scholarly journals MicroRNA-485 Modulates the TGF-β/ Smads Signaling Pathway in Chronic Asthmatic Mice by Targeting Smurf2

2018 ◽  
Vol 51 (2) ◽  
pp. 692-710 ◽  
Author(s):  
Jing Wang ◽  
Hong-Yan Li ◽  
Hu-Shan Wang ◽  
Zhen-Bo  Su
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Quantitative Polymerase Chain Reaction ◽  
Transforming Growth Factor Β ◽  
Airway Smooth Muscle Cell ◽  
Cell Cycle Distribution ◽  
Chronic Asthma ◽  
Expression Levels ◽  
Tgf Β1

Background/Aims: Chronic respiratory conditions continue to plague millions of people worldwide. We aimed to elucidate the detailed mechanisms of microRNA-485 (miR-485) in airway smooth muscle cell (ASMC) proliferation and apoptosis in chronic asthmatic mice. Methods: A mouse model of chronic asthma was established. Ovalbumin was used to induce chronic asthma in the mice. The levels of transforming growth factor β (TGF-β), interleukin (IL)-4, IL-5, IL-13 and IL-17 in bronchoalveolar lavage fluid in mice were measured by enzyme-linked immunoassays (ELISAs). ASMCs were transfected with miR-485 mimic, miR-485 inhibitor and siRNA-Smurf2. The reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analyses were applied to detect the mRNA and protein levels of Smurf2, α-SMA, TGF-β1 and decapentaplegic homolog (Smads). The MTT assay was utilized for cell proliferation, while flow cytometry was conducted to assess cell cycle distribution and apoptosis. Results: Lower expression of miR-485 and higher expression levels of TGF-β1, IL-4, IL-5, IL-13 and IL-17 were detected in mice with chronic asthma. Smurf2 was identified as the target gene of miR-485. Upregulation of miR-485 mimic and downregulation of Smurf2 decreased expression levels of Smurf2, α-SMA, TGF-β1 and Smad3, inhibited cell proliferation and increased apoptosis, while contrary results were observed in ASMCs transfected with miR-485 inhibitor. Conclusion: Overexpressed miR-485 inhibits cell proliferation and promotes apoptosis of ASMCs through the Smurf2-mediated TGF-β/Smads signaling pathway in mice with chronic asthma.

scholarly journals MicroRNA-224 Is Involved in Transforming Growth Factor-β-Mediated Mouse Granulosa Cell Proliferation and Granulosa Cell Function by Targeting Smad4

2010 ◽  
Vol 24 (3) ◽  
pp. 540-551 ◽  
Author(s):  
Guidong Yao ◽  
Mianmian Yin ◽  
Jie Lian ◽  
Hui Tian ◽  
Lin Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Granulosa Cell ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Ectopic Expression ◽  
Follicular Development ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Mrna Levels ◽  
Tgf Β1

Abstract Many members of the TGF-β superfamily are indicated to play important roles in ovarian follicular development, such as affecting granulosa cell function and oocyte maturation. Abnormalities associated with TGF-β1 signaling transduction could result in female infertility. MicroRNAs (miRNAs), as small noncoding RNAs, were recently found to regulate gene expression at posttranscriptional levels. However, little is known about the role of miRNAs in TGF-β-mediated granulosa cell proliferation and granulosa cell function. In this study, the miRNA expression profiling was identified from TGF-β1-treated mouse preantral granulosa cells (GCs), and three miRNAs were found to be significantly up-regulated and 13 miRNAs were down-regulated. Among up-regulated miRNAs, miR-224 was the second most significantly elevated miRNA. This up-regulation was attenuated by treatment of GCs with SB431542 (an inhibitor of TGFβ superfamily type I receptors, thus blocking phosphorylation of the downstream effectors Smad2/3), indicating that miR-224 expression was regulated by TGF-β1/Smads pathway. The ectopic expression of miR-224 can enhance TGF-β1-induced GC proliferation through targeting Smad4. Inhibition of endogenous miR-224 partially suppressed GC proliferation induced by TGF-β1. In addition, both miR-224 and TGF-β1 can promote estradiol release from GC, at least in part, through increasing CYP19A1 mRNA levels. This is the first demonstration that miRNAs can control reproductive functions resulting in promoting TGF-β1-induced GC proliferation and ovarian estrogen release. Such miRNA-mediated effects could be potentially used for regulation of reproductive processes or for treatment of reproductive disorders.

LncRNA HOTAIR promotes endometrial fibrosis by activating TGF-β1/Smad pathway

2020 ◽  
Vol 52 (12) ◽  
pp. 1337-1347
Author(s):  
Jianhong Wu ◽  
Lingge Jin ◽  
Yudi Zhang ◽  
Aihong Duan ◽  
Juhong Liu ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Therapeutic Option ◽  
Quantitative Polymerase Chain Reaction ◽  
Endometrial Stromal Cells ◽  
Expression Levels ◽  
Non Coding Rna ◽  
Smad Signaling Pathway ◽  
Tgf Β1

Abstract Homeobox transcript antisense RNA (HOTAIR) is a long non-coding RNA associated with a number of fibrosis-related diseases. The aim of this study was to investigate the specific role of HOTAIR in the development of endometrial fibrosis and to identify the molecular mechanisms underlying this process. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to determine the expression levels of HOTAIR in samples of intrauterine adhesion (IUA) tissue and in endometrial stromal cells (ESCs) that had been treated with transforming growth factor beta 1 (TGF-β1). Additionally, we transfected ESCs with either overexpression plasmid (pcDNA-HOTAIR) or silencing construct (si-HOTAIR) and then treated these cells with TGF-β1. We then performed RT-qPCR and western blot analysis, along with cell proliferation and apoptosis assays, to investigate the effects of HOTAIR on the transdifferentiation of ESCs into myofibroblasts. The results showed that the expression levels of HOTAIR were significantly elevated in IUA tissue and in ESCs that had been treated with TGF-β1. The overexpression of HOTAIR had a pro-fibrotic effect on ESCs, while the silencing of HOTAIR exerted an anti-fibrotic effect. Most importantly, the protein expression levels of p-Smad2 and p-Smad3 were significantly upregulated in TGF-β1-treated ESCs transfected with pcDNA-HOTAIR and were downregulated after transfection with si-HOTAIR constructs. These data indicate that HOTAIR promotes endometrial fibrosis by activating the TGF-β1/Smad signaling pathway, suggesting that the inhibition of HOTAIR may represent a promising therapeutic option for suppressing endometrial fibrosis.

Mechanism of Dandelion Sterol in Treating Pulmonary Fibrosis Through Transforming Growth Factor-β Signaling Pathway

2021 ◽  
Vol 11 (4) ◽  
pp. 612-618
Author(s):  
Qun Lv ◽  
Jianjun Wang ◽  
Zhaoyang Ruan
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Level ◽  
Lung Epithelial Cells ◽  
Migration And Invasion ◽  
Lung Epithelial ◽  
Tgf Β1

Background: The paper aimed to elucidate the molecular mechanism of Dandelion sterol in the treatment of pulmonary fibrosis, to study its effect on EMT of lung epithelial cells, and to find its target and downstream signaling pathways. Material and methods: The effects of Dandelion sterol on parathyroid (PQ)-induced EMT in lung epithelial cells were studied by immunofluorescence method. Immunohistochemistry and western-blot methods were used to verify that Dandelion sterol inhibited TGF-β1-induced EMT at the cellular level in animals, demonstrating that Dandelion sterol targets TGF-β1 to exert an anti-pulmonary fibrosis effect. Results: Dandelion sterol significantly inhibited PQ-induced migration and invasion of lung epithelial cells, and also inhibited the induced EMT. Dandelion sterol had a proper binding activity with the lung fibrosis-inducing factor TGF-β1. Dandelion sterol inhibited the TGF-β1-induced EMT process, and acted to treat pulmonary fibrosis by inhibiting the TGF-β1/Smad3 signaling pathway. Conclusion: Dandelion sterol can inhibit the pulmonary fibrosis by inhibiting the EMT process of lung epithelial cells through targeting the TGF- β1/Smad signaling pathway.

scholarly journals Arecoline Enhances Phosphodiesterase 4A Activity to Promote Transforming Growth Factor-β-Induced Buccal Mucosal Fibroblast Activation via cAMP-Epac1 Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Bo Zhang ◽  
Lihua Gao ◽  
Chunsheng Shao ◽  
Mingsi Deng ◽  
Liangjian Chen
Keyword(s):  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Clinical Investigation ◽  
Smooth Muscle Actin ◽  
Oral Submucous Fibrosis ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Camp Analog ◽  
Tgf Β1

Chewing areca nut (betel quid) is strongly associated with oral submucous fibrosis (OSF), a pre-cancerous lesion. Among the areca alkaloids, arecoline is the main agent responsible for fibroblast proliferation; however, the specific molecular mechanism of arecoline affecting the OSF remains unclear. The present study revealed that arecoline treatment significantly enhanced Transforming growth factor-β (TGF-β)-induced buccal mucosal fibroblast (BMF) activation and fibrotic changes. Arecoline interacts with phosphodiesterase 4A (PDE4A) to exert its effects through modulating PDE4A activity but not PDE4A expression. PDE4A silence reversed the effects of arecoline on TGF-β-induced BMFs activation and fibrotic changes. Moreover, the exchange protein directly activated by cAMP 1 (Epac1)-selective Cyclic adenosine 3′,5′-monophosphate (cAMP) analog (8-Me-cAMP) but not the protein kinase A (PKA)-selective cAMP analog (N6-cAMP) remarkably suppressed α-smooth muscle actin(α-SMA) and Collagen Type I Alpha 1 Chain (Col1A1) protein levels in response to TGF-β1 and arecoline co-treatment, indicating that cAMP-Epac1 but not cAMP-PKA signaling is involved in arecoline functions on TGF-β1-induced BMFs activation. In conclusion, arecoline promotes TGF-β1-induced BMFs activation through enhancing PDE4A activity and the cAMP-Epac1 signaling pathway during OSF. This novel mechanism might provide more powerful strategies for OSF treatment, requiring further in vivo and clinical investigation.

scholarly journals Human Papillomavirus Type 5 E6 Oncoprotein Represses the Transforming Growth Factor β Signaling Pathway by Binding to SMAD3

2006 ◽  
Vol 80 (24) ◽  
pp. 12420-12424 ◽  
Author(s):  
Jose-Andres Mendoza ◽  
Yves Jacob ◽  
Patricia Cassonnet ◽  
Michel Favre
Keyword(s):  
Human Papillomavirus ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Cellular Transformation ◽  
Transforming Growth Factor Β ◽  
Transforming Growth Factor Β1 ◽  
E6 Oncoprotein ◽  
E6 Protein ◽  
Tgf Β1

ABSTRACT Mechanisms of cellular transformation associated with human papillomavirus type 5 (HPV5), which is responsible for skin carcinomas in epidermodysplasia verruciformis (EV) patients, are poorly understood. Using a yeast two-hybrid screening and molecular and cellular biology experiments, we found that HPV5 oncoprotein E6 interacts with SMAD3, a key component in the transforming growth factor β1 (TGF-β1) signaling pathway. HPV5 E6 inhibits SMAD3 transactivation by destabilizing the SMAD3/SMAD4 complex and inducing the degradation of both proteins. Interestingly, the E6 protein of nononcogenic EV HPV9 failed to interact with SMAD3, suggesting that downregulation of the TGF-β1 signaling pathway could be a determinant in HPV5 skin carcinogenesis.

Regulatory effect of hsa-miR-5590-3P on TGFβ signaling through targeting of TGFβ-R1, TGFβ-R2, SMAD3 and SMAD4 transcripts

2019 ◽  
Vol 400 (5) ◽  
pp. 677-685 ◽  
Author(s):  
Elham Abedini Bakhshmand ◽  
Bahram Mohammad Soltani
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Quantitative Polymerase Chain Reaction ◽  
Direct Interaction ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Luciferase Assay ◽  
Regulatory Effect ◽  
Tgfβ Signaling ◽  
Smad Signaling Pathway

Abstract Transforming growth factor-β (TGFβ) signaling acts as suppressor and inducer of tumor progression during the early and late stages of cancer, respectively. Some miRNAs have shown a regulatory effect on TGFβ signaling and here, we have used a combination of bioinformatics and experimental tools to show that hsa-miR-5590-3p is a regulator of multiple genes expression in the TGFβ signaling pathway. Consistent with the bioinformatics predictions, hsa-miR-5590-3p had a negative correlation of expression with TGFβ-R1, TGFβ-R2, SMAD3 and SMAD4 genes, detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Then, the dual luciferase assay supported the direct interaction between hsa-miR-5590-3p and TGFβ-R1, TGFβ-R2, SMAD3 and SMAD4-3′UTR sequences. Consistently, the TGFβ-R1 protein level was reduced following the overexpression of hsa-miR-5590-3p, detected by Western analysis. Also, hsa-miR-5590-3p overexpression brought about the downregulation of TGFβ-R1, TGFβ-R2, SMAD3 and SMAD4 expression in HCT-116 cells, detected by RT-qPCR, followed by cell cycle arrest in the sub-G1 phase, detected by flow cytometry. RT-qPCR results indicated that hsa-miR-5590-3p is significantly downregulated in breast tumor tissues (late stage) compared to their normal pairs. Altogether, data introduces hsa-miR-5590-3p as a negative regulator of the TGFβ/SMAD signaling pathway which acts through downregulation of TGFβ-R1, TGFβ-R2, SMAD3 and SMAD4 transcripts. Therefore, it can be tested as a therapy target in cancers in which the TGFβ/SMAD pathway is deregulated.

scholarly journals Dendrobium Mixture Ameliorates Diabetic Nephropathy in db/db Mice by Regulating the TGF-β1/Smads Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Yong Chen ◽  
Xiaohui Lin ◽  
Yanfang Zheng ◽  
Wenzhen Yu ◽  
Fan Lin ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Lipid Level ◽  
Fasting Blood Glucose ◽  
Blood Lipid ◽  
Control Group ◽  
Expression Levels ◽  
Tgf Β1

Dendrobium mixture (DMix) is an effective treatment for diabetic nephropathy (DN), but the molecular mechanism underlying its action remains unclear. In this study, we investigated whether DMix regulates the transforming growth factor-β1 (TGF-β1)/Smads signal transduction pathway. Twenty-four db/db mice were randomly divided into three groups: the model, DMix, and gliquidone groups, while eight db/m mice were selected as the normal control group. The drug was administered by continuous gavage for 8 weeks. Body weight (BW), kidney weight (KW), kidney index, fasting blood glucose (FBG), blood lipid, 24-hour urinary albumin excretion rate, blood urea nitrogen, and serum creatinine levels were measured. Pathological changes in the renal tissue were observed under a light microscope. Real-time quantitative PCR and immunohistochemical staining were used to detect the mRNA and protein expression levels of TGF-β1 and alpha-smooth muscle actin (α-SMA), respectively, in renal tissues. TGF-β1, Smad2, p-Smad2, Smad3, p-Smad3, and α-SMA expression levels were measured using western blotting. The results showed that DMix significantly reduced the FBG level, BW, KW, and blood lipid level and improved renal function in db/db mice. Histopathology showed that DMix alleviated glomerular mesangial cell proliferation and renal interstitial fibrosis in db/db mice. Additionally, DMix reduced the protein and mRNA expression levels of TGF-β1 and α-SMA and inhibited Smad2 and Smad3 phosphorylation. We conclude that DMix may inhibit renal fibrosis and delay the progression of DN by regulating the TGF-β1/Smads signaling pathway.

scholarly journals Different macrophages equally induce EMT in endometria of adenomyosis and normal

Reproduction ◽  
2017 ◽  
Vol 154 (1) ◽  
pp. 79-92 ◽  
Author(s):  
Min An ◽  
Dong Li ◽  
Ming Yuan ◽  
Qiuju Li ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Quantitative Polymerase Chain Reaction ◽  
Immunohistochemical Analysis ◽  
Secretory Phase ◽  
Normal Endometrium ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Endometrial Cells

Endometrial cells and microenvironment are two important factors in the pathogenesis of adenomyosis. Our previous study demonstrated that macrophages can induce eutopic epithelial cells of adenomyosis to suffer from epithelial–mesenchymal transition (EMT). The aim of this study is to detect whether macrophages interacting with epithelial cells equally induce the EMT process in normal and eutopic endometria of healthy and adenomyotic patients; and whether macrophages parallelly polarize to M2. We investigated the expression levels of epithelial cadherin (E-cadherin), neural cadherin (N-cadherin), cytokeratin7 (CK7), vimentin, transforming growth factor-β1 (TGFB1), SMAD3 and pSMAD3 using immunohistochemistry and western blot, and then estimated the genetic levels of CD163, IL10 and MMP12 using real-time quantitative polymerase chain reaction (RT-PCR) in macrophages. Eutopic and normal endometrial tissues were obtained from 20 patients with adenomyosis and 11 control patients without adenomyosis, respectively. The immunohistochemical analysis shows distinct EMT in eutopic endometria in secretory phase; the expression levels of TGFB1, SMAD3 and pSMAD3 that indicate signal pathway of EMT were also higher in secretory phase. Macrophages can induce EMT process in primary endometrial epithelial cells derived from normal and eutopic endometria. After co-culturing, THP-1-derived macrophages polarized to M2. Compared with the eutopic endometrium group, further polarization to M2 was observed in the normal endometrium group. These results indicate that adenomyosis may be promoted by the pathologic EMT of epithelial cells, which is induced by macrophages that incapably polarize to M2.

scholarly journals Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

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