicine, Beaujon Hospital, Hôpitaux Universitaires Paris Nord Val de Seine, APHP, Clichy, France
| | - Benjamin Rossi
- Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France.,Department of Internal Medicine, Beaujon Hospital, Hôpitaux Universitaires Paris Nord Val de Seine, APHP, Clichy, France
| | - Nathalie Guedj
- Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France.,Laboratory of Pathology, Beaujon Hospital, Hôpitaux Universitaires Paris Nord Val de Seine, Assistance Publique-Hôpitaux de Paris (APHP), Clichy, France
| | - Vincent Descamps
- Department of Dermatology, Beaujon Hospital, Hôpitaux Universitaires Paris Nord Val de Seine, APHP, Clichy, France.,Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France
| | - Bruno Fantin
- Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France.,Department of Internal Medicine, Beaujon Hospital, Hôpitaux Universitaires Paris Nord Val de Seine, APHP, Clichy, France
| | - Patrick Le Bozec
- Department of Dermatology, Beaujon Hospital, Hôpitaux Universitaires Paris Nord Val de Seine, APHP, Clichy, France.,Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France
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24
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Wang D, Wang W, Liang Q, He X, Xia Y, Shen S, Wang H, Gao Q, Wang Y. DHEA-induced ovarian hyperfibrosis is mediated by TGF-β signaling pathway. J Ovarian Res 2018; 11:6. [PMID: 29321035 PMCID: PMC5763573 DOI: 10.1186/s13048-017-0375-7] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 12/22/2017] [Indexed: 01/17/2023] Open
Abstract
Background The polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder with pathological mechanisms remain unclear. The following study investigates the ovarian hyperfibrosis forming via transforming growth factor-β (TGF-β) signaling pathway in Dehydroepiandrosterone (DHEA)- induced polycystic ovary syndrome (PCOS) rat model. We furthermore explored whether TGF-βRI inhibitor (SB431542) decreases ovarian fibrosis by counterbalancing the expression of fibrotic biomarkers. Methods Thirty female Sprague-Dawley rats were randomly divided into Blank group (n = 6), Oil group (n = 6), and Oil + DHEA-induced model group (n = 6 + 12). The model groups were established by subcutaneous injection of DHEA for 35 consecutive days. The 12 successful model rats were additionally divided in vehicle group (n = 6) and SB431542-treated group (n = 6). Vehicle group and SB431542-treated group, served as administration group and were intraperitoneally injected with DMSO and SB431542 for additional 14 consecutive days. Ovarian morphology, fibrin and collagen localization and expression in ovaries were detected using H&E staining, immunohistochemistry and Sirius red staining. The ovarian protein and RNA were examined using Western blot and RT-PCR. Results In DHEA-induced ovary in rat, fibrin and collagen had significantly higher levels, while the main fibrosis markers (TGF-β, CTGF, fibronectin, a-SMA) were obviously upregulated. SB431542 significantly reduced the expression of pro-fibrotic molecules (TGF-β, Smad3, Smad2, a-SMA) and increased anti-fibrotic factor MMP2. Conclusion TGF-βRI inhibitor (SB431542) inhibits the downstream signaling molecules of TGF-β and upregulates MMP2, which in turn prevent collagen deposition. Moreover, ovarian hyperfibrosis in DHEA-induced PCOS rat model could be improved by TGF-βRI inhibitor (SB431542) restraining the transcription of accelerating fibrosis genes and modulating EMT mediator. Electronic supplementary material The online version of this article (10.1186/s13048-017-0375-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Daojuan Wang
- State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical school, Nanjing University, Nanjing, 210093, China
| | - Wenqing Wang
- State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical school, Nanjing University, Nanjing, 210093, China
| | - Qiao Liang
- State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical school, Nanjing University, Nanjing, 210093, China
| | - Xuan He
- State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical school, Nanjing University, Nanjing, 210093, China
| | - Yanjie Xia
- Prenatal Diagnosis Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Shanmei Shen
- Divisions of Endocrinology, the Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210093, China
| | - Hongwei Wang
- State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical school, Nanjing University, Nanjing, 210093, China
| | - Qian Gao
- State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical school, Nanjing University, Nanjing, 210093, China
| | - Yong Wang
- State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical school, Nanjing University, Nanjing, 210093, China.
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25
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Li Y, Zhang J, Lei Y, Lyu L, Zuo R, Chen T. MicroRNA-21 in Skin Fibrosis: Potential for Diagnosis and Treatment. Mol Diagn Ther 2017; 21:633-642. [DOI: 10.1007/s40291-017-0294-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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