scholarly journals SFRP4 Expression Is Linked to Immune-Driven Fibrotic Conditions, Correlates with Skin and Lung Fibrosis in SSc and a Potential EMT Biomarker

2021 ◽  
Vol 10 (24) ◽  
pp. 5820
Author(s):  
Ilaria Tinazzi ◽  
Panji Mulipa ◽  
Chiara Colato ◽  
Giuseppina Abignano ◽  
Andrea Ballarin ◽  
...  
Keyword(s):  
Lung Fibrosis ◽  
Chronic Gvhd ◽  
Dermal Fibroblasts ◽  
Skin Fibrosis ◽  
Receptor Protein ◽  
Mesenchymal Transition ◽  
Caveolin 1 ◽  
Pathologic Features ◽  
Skin Biopsies

Secreted Frizzled Receptor Protein 4 (SFRP4) has been shown to be increased in Scleroderma (SSc). To determine its role in immune-driven fibrosis, we analysed SSc and sclerotic Chronic Graft Versus Host Disease (sclGVHD) biosamples; skin biopsies (n = 24) from chronic GVHD patients (8 with and 5 without sclGVHD), 8 from SSc and 3 healthy controls (HC) were analysed by immunofluorescence (IF) and SSc patient sera (n = 77) assessed by ELISA. Epithelial cell lines used for in vitro Epithelial-Mesenchymal-Transition (EMT) assays and analysed by Western Blot, RT-PCR and immunofluorescence. SclGVHD skin biopsies resembled pathologic features of SSc. IF of fibrotic skin biopsies indicated the major source of SFRP4 expression were dermal fibroblasts, melanocytes and vimentin positive/caveolin-1 negative cells in the basal layer of the epidermis. In vitro studies showed increased vimentin and SFRP4 expression accompanied with decreased caveolin-1 expression during TGFβ-induced EMT. Additionally, SFRP4 serum concentration correlated with severity of lung and skin fibrosis in SSc. In conclusion, SFRP4 expression is increased during skin fibrosis in two different immune-driven conditions, and during an in vitro EMT model. Its serum levels correlate with skin and lung fibrosis in SSc and may function as biomarker of EMT. Further studies are warranted to elucidate the role of SFRP4 in EMT within the pathogenesis of tissue fibrosis.

The Compound LG283 Inhibits Bleomycin-induced Skin Fibrosis and Vascular Injury via Antagonizing TGF-β /Smad/Snail Mesenchymal Transition Pathways

2021 ◽  
Author(s):  
Akira Utsunomiya ◽  
Takenao Chino ◽  
Natsuko Utsunomiya ◽  
Vu Huy Luong ◽  
Takashi Matsushita ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β ◽  
Dermal Fibroblasts ◽  
Skin Fibrosis ◽  
Mesenchymal Transition ◽  
Transition Pathways ◽  
Smad3 Phosphorylation

Abstract BackgroundSystemic sclerosis (SSc) is a collagen disease that exhibits intractable fibrosis and vascular injury of the skin and internal organs. Transforming growth factor-β (TGF-β)/Smad signaling plays a central role in extracellular matrix (ECM) production by myofibroblasts. Myofibroblasts may be derived from epithelial and endothelial precursor cells in addition to resident fibroblasts. Recently, our high-throughput in vitro screening discovered a small compound, LG283, that can disrupt the differentiation of dermal fibroblasts into myofibroblasts. This compound was originally generated as a curcumin derivative. MethodsIn this study, we investigated the effect of LG283 on inhibiting fibrosis and vascular injury. The action of LG283 on TGF-β-dependent fibrogenic activity, epithelial mesenchymal transition (EMT), and endothelial cell mesenchymal transition (EndoMT) was analyzed in vitro. The effects of LG283 were also examined in a bleomycin-induced skin fibrosis mouse model.ResultsLG283 suppressed TGF-β-induced ECM expression, Smad3 phosphorylation, and expression of transcription factors responsible for the mesenchymal transition, Snail 1 and 2, in cultured human dermal fibroblasts. LG283 was also found to block EMT and EndoMT in cultured human epithelial cells and endothelial cells, respectively. During these processes, Smad3 phosphorylation and/or expression of Snail 1 and 2 were inhibited by LG283 treatment. In the bleomycin-induced skin fibrosis model, oral administration of LG283 efficiently protected against the development of fibrosis and vascular injury without affecting cell infiltration or cytokine concentrations in the skin. No apparent adverse effects of LG283 were found. LG283 treatment remarkably inhibited the enhanced expression of phosphorylated Smad3 in the bleomycin-injected skin. Increased expression of Snail 1 and 2 were reduced by LG283 treatment in the mouse model. ConclusionsThe LG283 compound exhibits antagonistic activity on fibrosis and vascular injury through inhibition of TGF-β/Smad/Snail mesenchymal transition pathways and thus, may be a candidate therapeutic for treatment of SSc. Furthermore, the screening of EMT and/or EndoMT regulatory compounds may be an attractive approach for SSc therapy.

Antifibrotic properties of caveolin-1 scaffolding domain in vitro and in vivo

2008 ◽  
Vol 294 (5) ◽  
pp. L843-L861 ◽  
Author(s):  
Elena Tourkina ◽  
Mathieu Richard ◽  
Pal Gööz ◽  
Michael Bonner ◽  
Jaspreet Pannu ◽  
...  
Keyword(s):  
Lung Fibrosis ◽  
Smooth Muscle Actin ◽  
Lung Fibroblasts ◽  
Normal Lung ◽  
Signaling Molecule ◽  
Caveolin 1 ◽  
Tenascin C ◽  
Ecm Proteins

Lung fibrosis involves the overexpression of ECM proteins, primarily collagen, by α-smooth muscle actin (ASMA)-positive cells. Caveolin-1 is a master regulator of collagen expression by cultured lung fibroblasts and of lung fibrosis in vivo. A peptide equivalent to the caveolin-1 scaffolding domain (CSD peptide) inhibits collagen and tenascin-C expression by normal lung fibroblasts (NLF) and fibroblasts from the fibrotic lungs of scleroderma patients (SLF). CSD peptide inhibits ASMA expression in SLF but not NLF. Similar inhibition of collagen, tenascin-C, and ASMA expression was also observed when caveolin-1 expression was upregulated using adenovirus. These observations suggest that the low caveolin-1 levels in SLF cause their overexpression of collagen, tenascin-C, and ASMA. In mechanistic studies, MEK, ERK, JNK, and Akt were hyperactivated in SLF, and CSD peptide inhibited their activation and altered their subcellular localization. These studies and experiments using kinase inhibitors suggest many differences between NLF and SLF in signaling cascades. To validate these data, we determined that the alterations in signaling molecule activation observed in SLF also occur in fibrotic lung tissue from scleroderma patients and in mice with bleomycin-induced lung fibrosis. Finally, we demonstrated that systemic administration of CSD peptide to bleomycin-treated mice blocks epithelial cell apoptosis, inflammatory cell infiltration, and changes in tissue morphology as well as signaling molecule activation and collagen, tenascin-C, and ASMA expression associated with lung fibrosis. CSD peptide may be a prototype for novel treatments for human lung fibrosis that act, in part, by inhibiting the expression of ASMA and ECM proteins.

Maresin 1 Inhibits Epithelial-to-Mesenchymal Transition in Vitro and Attenuates Bleomycin Induced Lung Fibrosis in Vivo

Shock ◽  
2015 ◽  
Vol 44 (5) ◽  
pp. 496-502 ◽  
Author(s):  
Yaxin Wang ◽  
Ruidong Li ◽  
Lin Chen ◽  
Wen Tan ◽  
Zhipeng Sun ◽  
...  
Keyword(s):  
Lung Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Maresin 1

Curcumin ameliorates epithelial-to-mesenchymal transition of podocytes in vivo and in vitro via regulating caveolin-1

2014 ◽  
Vol 68 (8) ◽  
pp. 1079-1088 ◽  
Author(s):  
Li-na Sun ◽  
Zhi-xin Chen ◽  
Xiang-chun Liu ◽  
Hai-ying Liu ◽  
Guang-ju Guan ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Caveolin 1

scholarly journals Mouse Mesenchymal Stem Cell-derived Exosomal Mir-466f-3p Reverses Emt Process Through Inhibiting Akt/gsk3β Pathway via C-met in Radiation-induced Lung Injury

2022 ◽  
Author(s):  
Yi Li ◽  
Zhufu Shen ◽  
Xiao Jiang ◽  
Yuanyuan Wang ◽  
Zuozhang Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Lung Injury ◽  
Lung Fibrosis ◽  
Luciferase Assay ◽  
Mechanistic Study ◽  
Protective Effects ◽  
Mesenchymal Transition ◽  
Radiation Induced

Abstract Background: Radiation-induced lung fibrosis (RILF) is a common complication of thoracic radiotherapy. Alveolar epithelial cells play a crucial role in lung fibrosis via epithelial-mesenchymal transition (EMT). Exosomes derived from mesenchymal stem cells own the beneficial properties to repair and regeneration of damaged tissues, however the underlying mechanisms remain poorly understood. Methods: Mouse mesenchymal stem cells-derived exosomes (mMSCs-Exo) were isolated by differential centrifugation, and their protective effects were assessed in vivo and in vitro , respectively. EMT-associated proteins were measured via western blot assay and/or immunofluorescence staining. The miRNA expression was measured by microarray assay and qPCR. Furthermore, bioinformatics prediction with KEGG analysis, luciferase assay, and rescue experiments were performed to explore the molecular mechanism underlying miR-466f-3p. Results: mMSCs-Exos were efficiently isolated ranging from 90-150 nm with high expression of exosomal markers (CD63, TSG101, and CD9). mMSCs-Exos administration efficiently relieved radiation-induced lung injury with less collagen deposition and lower levels of IL-1β and IL-6. Meanwhile, in vitro results showed mMSCs-Exos treatment obviously reversed EMT process induced by radiation. Among enriched miRNA cargo in exosomes, miR-466f-3p was primarily responsible for the protective effects via inhibition of AKT/GSK3β pathway. Our mechanistic study further demonstrated that c-MET was the direct target of miR-466f-3p, whose restoration partially abrogated mMSCs-Exo-mediated inhibition in both EMT process and AKT/GSK3β signaling activity induced by radiation. Conclusions: Our findings indicated that exosomal miR-466f-3p derived from mMSCs may possess anti-fibrotic properties and prevent radiation-induced EMT through inhibition of AKT/GSK3β via c-MET, providing a promising therapeutic modality for radiation-induced lung fibrosis.

scholarly journals Arctigenin Suppressed Epithelial-Mesenchymal Transition Through Wnt3a/β-Catenin Pathway in PQ-Induced Pulmonary Fibrosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Fei Gao ◽  
Yun Zhang ◽  
Zhizhou Yang ◽  
Mengmeng Wang ◽  
Zhiyi Zhou ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Lung Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Underlying Mechanism ◽  
Alveolar Type ◽  
Mesenchymal Transition

Arctigenin (ATG), a major bioactive substance of Fructus Arctii, counters renal fibrosis; however, whether it protects against paraquat (PQ)-induced lung fibrosis remains unknown. The present study was to determine the effect of ATG on PQ-induced lung fibrosis in a mouse model and the underlying mechanism. Firstly, we found that ATG suppressed PQ-induced pulmonary fibrosis by blocking the epithelial-mesenchymal transition (EMT). ATG reduced the expressions of Vimentin and α-SMA (lung fibrosis markers) induced by PQ and restored the expressions of E-cadherin and Occludin (two epithelial markers) in vivo and in vitro. Besides, the Wnt3a/β-catenin signaling pathway was significantly activated in PQ induced pulmonary fibrosis. Further analysis showed that pretreatment of ATG profoundly abrogated PQ-induced EMT-like phenotypes and behaviors in A549 cells. The Wnt3a/β-catenin signaling pathway was repressed by ATG treatment. The overexpression of Wnt3a could weaken the therapeutic effect of ATG in A549 cells. These findings suggested that ATG could serve as a new therapeutic candidate to inhibit or even reverse EMT-like changes in alveolar type II cells during PQ-induced lung fibrosis, and unraveled that the Wnt3a/β-catenin pathway might be a mechanistic tool for ATG to control pulmonary fibrosis.

scholarly journals Knockdown of MSI2 inhibits metastasis by interacting with caveolin-1 and inhibiting its ubiquitylation in human NF1-MPNST cells

2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Kang Yang ◽  
Jianwei Du ◽  
Dai Shi ◽  
Feng Ji ◽  
Yong Ji ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
High Mobility ◽  
Neurofibromatosis Type ◽  
Migration And Invasion ◽  
High Mobility Group Protein ◽  
Mesenchymal Transition ◽  
Caveolin 1 ◽  
Group Protein

AbstractMalignant peripheral nerve sheath tumours (MPNSTs) are highly aggressive Schwann cell-derived sarcomas, and they are either associated with neurofibromatosis type 1 (NF1) or sporadic. Our previous study found that high mobility group protein A2 (HMGA2) regulates NF1-MPNST growth through Musashi-2 (MSI2); however, whether MSI2 regulates MPNST metastasis and what the mechanism is remain unclear. Here, we demonstrated that the protein caveolin-1 (CAV1) directly interacts with MSI2 in human NF1-MPNST cells. Moreover, we discovered that knockdown of MSI2 induces CAV1 protein expression by inhibiting its ubiquitylation level in NF1-MPNSTs. In addition, CAV1 mediates the suppressive function of MSI2 in epithelial-mesenchymal transition, migration and invasion in vitro and metastasis in vivo. These results help to reveal the potential mechanisms of MSI2 as a target of antimetastatic treatment for human NF1-MPNST.

Caveolin-1/PTRF upregulation constitutes a mechanism for mediating p53-induced cellular senescence: implications for evidence-based therapy of delayed wound healing in diabetes

2013 ◽  
Vol 305 (8) ◽  
pp. E951-E963 ◽  
Author(s):  
Milad S. Bitar ◽  
Samy M. Abdel-Halim ◽  
Fahd Al-Mulla
Keyword(s):  
Oxidative Stress ◽  
Wound Healing ◽  
Cellular Senescence ◽  
Dermal Fibroblasts ◽  
Premature Senescence ◽  
Mrna Levels ◽  
Impaired Wound Healing ◽  
Caveolin 1

A heightened state of oxidative stress and senescence of fibroblasts constitute potential therapeutic targets in nonhealing diabetic wounds. Here, we studied the underlying mechanism mediating diabetes-induced cellular senescence using in vitro cultured dermal fibroblasts and in vivo circular wounds. Our results demonstrated that the total antioxidant capacity and mRNA levels of thioredoxinreductase and glucose-6-phosphate dehydrogenase as well as the ratio of NADPH/NADP were decreased markedly in fibroblasts from patients with type 2 diabetes (DFs). Consistent with this shift in favor of excessive reactive oxygen species, DFs also displayed a significant increase in senescence-associated β-galactosidase activity and phospho-γ-histone H2AX (pH2AX) level. Moreover, the ability of PDGF to promote cell proliferation/migration and regulate the phosphorylation-dependent activation of Akt and ERK1/2 appears to be attenuated as a function of diabetes. Mechanistically, we found that diabetes-induced oxidative stress upregulated caveolin-1 (Cav-1) and PTRF expression, which in turn sequestered Mdm2 away from p53. This process resulted in the activation of a p53/p21-dependent pathway and the induction of premature senescence in DFs. Most of the aforementioned oxidative stress and senescence-based features observed in DFs were recapitulated in a 10-day-old diabetic wound. Intriguingly, we confirmed that the targeted depletion of Cav-1 or PTRF using siRNA- or Vivo-Morpholino antisense-based gene therapy markedly inhibited diabetes/oxidative stress-induced premature senescence and also accelerated tissue repair in this disease state. Overall, our data illuminate Cav-1/PTRF-1 as a key player of a novel signaling pathway that may link a heightened state of oxidative stress to cellular senescence and impaired wound healing in diabetes.

scholarly journals Pinocembrin Ameliorates Skin Fibrosis via Inhibiting TGF-β1 Signaling Pathway

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1240
Author(s):  
Xiaohe Li ◽  
Yunqian Zhai ◽  
Buri Xi ◽  
Wei Ma ◽  
Jianwei Zhang ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Potential Effect ◽  
Dermal Fibroblasts ◽  
Skin Fibrosis ◽  
In Vivo Studies ◽  
Migration And Invasion ◽  
Therapeutic Modalities ◽  
Tgf Β1

Skin fibrotic diseases, such as keloids, are mainly caused by pathologic scarring of wounds during healing and characterized by benign cutaneous overgrowths of dermal fibroblasts. Current surgical and therapeutic modalities of skin fibrosis are unsatisfactory. Pinocembrin, a natural flavonoid, has been shown to possess a vast range of pharmacological activities including antimicrobial, antioxidant, anti-inflammatory, and anti-tumor activities. In this study we explored the potential effect and mechanisms of pinocembrin on skin fibrosis in vitro and in vivo. In vitro studies indicated that pinocembrin dose-dependently suppressed proliferation, migration, and invasion of keloid fibroblasts and mouse primary dermal fibroblasts. The in vivo studies showed that pinocembrin could effectively alleviate bleomycin (BLM)-induced skin fibrosis and reduce the gross weight and fibrosis-related protein expression of keloid tissues in xenograft mice. Further mechanism studies indicated that pinocembrin could suppress TGF-β1/Smad signaling and attenuate TGF-β1-induced activation of skin fibroblasts. In conclusion, our results demonstrate the therapeutic potential of pinocembrin for skin fibrosis.

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