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12 záznamů v Medvik Filtry

Článek

miR-491-5p inhibits Emilin 1 to promote fibroblasts proliferation and fibrosis in gluteal muscle contracture via TGF-Beta1/Smad2 pathway

Chen, Shuai
Autor Chen, Shuai Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China Xiamen Key Laboratory of Otolaryngology Head and Neck Surgery, Xiamen, China
Wu, Qiuwan
Autor Wu, Qiuwan Department Science and Technology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
Wang, Yang
Autor Wang, Yang Sports Department of Tianjin Cheng Jian University, Tianjin, China
Xu, Jie
Autor Xu, Jie Department of Science and Technology, Tianjin University of Sport, Tianjin, China
Wang, Ye
Autor Wang, Ye Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China Xiamen Key Laboratory of Otolaryngology Head and Neck Surgery, Xiamen, China
Luo, Xianyang
Autor Luo, Xianyang Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China Xiamen Key Laboratory of Otolaryngology Head and Neck Surgery, Xiamen, China

Physiological research. 2022 ; 71 (2) : 219-231. [pub] 20220411

Physiol. Res. (Print)
ISSN 1802-9973
Medvik
Zdroj

Gluteal muscle contracture (GMC) is a chronic fibrotic disease of gluteal muscles due to multiple etiologies. Emilin 1 plays a determinant role in fibers formation, but its role in the progression of GMC remains unclear. The present study was aimed to search for the predictive role and regulatory mechanism of Emilin 1 on GMC. Here, Protein and mRNA expression of Emilin 1 were decreased in GMC tissues compared to normal muscle tissues. Using the anslysis of target prediction, Emilin 1 was observed to be a potential downstream sponge of miR-491-5p. In comparison to Emilin 1, miR-491-5p showed a aberrant elevation in GMC tissues, which was further proven to have a negative correlation with Emilin 1. The direct binding of miR-491-5p to Emilin 1 mRNA was confirmed by luciferase reporter gene assay, and miR-491-5p mimics inhibited, while miR-491-5p inhibitor promoted the protein expression and secretion of Emilin 1 in contraction bands (CB) fibroblasts. Additionally, miR-491-5p mimics promoted the expression of cyclin-dependent kinase 2 and cyclin D1 and the proliferation of CB fibroblasts, which could be reversed by Emilin 1 overexpression. Mechanistically, miR-491-5p mimics possibly activated transforming growth factor beta1 (TGF-beta1)/Smad3 signal cascade via binding to 3'-untranslated region of Emilin 1 mRNA, thereby promoting the progression of fibrosis of CB fibroblasts. Collectively, miR-491-5p inhibited Emilin 1 expression, and subsequently promoted CB fibroblasts proliferation and fibrosis via activating TGF-beta1/Smad3 signal axis. MiR-491-5p might be a potentially effective biomarker for predicting GMC, providing a novel therapeutic strategy for GMC.

MeSH
fibroblasty metabolismus MeSH
fibróza MeSH
kontraktura * patologie MeSH
kosterní svaly metabolismus MeSH
lidé MeSH
membránové glykoproteiny MeSH
messenger RNA metabolismus MeSH
mikro RNA * genetika metabolismus MeSH
proliferace buněk MeSH
protein Smad2 metabolismus MeSH
transformující růstový faktor beta1 genetika MeSH
Check Tag
lidé MeSH
Publikační typ
časopisecké články MeSH

Článek

GDF11 rapidly increases lipid accumulation in liver cancer cells through ALK5-dependent signaling

Biochimica et biophysica acta. Molecular and cell biology of lipids. 2021 ; 1866 (6) : 158920. [pub] 20210306

Biochem Biophys Acta
ISSN 1879-2618
Medvik
Zdroj

Hepatocellular carcinoma (HCC) is one of the fastest-growing causes of cancer-related mortalities worldwide and this trend is mimicked by the surge of non-alcoholic fatty liver disease (NAFLD). Altered hepatic lipid metabolism promotes HCC development through inflammation and activation of oncogenes. GDF11 is a member of the TGF-β superfamily and recent data have implicated GDF11 as an anti-aging factor that can alleviate high-fat diet induced obesity, hyperglycemia, insulin resistance and NAFLD. However, its role in hepatic lipid metabolism is still not fully delineated. The aim of the present study was to characterize the role of GDF11 in hepatic and HCC cells lipid accumulation. To achieve this, we performed imaging, biochemical, lipidomic, and transcriptomic analyses in primary hepatocytes and in HCC cells treated with GDF11 to study the GDF11-activated signaling pathways. GDF11 treatment rapidly triggered ALK5-dependent SMAD2/3 nuclear translocation and elevated lipid droplets in HCC cells, but not in primary hepatocytes. In HCC cells, ALK5 inhibition hampered GDF11-mediated SMAD2/3 signaling and attenuated lipid accumulation. Using ultra-high-performance liquid chromatography/mass spectrometry, we detected increased accumulation of longer acyl-chain di/tri-acylglycerols and glycerophospholipids. Unbiased transcriptomic analysis identified TGF-β and PI3K-AKT signaling among the top pathways/cellular processes activated in GDF11 treated HCC cells. In summary, GDF11 supplementation promotes pro-lipogenic gene expression and lipid accumulation in HCC cells. Integration of our "omics" data pointed to a GDF11-induced upregulation of de novo lipogenesis through activation of ALK5/SMAD2/3/PI3K-AKT pathways. Thus, GDF11 could contribute to metabolic reprogramming and dysregulation of lipid metabolism in HCC cells, without effects on healthy hepatocytes.

MeSH
hepatocelulární karcinom patologie MeSH
hepatocyty metabolismus MeSH
kostní morfogenetické proteiny metabolismus MeSH
lidé MeSH
lipogeneze MeSH
metabolismus lipidů * MeSH
nádorové buněčné linie MeSH
nádory jater patologie MeSH
protein Smad2 metabolismus MeSH
růstové diferenciační faktory metabolismus MeSH
signální transdukce * MeSH
TGF-beta receptor I. typu metabolismus MeSH
upregulace MeSH
Check Tag
lidé MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH

Článek

Integrin αvβ6 mediates epithelial-mesenchymal transition in human bronchial epithelial cells induced by lipopolysaccharides of Pseudomonas aeruginosa via TGF-β1-Smad2/3 signaling pathway

Folia microbiologica. 2020 ; 65 (2) : 329-338. [pub] 20190626

Folia microbiol. (Prague)
ISSN 1874-9356
Medvik
Zdroj

Lower respiratory tract infection due to Pseudomonas aeruginosa has become increasingly challenging, resulting in a worse morbidity and mortality. Airway remodeling is a common phenomenon in this process, to which epithelial-mesenchymal transition (EMT) may contribute as an important promoter. Previous studies showed that epithelium-specific integrin αvβ6-mediated EMT was involved in pulmonary fibrosis via transforming growth factor-β1 (TGF-β1) signaling, but whether integrin αvβ6 plays a role in the P. aeruginosa-associated airway remodeling remains unknown. BEAS-2B cells were incubated with lipopolysaccharide (LPS) from P. aeruginosa in the presence or the absence of integrin αvβ6-blocking antibodies. Morphologic changes were observed by an inverted microscopy. The EMT markers were detected using Western blotting and immunofluorescence. The activation of TGF-β1-Smad2/3 signaling pathway was assessed. Furthermore, matrix metalloproteinase (MMP)-2 and -9 in the medium were measured using ELISA. P. aeruginosa's LPS decreased the expression of the epithelial marker E-cadherin and promoted the mesenchymal markers, vimentin and α-smooth muscle actin in BEAS-2B cells. The expression of integrin αvβ6 was significantly increased during EMT process. Blocking integrin αvβ6 could attenuate P. aeruginosa's LPS-induced EMT markers' expression via TGF-β1-Smad2/3 signaling pathway. Furthermore, blocking integrin αvβ6 could prevent morphologic changes and oversecretion of MMP-2 and -9. Integrin αvβ6 mediates epithelial-mesenchymal transition in human bronchial epithelial cells induced by lipopolysaccharides of P. aeruginosa via TGF-β1-Smad2/3 signaling pathway and might be a promising therapeutic target for P. aeruginosa-associated airway remodeling.

Článek

Wnt/β-catenin signaling is an evolutionarily conserved determinant of chordate dorsal organizer

eLife. 2020 ; 9 (-) : . [pub] 20200526

ISSN 2050-084X
Medvik
Zdroj

Deciphering the mechanisms of axis formation in amphioxus is a key step to understanding the evolution of chordate body plan. The current view is that Nodal signaling is the only factor promoting the dorsal axis specification in the amphioxus, whereas Wnt/β-catenin signaling plays no role in this process. Here, we re-examined the role of Wnt/βcatenin signaling in the dorsal/ventral patterning of amphioxus embryo. We demonstrated that the spatial activity of Wnt/β-catenin signaling is located in presumptive dorsal cells from cleavage to gastrula stage, and provided functional evidence that Wnt/β-catenin signaling is necessary for the specification of dorsal cell fate in a stage-dependent manner. Microinjection of Wnt8 and Wnt11 mRNA induced ectopic dorsal axis in neurulae and larvae. Finally, we demonstrated that Nodal and Wnt/β-catenin signaling cooperate to promote the dorsal-specific gene expression in amphioxus gastrula. Our study reveals high evolutionary conservation of dorsal organizer formation in the chordate lineage.

Článek

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Nature communications. 2019 ; 10 (1) : 3616. [pub] 20190809

Nat Commun
ISSN 2041-1723
Medvik
Zdroj

Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.

MeSH
dospělí MeSH
extracelulární matrix - proteiny metabolismus MeSH
fibróza genetika metabolismus MeSH
genetická predispozice k nemoci * genetika MeSH
genové regulační sítě * MeSH
kardiomyopatie genetika metabolismus MeSH
lidé středního věku MeSH
lidé MeSH
mladiství MeSH
mladý dospělý MeSH
myši transgenní MeSH
myši MeSH
nemoci srdce genetika metabolismus MeSH
protein - isoformy MeSH
protein Smad2 genetika metabolismus MeSH
regulace genové exprese MeSH
senioři MeSH
transformující růstový faktor beta metabolismus MeSH
ubikvitinligasy genetika metabolismus MeSH
zvířata MeSH
Check Tag
dospělí MeSH
lidé středního věku MeSH
lidé MeSH
mladiství MeSH
mladý dospělý MeSH
mužské pohlaví MeSH
myši MeSH
senioři MeSH
ženské pohlaví MeSH
zvířata MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH

Článek

Soluble endoglin and hypercholesterolemia aggravate endothelial and vessel wall dysfunction in mouse aorta

Atherosclerosis. 2018 ; 271 (-) : 15-25. [pub] 20180209

ISSN 1879-1484
Medvik
Zdroj

BACKGROUND AND AIMS: Increased plasma levels of soluble endoglin (sEng) were detected in patients with endothelial dysfunction-related disorders and hypercholesterolemia. In this study, we hypothesized that high levels of sEng accompanied by mild hypercholesterolemia could aggravate endothelial and vessel wall dysfunction and affect endoglin/eNOS signaling in mouse aorta. METHODS: Three-month-old female transgenic mice on CBAxC57BL/6J background, with high levels of sEng (Sol-Eng+high HFD), and their littermates with low levels of sEng (Sol-Eng+low HFD), were fed a high fat diet for six months. Plasma samples were used for biochemical, ELISA and Luminex analyses of total cholesterol, sEng and inflammatory markers. Functional parameters of aorta were assessed with wire myograph 620M. Western blot analyses of membrane endoglin/eNOS signaling and endothelial dysfunction/inflammation markers in aorta were performed. RESULTS: Functional analysis of aorta showed impaired KCl induced vasoconstriction, endothelial-dependent relaxation after the administration of acetylcholine as well as endothelial-independent relaxation induced by sodium nitroprusside in the Sol-Eng+high HFD group compared to the Sol-Eng+low HFD group. Ach-induced vasodilation after administration of l-NAME was significantly higher in the Sol-Eng+high HFD group compared to the Sol-Eng+low HFD group. The expression of endoglin, p-eNOS/eNOS, pSmad2/3/Smad2/3 signaling pathway was significantly lower in the Sol-Eng+high HFD group compared to the Sol-Eng+low HFD group. CONCLUSIONS: The results indicate that long-term hypercholesterolemia combined with high levels of sEng leads to the aggravation of endothelial and vessel wall dysfunction in aorta, with possible alterations of the membrane endoglin/eNOS signaling, suggesting that high levels of soluble endoglin might be considered as a risk factor of cardiovascular diseases.

Článek

S100A4 amplifies TGF-β-induced fibroblast activation in systemic sclerosis

Annals of the rheumatic diseases. 2015 ; 74 (9) : 1748-55. [pub] 20140407

Ann Rheum Dis
ISSN 1468-2060
Medvik
Zdroj

OBJECTIVES: S100A4 is a calcium binding protein with regulatory functions in cell homeostasis, proliferation and differentiation that has been shown to promote cancer progression and metastasis. In the present study, we evaluated the role of S100A4 in fibroblast activation in systemic sclerosis (SSc). METHODS: The expression of S100A4 was analysed in human samples, murine models of SSc and in cultured fibroblasts by real-time PCR, immunohistochemistry and western blot. The functional role of S100A4 was evaluated using siRNA, overexpression, recombinant protein and S100A4 knockout (S100A4(-/-)) mice. Transforming growth factor β (TGF-β) signalling was assessed by reporter assays, staining for phosphorylated Smad2/3 and analyses of target genes. RESULTS: The expression of S100A4 was increased in SSc skin and in experimental fibrosis in a TGF-β/Smad-dependent manner. Overexpression of S100A4 or stimulation with recombinant S100A4 induced an activated phenotype in resting normal fibroblasts. In contrast, knockdown of S100A4 reduced the pro-fibrotic effects of TGF-β and decreased the release of collagen. S100A4(-/-) mice were protected from bleomycin-induced skin fibrosis with reduced dermal thickening, decreased hydroxyproline content and lower myofibroblast counts. Deficiency of S100A4 also ameliorated fibrosis in the tight-skin-1 (Tsk-1) mouse model. CONCLUSIONS: We characterised S100A4 as a downstream mediator of the stimulatory effects of TGF-β on fibroblasts in SSc. TGF-β induces the expression of S100A4 to stimulate the release of collagen in SSc fibroblasts and induce fibrosis. Since S100A4 is essentially required for the pro-fibrotic effects of TGF-β and neutralising antibodies against S100A4 are currently evaluated, S100A4 might be a candidate for novel antifibrotic therapies.

MeSH
dospělí MeSH
fibroblasty metabolismus MeSH
kůže metabolismus MeSH
lidé středního věku MeSH
lidé MeSH
mladý dospělý MeSH
modely nemocí na zvířatech MeSH
myši knockoutované MeSH
myši MeSH
protein Smad2 metabolismus MeSH
protein Smad3 metabolismus MeSH
proteiny S100 metabolismus MeSH
senioři MeSH
systémová sklerodermie metabolismus MeSH
transformující růstový faktor beta metabolismus MeSH
zvířata MeSH
Check Tag
dospělí MeSH
lidé středního věku MeSH
lidé MeSH
mladý dospělý MeSH
mužské pohlaví MeSH
myši MeSH
senioři MeSH
ženské pohlaví MeSH
zvířata MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH

Článek

PTP1B is an effector of activin signaling and regulates neural specification of embryonic stem cells

Cell stem cell. 2013 ; 13 (6) : 706-19.

Cell Stem Cell
ISSN 1875-9777
Medvik
Zdroj

During embryogenesis, the Activin/Nodal pathway promotes the mesendodermal lineage and inhibits neural fate. The molecular mechanisms underlying this role of the Activin/Nodal pathway are not clear. In this study, we report a role for protein tyrosine phosphatase 1B (PTP1B) in Activin-mediated early fate decisions during ESC differentiation and show that PTP1B acts as an effector of the Activin pathway to specify mesendodermal or neural fate. We found that the Activin/ALK4 pathway directly recruits PTP1B and stimulates its release from the endoplasmic reticulum through ALK4-mediated cleavage. Subsequently, PTP1B suppresses p-ERK1/2 signaling to inhibit neural specification and promote mesendodermal commitment. These findings suggest that a noncanonical Activin signaling pathway functions in lineage specification of mouse and human embryonic stem cells.

Článek

Activation of TGF-β receptors and Smad proteins by atorvastatin is related to reduced atherogenesis in ApoE/LDLR double knockout mice

Journal of atherosclerosis and thrombosis. 2012 ; 19 (2) : 115-26.

J Atheroscler Thromb
ISSN 1880-3873
Medvik
Zdroj

AIM: Transforming growth factor-beta (TGF-β) plays important role in atherogenesis via TGF-β receptors and Smad proteins, which determine its signaling activity. In this study, we hypothesized, whether non-lipid related effects of atorvastatin, affect both endoglin/ALK-5/Smad2/eNOS and/or endoglin/ALK-1/Smad1/VEGF previously proposed pathways in ApoE/LDLR double knockout mice. METHODS: ApoE/LDLR double knockout mice were divided into two groups. The chow group (CHOW) (n =8) was fed with chow diet, while in the atorvastatin group (ATV) (n =8) atorvastatin was added to the chow diet at dose 50 mg/kg/day. Biochemical analyses of lipid profile, lesion area measurement, immunohistochemistry and Western blot analysis of endoglin, ALK-1, 5, phosphorylated and non-phosphorylated forms Smad-1, 2, VEGF and eNOS proteins in mice aorta were performed. RESULTS: Biochemical analysis of blood serum and morphometric analysis of aortic lesion size showed that atorvastatin treatment resulted in a significant increase of cholesterol levels and simultaneously in reduced lesion size in aortic sinus when compared to CHOW mice. Western blot analysis revealed that atorvastatin treatment significantly increase the expressions of endoglin by 102%, ALK-1 by 113%, ALK-5 by 296%, pSmad-1 by 202%, pSmad-2 by 34%, VEGF by 68% and eNOS by 687% as compared with CHOW mice. Immunofluorescence staining revealed endoglin coexpression with all studied markers that were increased by atorvastatin treatment mainly in endothelial cells covering atherosclerotic plaques. CONCLUSION: This study shows that atorvastatin treatment increases the expression of endoglin, ALK-1, ALK-5, phosphorylated forms of Smad1 and Smad2, VEGF and eNOS and reduces atherosclerotic lesion size beyond its lipid lowering effects. Therefore, we propose that endoglin related receptors and signal transducers might play protective role in atherogenesis.

Článek

Cholesterol effects on endoglin and its downstream pathways in ApoE/LDLR double knockout mice

Circulation journal. 2011 ; 75 (7) : 1747-1755. [pub] 20110517

Circ J
ISSN 1347-4820
Medvik
Zdroj

BACKGROUND: The aim of the study was to evaluate whether cholesterol-rich diet affects transforming growth factor-β-RIII (endoglin) levels in blood and 2 endoglin-related pathways in the aorta of ApoE/LDLR double knockout mice. METHODS AND RESULTS: Mice were fed either chow diet (CHOW) (n=8) or by 1% cholesterol-rich diet (CHOL) (n=8). Biochemical analysis of cholesterol and endoglin levels in blood, lesion size area, immunohistochemistry and Western blot analysis in mice aortas were performed. Biochemical analysis showed that cholesterol-rich diet resulted in a significant increase of cholesterol and endoglin levels in serum, and increased plaque size in the aorta. In addition, a cholesterol-rich diet significantly decreased the expressions of endoglin by 92%, activin receptor-like kinase (ALK)-1 by 71%, p-Smad2 by 21%, and vascular endothelial growth factor (VEGF) by 37% when compared to CHOW mice, but ALK-5, p-Smad1, and endothelial nitric oxide synthase were not significantly affected. CONCLUSIONS: Hypercholesterolemia increases endoglin levels in blood and simultaneously decreases its expression in aorta, together with atherosclerosis protective markers p-Smad2 and VEGF, followed by increased plaque size. Inhibition of endoglin signaling might be one of the mechanisms responsible for the promoting of endothelial dysfunction and atherogenesis. Moreover, the monitoring of endoglin serum levels might represent an attractive blood marker of progression of disease; however, the precise source and role of endoglin in blood serum remains to be elucidated.

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