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Hannah Murphy-Marshman, Katherine Quensel, Xu Shi-Wen, Rebecca Barnfield, Jacalyn Kelly, Alex Peidl, Richard J Stratton, Andrew Leask
TGFbeta induces fibrogenic responses in fibroblasts. Reactive oxygen species (ROS)/nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) may contribute to fibrogenic responses. Here, we examine if the antioxidant N-acetylcysteine (NAC), the NOX inhibitor diphenyleneiodonium (DPI) and the selective NOX1/NOX4 inhibitor GKT-137831 impairs the ability of TGFbeta to induce profibrotic gene expression in human gingival (HGF) and dermal (HDF) fibroblasts. We also assess if GKT-137831 can block the persistent fibrotic phenotype of lesional scleroderma (SSc) fibroblasts...
2017: PloS One
Jiong-Wei Wang, Magda S C Fontes, Xiaoyuan Wang, Suet Yen Chong, Elise L Kessler, Ya-Nan Zhang, Judith J de Haan, Fatih Arslan, Saskia C A de Jager, Leo Timmers, Toon A B van Veen, Carolyn S P Lam, Dominique P V de Kleijn
An involement of Toll-like receptor 2 (TLR2) has been established in cardiac dysfunction after acute myocardial infarction; however, its role in chronic pressure overload is unclear. We sought to evaluate the role of TLR2 in cardiac hypertrophy, fibrosis and dysfunction in sustained pressure overload. We induced pressure overload via transverse aortic constriction (TAC) in TLR2(-/-) and wild type (WT) mice, and followed temporal changes over 8 weeks. Despite similar increases in heart weight, left ventricular (LV) ejection fraction (EF) and diastolic function (mitral E/A ratio) were preserved in TLR2(-/-) mice but impaired in WT mice following TAC...
August 23, 2017: Scientific Reports
Hardik R Mody, Sau Wai Hung, Rakesh K Pathak, Jazmine Griffin, Zobeida Cruz-Monserrate, Rajgopal Govindarajan
Previous studies in our laboratory identified that 3-deazaneplanocin A (DZNep), a carbocyclic adenosine analog and histone methyl transferase inhibitor, suppresses TGFβ-induced epithelial-to-mesenchymal (EMT) characteristics. In addition, DZNep epigenetically reprograms miRNAs to regulate endogenous TGFβ1 levels via miR-663/4787-mediated RNA interference (Mol Cancer Res. 2016 Sep 13. pii: molcanres.0083.2016) (1). Although DZNep also attenuates exogenous TGFβ-induced EMT response, the mechanism of this inhibition was unclear...
August 2017: Molecular Cancer Research: MCR
Hongying Zhao, Jun Zhang, Haiyu Shao, Jianwen Liu, Mengran Jin, Jinping Chen, Yazeng Huang
Transforming growth factor β1 (TGFβ1)/Smad4 signaling plays a pivotal role in maintenance of the dynamic balance between bone formation and resorption. The microRNA miR-155 has been reported to exert a significant role in the differentiation of macrophage and dendritic cells. The goal of this study was to determine whether miR-155 regulates osteoclast differentiation through TGFβ1/Smad4 signaling. Here, we present that TGFβ1 elevated miR-155 levels during osteoclast differentiation through the stimulation of M-CSF and RANKL...
March 2017: Molecules and Cells
Marco De Santis Puzzonia, Angela Maria Cozzolino, Germana Grassi, Francesca Bisceglia, Raffaele Strippoli, Giulia Guarguaglini, Franca Citarella, Benedetto Sacchetti, Marco Tripodi, Alessandra Marchetti, Laura Amicone
In all mammals, the adult liver shows binucleated as well as mononucleated polyploid hepatocytes. The hepatic polyploidization starts after birth with an extensive hepatocyte binucleation and generates hepatocytes of several ploidy classes. While the functional significance of hepatocyte polyploidy is becoming clearer, how it is triggered and maintained needs to be clarified. Aim of this study was to identify a major inducer of hepatocyte binucleation/polyploidization and the cellular and molecular mechanisms involved...
2016: PloS One
Stefano Soldano, Carmen Pizzorni, Sabrina Paolino, Amelia Chiara Trombetta, Paola Montagna, Renata Brizzolara, Barbara Ruaro, Alberto Sulli, Maurizio Cutolo
BACKGROUND: Alternatively activated (M2) macrophages are phenotypically characterized by the expression of specific markers, mainly macrophage scavenger receptors (CD204 and CD163) and mannose receptor-1 (CD206), and participate in the fibrotic process by over-producing pro-fibrotic molecules, such as transforming growth factor-beta1 (TGFbeta1) and metalloproteinase (MMP)-9. Endothelin-1 (ET-1) is implicated in the fibrotic process, exerting its pro-fibrotic effects through the interaction with its receptors (ETA and ETB)...
2016: PloS One
Hardik R Mody, Sau Wai Hung, Mohammad AlSaggar, Jazmine Griffin, Rajgopal Govindarajan
The identification of epigenetic reversal agents for use in combination chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an unmet clinical need. Pharmacologic inhibitors of Enhancer of Zeste Homolog 2 (EZH2) are emerging as potential histone methylation reversal agents for the treatment of various solid tumors and leukemia; however, the surprisingly small set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms contribute to their antitumorigenic effects. Here, 3-deazaneplanocin-A (DZNep), an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methyltransferase, significantly reprograms noncoding microRNA (miRNA) expression and dampens TGFβ1-induced epithelial-to-mesenchymal (EMT) signals in pancreatic cancer...
November 2016: Molecular Cancer Research: MCR
John Martin, Adam Midgley, Soma Meran, Emma Woods, Timothy Bowen, Aled O Phillips, Robert Steadman
Fibroblasts are central to wound healing and fibrosis through TGFβ1-triggered differentiation into contractile, α-smooth muscle actin (α-SMA)-positive myofibroblasts. This is mediated by accumulation of a pericellular matrix of hyaluronan (HA) and the HA-dependent co-localization of CD44 with the epidermal growth factor receptor (EGFR). Interactions of HA with hyaladherins, such as inter-α-inhibitor (IαI) and tumor necrosis factor-stimulated gene-6 (TSG-6), are also essential for differentiation. This study investigated the mechanisms involved...
June 24, 2016: Journal of Biological Chemistry
Zhou-xin Ren, Hai-bin Yu, Jian-sheng Li, Jun-ling Shen, Jun-kai Li, Shan Luo
In the study, the effects of Panax notoginseng saponins (PNS) on alveolar epithelial to mesenchymal transition (EMT) and extracellular matrix degradation were observed in a type of human alveolar epithelial cell, A549 cells, stimulated by TGF-beta1. Firstly, MTT method was applied to evaluation of cellular proliferation and found that PNS from 12.5 mg x L(-1) to 200 mg x L(-1) dosage could not inhibit significantly cellular proliferation. Then, cells were divided into five groups, normal group, TGF-beta1 group, TGF-beta1 + 50 mg x L(-1) PNS group, TGF-beta1 + 100 mg x L(-1) PNS group and TGF-beta1 + 200 mg x L(-1) PNS group...
December 2015: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Shengzheng Luo, Zhenghong Li, Mingyi Xu, Qingqing Zhang, Ying Qu, Lungen Lu
OBJECTIVE: To investigate the role of TGF-beta1 and STAT3 signaling in liver fibrosis using a rat model system and to determine the therapeutic mechanism of AG490 in relation to this signaling pathway. METHODS: Rats were randomly divided into a control group and DENA-induced liver fibrosis model group, and then subdivided into AG490 treatment groups. During fibrosis development, liver tissue samples were collected at different time points (0, 4 and 8 weeks) and evaluated according to the Scheuer scoring system...
December 2015: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
Fanli Meng, Blaise Forrester-Gauntlett, Pavla Turner, Harold Henderson, Björn Oback
The inner cell mass (ICM) of mammalian blastocysts consists of pluripotent epiblast and hypoblast lineages, which develop into embryonic and extraembryonic tissues, respectively. We conducted a chemical screen for regulators of epiblast identity in bovine Day 8 blastocysts. From the morula stage onward, in vitro fertilized embryos were cultured in the presence of cell-permeable small molecules targeting nine principal signaling pathway components, including TGFbeta1, BMP, EGF, VEGF, PDGF, FGF, cAMP, PI3K, and JAK signals...
December 2015: Biology of Reproduction
Susanne Proksch, Gido Bittermann, Kirstin Vach, Roland Nitschke, Pascal Tomakidi, Elmar Hellwig
Human mesenchymal stem cells (hMSCs) are promising candidates for regenerative periodontal strategies, due to the broad spectrum of supportive effects on cells and tissues at the site of application. Although positive effects are visible, the understanding of their underlying mechanisms still requires further elucidation. Recently, we have shown that hMSCs are capable to prompt osteogenic differentiation of alveolar osteoblasts, thereby presumably contributing to alveolar bone regeneration. Another issue that is critical in this context is the attraction of hard tissue-forming cells to regeneration sites, but it is an open question whether hMSCs can afford this...
October 2015: Stem Cells
Dan Li, Xiao-Wei Zhang, Xing-Quan Jiang, Yong-Jie Yin, Zhe Fan, Cheng-Bo Sun, Xing-Hai Chen, Yan-Hui Li, Ke-Xiang Liu
BACKGROUND: This study was designed to evaluate the protective effects of thalidomide on paraquat (PQ)-induced lung injuries in a rat model and to explore the underlying mechanisms. METHODS: Rats were exposed to 50 mg/kg PQ by oral gavage, and treated with thalidomide through oral administration at 60 mg/kg once a day, 6 days/week for 2 weeks. Serum levels of IL-6, TNF-alpha, TGFbeta1 and COL1A1 were detected at different time points after paraquat exposure...
2015: Journal of Inflammation
Kinga Musiał, Agnieszka Bargenda, Danuta Zwolińska
CONTEXT: Epithelial-mesenchymal transition (EMT) leads to renal fibrosis and chronic kidney disease (CKD). OBJECTIVE: The aim of this study was to assess the usefulness of survivin, E-cadherin and metalloproteinases (MMPs) as biomarkers of CKD-related complications. MATERIAL AND METHODS: Survivin, E-cadherin, MMP-2, MMP-9 and TGFbeta1 were assessed by ELISA in 41 children with CKD stages 3 to 5 and in 23 controls. RESULTS: The serum and urine values of analyzed parameters were significantly elevated in CKD patients versus controls and correlated with each other...
2015: Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals
Kinga Musiał, Agnieszka Bargenda, Danuta Zwolińska
BACKGROUND: Transforming growth factor (TGF)beta1 and matrix metalloproteinases (MMPs) play an essential role in CKD-related tissue remodeling. However, there are no data on urine MMPs and their extracellular inducer EMMPRIN in CKD patients. The aim of study was to assess the concentrations of MMP-2, MMP-7, MMP-9, EMMPRIN and TGFbeta1 in serum and urine of CKD children and to analyze the potential relations between those parameters. METHODS: Forty-one pre-dialysis CKD children and 23 age-matched controls were enrolled in the study...
July 2015: Renal Failure
Jun Liu, Jian Cao, Xiaokun Zhao
BACKGROUND: Distant metastasis is the major cause of cancer-related death, and epithelial-to-mesenchymal transition (EMT) has a critical role in this process. Accumulating evidence indicates that EMT can be regulated by microRNAs (miRNAs). miR-221, as oncogenes in several human cancers, was significantly up-regulated in bladder cancers. However, the role of miR-221 in the progression of bladder cancer metastasis remains largely unknown. METHODS: We used qRT-PCR and western blot to accurately measure the levels of miR-221, STMN1 and EMT markers in TGFβ1 induced EMT of bladder cancer cells...
2015: BMC Urology
O F Gordeeva
TGFP3 family factors play an important role in regulating the balance of self-renewal and differentiation of mouse and human pluripotent stem and embryonic teratocarcinoma cells. The expression patterns of TGFbeta family signaling ligands and functional roles of these signaling pathways differ significantly in mouse and human embryonic stem cells, but the activity and functional role of these factors in mouse and human embryonic teratocarcinoma cells were not sufficiently investigated. Comparative quantitative real-time PCR analysis of the expression of TGF@[beta] family factors in mouse embryonic stem, embryonic germ, and embryonic teratocarcinoma cells showed that embryonic teratocarcinoma cells express lower ActivinA than pluripotent stem cells but similar levels of factors Nodal, Lefty 1, TGFbeta1, BMP4, and GDF3...
July 2014: Ontogenez
Kota Matsuki, Catherine K Hathaway, Albert S Chang, Oliver Smithies, Masao Kakoki
PURPOSE OF REVIEW: It is well established that blocking the renin-angiotensin-aldosterone system (RAAS) is effective for the treatment of cardiovascular and renal complications in hypertension and diabetes mellitus. Although the induction of transforming growth factor beta1 (TGFbeta1) by components of the RAAS mediates the hypertrophic and fibrogenic changes in cardiovascular-renal complications, it is still controversial as to whether TGFbeta1 can be a target to prevent such complications...
March 2015: Current Opinion in Nephrology and Hypertension
Wei Zhang, Xiaoming Dai, Hong Yu, Luyan Wang, Shihui Sun, Junfeng Li, Yusen Zhou
OBJECTIVE: To construct a dual-reporter gene system that will be applicable for use as a tool to screen and evaluate therapeutic drug compounds that inhibit transcription of the gene encoding collagen I, chain at1 (COL1A1). METHODS: The full-length eDNA of transforming growth factor beta1 (TGFbeta1) was cloned by RT-PCR and inserted into two vectors, pcDNA3.1 and pJW4303, for construction of two eukaryotic expression vectors, pcDNA3.1-TGFbeta1 and pJW4303-TGFbeta1...
October 2014: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
Amiq Gazdhar, Iwona Grad, Luca Tamò, Mathias Gugger, Anis Feki, Thomas Geiser
INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrotic lung disease, resulting in respiratory insufficiency and reduced survival. Pulmonary fibrosis is a result of repeated alveolar epithelial microinjuries, followed by abnormal regeneration and repair processes in the lung. Recently, stem cells and their secretome have been investigated as a novel therapeutic approach in pulmonary fibrosis. We evaluated the potential of induced pluripotent stem cells (iPSC) conditioned media (iPSC-cm) to regenerate and repair the alveolar epithelium in vitro and improve bleomycin induced lung injury in vivo...
2014: Stem Cell Research & Therapy
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