scholarly journals MicroRNA-195-5p Downregulation Inhibits Endothelial Mesenchymal Transition and Myocardial Fibrosis in Diabetic Cardiomyopathy by Targeting Smad7 and Inhibiting Transforming Growth Factor Beta 1-Smads-Snail Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Huaisheng Ding ◽  
Jianhui Yao ◽  
Hongxiang Xie ◽  
Chengyu Wang ◽  
Jing Chen ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Left Ventricular ◽  
Collagen Deposition ◽  
Mesenchymal Transition ◽  
Growth Factor Beta ◽  
Endothelial Mesenchymal Transition ◽  
Tgf Β1

Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus, which is associated with fibrosis and microRNAs (miRs). This study estimated the mechanism of miR-195-5p in endothelial mesenchymal transition (EndMT) and myocardial fibrosis in DCM. After the establishment of DCM rat models, miR-195-5p was silenced by miR-195-5p antagomir. The cardiac function-related indexes diastolic left ventricular anterior wall (LVAW, d), systolic LVAW (d), diastolic left ventricular posterior wall (LVPW, d), systolic LVPW (d), left ventricular ejection fraction (LVEF), and fractional shortening (FS) were measured and miR-195-5p expression in myocardial tissue was detected. Myocardial fibrosis, collagen deposition, and levels of fibrosis markers were detected. Human umbilical vein endothelial cells (HUVECs) were exposed to high glucose (HG) and miR-195-5p was silenced. The levels of fibrosis proteins, endothelial markers, fibrosis markers, EndMT markers, and transforming growth factor beta 1 (TGF-β1)/Smads pathway-related proteins were measured in HUVECs. The interaction between miR-195-5p and Smad7 was verified. In vivo, miR-195-5p was highly expressed in the myocardium of DCM rats. Diastolic and systolic LVAW, diastolic and systolic LVPW were increased and LVEF and FS were decreased. Inhibition of miR-195-5p reduced cardiac dysfunction, myocardial fibrosis, collagen deposition, and EndMT, promoted CD31 and VE-cadehrin expressions, and inhibited α-SMA and vimentin expressions. In vitro, HG-induced high expression of miR-195-5p and the expression changes of endothelial markers CD31, VE-cadehrin and fibrosis markers α-SMA and vimentin were consistent with those in vivo after silencing miR-195-5p. In mechanism, miR-195-5p downregulation blocked EndMT by inhibiting TGF-β1-smads pathway. Smad7 was the direct target of miR-195-5p and silencing miR-195-5p inhibited EndMT by promoting Smad7 expression. Collectively, silencing miR-195-5p inhibits TGF-β1-smads-snail pathway by targeting Smad7, thus inhibiting EndMT and alleviating myocardial fibrosis in DCM.

scholarly journals IN VIVO EFFICACY OF TOPICAL BINAHONG (ANREDERA CORDIFOLIA (TEN.) STEENIS) LEAF ETHANOLIC EXTRACT ON TRANSFORMING GROWTH FACTOR-BETA 1 IN INFECTED WOUNDS

2021 ◽  
pp. 99-102
Author(s):  
RIZKI ANDINI NAWAWI ◽  
MUHAMMAD TOTONG KAMALUDDIN ◽  
THEODORUS
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Ethanolic Extract ◽  
Bacterial Count ◽  
Treatment Groups ◽  
Infected Wounds ◽  
Growth Factor Beta ◽  
Tgf Β1

Objective: This study’s aim was to assess the efficacy of topical Binahong (Anredera cordifolia (Ten.) Steenis) leaf ethanolic extract administration on serum transforming growth factor-beta 1 (TGF-β1) in infected wounds. Methods: An experimental study, in vivo, was conducted in the Biotechnology Laboratory and Animal House, Faculty of Medicine, Universitas Sriwijaya, Palembang, from July to September 2020. There were 30 male Wistar rats aged 10–12 weeks with excisional wounds infected with Staphylococcus aureus ATCC 25923. The rats were divided into five groups and received three concentrations of Binahong leaf extracts (2.5%, 5%, and 10%), salve base, and povidone iodine 10% topically twice daily for 14 days. Serum was obtained before treatment and after 14 days of treatment. Wound area and bacterial count were also recorded and analyzed. Data analysis was performed using computer software. Results: Wound size and bacterial count were significantly decreased in treatment groups receiving topical Binahong leaf ethanolic extract. No significant increase in serum TGF-β1 was observed in all treatment groups. Conclusion: Topical administration of Binahong leaf ethanolic extract on rats with infected wounds for 14 days did not significantly increase serum TGF-β1.

scholarly journals TGFβ1-induced cell motility is mediated through Cten in colorectal cancer

2018 ◽  
Author(s):  
Abdulaziz Asiri ◽  
Teresa Pereira Raposo ◽  
Abdulaziz Alfahed ◽  
Mohammad Ilyas
Keyword(s):  
Colorectal Cancer ◽  
Cell Motility ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Growth Factor Beta ◽  
Emt Markers ◽  
Tgf Β1

ABSTRACTCten is a tensin which promotes epithelial-mesenchymal transition (EMT) and cell motility. The precise mechanisms regulating Cten are unknown, although Cten could be regulated by several cytokines and growth factors. Since Transforming growth factor beta 1 (TGF-β1) regulates integrin function and promotes EMT / cell motility, we investigated whether this happens through Cten signalling in colorectal cancer (CRC).TGF-β1 signalling was modulated by either stimulation or knockdown in the CRC cell lines SW620 and HCT116. The effect of this modulation on expression of Cten, EMT markers and cellular function was tested. Cten role as a direct mediator of TGF-β1 signalling was investigated in a CRC cell line with a deleted Cten gene (SW620ΔCten).When TGF-β1 was stimulated or inhibited, this resulted in, respectively, upregulation and downregulation of Cten expression and EMT markers. Cell migration and invasion were significantly increased following TGF-β1 stimulation and lost by TGF-β1 knockdown. TGF-β1 stimulation in SW620ΔCten resulted in selective loss of the effect of TGF-β1 signalling on EMT and cell motility whilst the stimulatory effect on cell proliferation was retained.These data suggested Cten may play an essential role in mediating TGF-β1-induced EMT and cell motility and may play a role in metastasis in CRC.

scholarly journals Celastrol-Induced Suppression of the MiR-21/ERK Signalling Pathway Attenuates Cardiac Fibrosis and Dysfunction

2016 ◽  
Vol 38 (5) ◽  
pp. 1928-1938 ◽  
Author(s):  
Mian Cheng ◽  
Gang Wu ◽  
Yue Song ◽  
Lin Wang ◽  
Ling Tu ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Signalling Pathway ◽  
Tgf Β1

Backgroud: Myocardial fibrosis results in myocardial remodelling and dysfunction. Celastrol, a traditional oriental medicine, has been suggested to have cardioprotective effects. However, its underlying mechanism is unknown. This study investigated the ability of celastrol to prevent cardiac fibrosis and dysfunction and explored the underlying mechanisms. Methods: Animal and cell models of cardiac fibrosis were used in this study. Myocardial fibrosis was induced by transverse aortic constriction (TAC) in mice. Cardiac hypertrophy and fibrosis were evaluated based on histological and biochemical measurements. Cardiac function was evaluated by echocardiography. The levels of transforming growth factor beta 1 (TGF-β1), extracellular signal regulated kinases 1/2 (ERK1/2) signalling were measured using Western blotting, while the expression of miR-21was analyzed by real-time qRT-PCR in vitro and in vivo. In vitro studies, cultured cardiac fibroblasts (CFs) were treated with TGF-β1 and transfected with microRNA-21(miR21). Results: Celastrol treatment reduced the increased collagen deposition and down-regulated α-smooth muscle actin (α-SMA), atrial natriuretic peptide (ANP), brain natriuretic peptides (BNP), beta-myosin heavy chain (β-MHC), miR-21 and p-ERK/ERK. Cardiac dysfunction was significantly attenuated by celastrol treatment in the TAC mice model. Celastrol treatment reduced myocardial fibroblast viability and collagen content and down-regulated α-SMA in cultured CFs in vitro. Celastrol also inhibited the miR-21/ERK signalling pathway. Celastrol attenuated miR-21 up-regulation by TGF-β1 and decreased elevated p-ERK/ERK levels in CFs transfected with miR-21. Conclusion: MiR-21/ERK signalling could be a potential therapeutic pathway for the prevention of myocardial fibrosis. Celastrol ameliorates myocardial fibrosis and cardiac dysfunction, these probably related to miR-21/ERK signaling pathways in vitro and in vivo.

scholarly journals Cooperation between Snail and LEF-1 Transcription Factors Is Essential for TGF-β1-induced Epithelial-Mesenchymal Transition

2006 ◽  
Vol 17 (4) ◽  
pp. 1871-1879 ◽  
Author(s):  
Damian Medici ◽  
Elizabeth D. Hay ◽  
Daniel A. Goodenough
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Mdckii Cells ◽  
Growth Factor Beta ◽  
Tgf Β1 ◽  
Expression Loss ◽  
E Cadherin

Transforming growth factor beta 1 (TGF-β1) has been shown to induce epithelial-mesenchymal transition (EMT) during various stages of embryogenesis and progressive disease. This alteration in cellular morphology is typically characterized by changes in cell polarity and loss of adhesion proteins such as E-cadherin. Here we demonstrate that EMT is associated with loss of claudin-1, claudin-2, occludin, and E-cadherin expression within 72 h of exposure to TGF-β1 in MDCKII cells. It has been suggested that this expression loss occurs through TGF-β1 in a Smad-independent mechanism, involving MEK and PI3K pathways, which have previously been shown to induce expression of the Snail (SNAI-1) gene. Here we show that these pathways are responsible for loss of tight junctions and a partial loss of E-cadherin. However, our results also demonstrate that a complete loss of E-cadherin and transformation to the mesenchymal phenotype are dependent on Smad signaling, which subsequently stimulates formation of β-catenin/LEF-1 complexes that induce EMT.

scholarly journals TGF-β Pathway in Salivary Gland Fibrosis

2020 ◽  
Vol 21 (23) ◽  
pp. 9138
Author(s):  
Xianglan Zhang ◽  
Jun Seop Yun ◽  
Dawool Han ◽  
Jong In Yook ◽  
Hyun Sil Kim ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Post Radiation ◽  
Growth Factor Beta ◽  
Multiple Levels ◽  
In Vivo Delivery ◽  
Tgf Β1

Fibrosis is presented in various physiologic and pathologic conditions of the salivary gland. Transforming growth factor beta (TGF-β) pathway has a pivotal role in the pathogenesis of fibrosis in several organs, including the salivary glands. Among the TGF-β superfamily members, TGF-β1 and 2 are pro-fibrotic ligands, whereas TGF-β3 and some bone morphogenetic proteins (BMPs) are anti-fibrotic ligands. TGF-β1 is thought to be associated with the pro-fibrotic pathogenesis of sialadenitis, post-radiation salivary gland dysfunction, and Sjögren’s syndrome. Potential therapeutic strategies that target multiple levels in the TGF-β pathway are under preclinical and clinical research for fibrosis. Despite the anti-fibrotic effect of BMPs, their in vivo delivery poses a challenge in terms of adequate clinical efficacy. In this article, we will review the relevance of TGF-β signaling in salivary gland fibrosis and advances of potential therapeutic options in the field.

scholarly journals The Expression of BNP, ET-1, and TGF-β1 in Myocardium of Rats with Ventricular Arrhythmias

2019 ◽  
Vol 20 (23) ◽  
pp. 5845 ◽  
Author(s):  
Tian ◽  
Xiao ◽  
Xue ◽  
Zhang ◽  
Jia ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Quantitative Polymerase Chain Reaction ◽  
Type I ◽  
Rat Myocardium ◽  
Novel Biomarkers ◽  
Growth Factor Beta ◽  
Polymerase Chain ◽  
Tgf Β1

Ventricular arrhythmia (VA) is a major component of sudden cardiac death (SCD). To investigate the expression of brain natriuretic peptide (BNP), endothelin-1 (ET-1), and transforming growth factor-beta 1 (TGF-β1) during VA, we established a rat model of VA induced by BaCl2 solution through a microinjector pump. PD142893 (ET-1 receptor blocker) and SB431542 (TGF-β1 receptor type I blocker) were used to explore the effect of ET-1 and TGF-β1 on BNP expression in the myocardium after VA. BNP, ET-1, and TGF-β1 in rat myocardium were assayed by western blot and immunohistochemical staining for proteins, and real-time quantitative polymerase chain reaction for mRNAs. We found increased expression of BNP and ET-1 in rat myocardium that was associated with the duration of VA. However, TGF-β1 protein expression remained unchanged. Such early increases in BNP and ET-1 may be attributed to fatal arrhythmias associated with SCD, suggesting these may be novel biomarkers of this disease. After intraperitoneal injection of PD142893 and SB431542, respectively, BNP was downregulated in the myocardium of the left ventricle; however, this was abrogated by co-application of the two inhibitors. These results suggested that both ET-1 and TGF-β1, by specifically binding to their receptors, might be involved in the myocardial synthesis of BNP during VA in vivo.

scholarly journals Micellized Protein Transduction Domain-Bone Morphogenetic Protein-7 Efficiently Blocks Renal Fibrosis Via Inhibition of Transforming Growth Factor-Beta–Mediated Epithelial–Mesenchymal Transition

2020 ◽  
Vol 11 ◽  
Author(s):  
Seonghun Kim ◽  
Cheol-Hee Jeong ◽  
Sang Hyun Song ◽  
Jo Eun Um ◽  
Hyun Sil Kim ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Protein Transduction ◽  
Mesenchymal Transition ◽  
Ureter Obstruction ◽  
Morphogenetic Protein ◽  
Growth Factor Beta

Tubulointerstitial renal fibrosis is a chronic disease process affecting chronic kidney disease (CKD). While the etiological role of transforming growth factor-beta (TGF-β) is well known for epithelial–mesenchymal transition (EMT) in chronic kidney disease, effective therapeutics for renal fibrosis are largely limited. As a member of the TGF-β superfamily, bone morphogenetic protein-7 (BMP-7) plays an important role as an endogenous antagonist of TGF-β, inhibiting fibrotic progression in many organs. However, soluble rhBMP-7 is hardly available for therapeutics due to its limited pharmacodynamic profile and rapid clearance in clinical settings. In this study, we have developed a novel therapeutic approach with protein transduction domain (PTD) fused BMP-7 in micelle (mPTD-BMP-7) for long-range signaling in vivo. Contrary to rhBMP-7 targeting its cognate receptors, the nano-sized mPTD-BMP-7 is transduced into cells through an endosomal pathway and secreted to the exosome having active BMP-7. Further, transduced mPTD-BMP-7 successfully activates SMAD1/5/8 and inhibits the TGF-β–mediated epithelial–mesenchymal transition process in vitro and in an in vivo unilateral ureter obstruction model. To determine the clinical relevance of our strategy, we also developed an intra-arterial administration of mPTD-BMP-7 through renal artery in pigs. Interestingly, mPTD-BMP-7 through renal artery intervention effectively delivered into Bowman’s space and inhibits unilateral ureter obstruction–induced renal fibrosis in pigs. Our results provide a novel therapeutic targeting TGF-β–mediated renal fibrosis and other organs as well as a clinically available approach for kidney.

scholarly journals MicroRNA-34a Promotes EMT and Liver Fibrosis in Primary Biliary Cholangitis by Regulating TGF-β1/smad Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Ying Pan ◽  
Jing Wang ◽  
Lan He ◽  
Fengchun Zhang
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Peripheral Blood ◽  
Transforming Growth Factor ◽  
Primary Biliary Cholangitis ◽  
Smad Pathway ◽  
Mesenchymal Transition ◽  
Growth Factor Beta ◽  
Tgf Β1

Background and Aims. Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease. We found microRNA-34a (miR-34a), as the downstream gene of p53, was overexpressed in some of fibrogenic diseases. In this study, we sought to explore whether miR-34a plays a role in the fibrosis of PBC. Methods. The peripheral blood of PBC patients and controls was collected to analyze the level of miR-34a. Human intrahepatic biliary epithelial cells (HIBEC) were cultured. The expression of miR-34a was regulated by miR-34a mimics and inhibitor. The biomarkers of epithelium-mesenchymal transition (EMT), fibrogenesis, inflammation, and transforming growth factor- (TGF-) β1/smad pathway were analyzed. Results. We found that miR-34a was overexpressed in the peripheral blood in PBC patients. In vitro, overexpressed miR-34a increased the EMT and fibrogenesis activity of HIBEC. Transforming growth factor-beta type 1 receptor (TβR1), TGF-β1, and p-smad2/3 were upregulated by miR-34a. Inflammatory factors such as IL-6 and IL-17 were also upregulated. Finally, we showed that miR-34a promoted EMT and liver fibrosis in PBC by targeting the TGF-β1/smad pathway antagonist transforming growth factor-beta-induced factor homeobox 2 (TGIF2). Conclusions. Our findings show that miR-34a plays an important role in the EMT and fibrosis of PBC through the TGF-β1/smad pathway by targeting TGIF2. This study suggests that miR-34a may be a new marker of fibrogenesis in PBC. Inhibition of miR-34a may be a promising strategy in treating PBC and improving the prognosis of the disease.

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