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Alk5 inhibitor

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https://www.readbyqxmd.com/read/28969055/mir-338-3p-inhibits-the-invasion-of-renal-cell-carcinoma-by-downregulation-of-alk5
#1
Xiaoqian Zhang, Chunxia Wang, Hui Li, Xiaobin Niu, Xinwei Liu, Dongxu Pei, Xiaolan Guo, Xiaona Xu, Yongwei Li
BACKGROUND: The current study aims to elucidate the role of miRNA-338-3p (miR-338-3p) in the invasion of renal cell carcinoma (RCC). METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to detect the expression of miR-338-3p in human RCC cell lines with high metastatic potential (Caki-1) and low metastatic potential (786-O), respectively. The Caki-1 and 786-O cells were transfected with miR-338-3p mimic or inhibitor. Wound healing assay, Transwell assay and western blotting were performed to analyze the invasive ability and expression of activin receptor-like kinase 5 (ALK5) in the RCC cell lines...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28939526/inhibition-of-the-tgf-%C3%AE-1-smad-signaling-pathway-protects-against-cartilage-injury-and-osteoarthritis-in-a-rat-model
#2
Yong-Jian Wang, Min Shen, Shan Wang, Xin Wen, Xin-Rui Han, Zi-Feng Zhang, Hui Li, Fei Wang, Dong-Mei Wu, Jun Lu, Yuan-Lin Zheng
Transforming growth factor-β1 (TGF-β1) in osteoblastic cells triggers pathological changes observed in osteoarthritis (OA). Thus, we hypothesized that the inhibition of the TGF-β1/Smad signaling pathway could act to protect against cartilage injury in rats with OA. After establishment of rat models induced by papain and L-cysteine, rats were subsequently assigned into the TβRI inhibitors, normal control (NC) and OA model groups. RT-qPCR and western blotting were performed to determine mRNA and protein expressions of TGFβ1, Smad2, Smad3 and Activin receptor-like kinase 5 (ALK5), respectively...
September 19, 2017: Life Sciences
https://www.readbyqxmd.com/read/28842394/transforming-growth-factor-%C3%AE-1-activin-receptor-like-kinase-5-mediated-cell-migration-is-dependent-on-the-protein-proteinase-activated-receptor-2-but-not-on-proteinase-activated-receptor-2-stimulated-gq-calcium-signaling
#3
Hendrik Ungefroren, David Witte, Koichiro Mihara, Bernhard H Rauch, Petra Henklein, Olaf Jöhren, Shirin Bonni, Utz Settmacher, Hendrik Lehnert, Morley D Hollenberg, Roland Kaufmann, Frank Gieseler
Transforming growth factor-β (TGF-β), serine proteinases such as trypsin, and proteinase-activated receptor 2 (PAR2) promote tumor development by stimulating invasion and metastasis. Previously, we found that in cancer cells derived from pancreatic ductal adenocarcinoma (PDAC) PAR2 protein is necessary for TGF-β1-dependent cell motility. Here, we show in the same cells that, conversely, the type I TGF-β receptor activin receptor-like kinase 5 is dispensable for trypsin and PAR2 activating peptide (PAR2-AP)-induced migration...
November 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28815607/a-3d-tri-culture-system-reveals-that-activin-receptor-like-kinase-5-and-connective-tissue-growth-factor-drive-human-glomerulosclerosis
#4
John P Waters, Yvonne C Richards, Jeremy N Skepper, Mark Southwood, Paul D Upton, Nicholas W Morrell, Jordan S Pober, John R Bradley
Glomerular scarring, known as glomerulosclerosis, occurs in many chronic kidney diseases and involves interaction between glomerular endothelial cells (GECs), podocytes, and mesangial cells (MCs), leading to signals that promote extracellular matrix deposition and endothelial cell dysfunction and loss. We describe a 3D tri-culture system to model human glomerulosclerosis. In 3D monoculture, each cell type alters its phenotype in response to TGFβ, which has been implicated as an important mediator of glomerulosclerosis...
August 16, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28781950/role-of-the-tgf-%C3%AE-pathway-in-dedifferentiation-of-human-mature-adipocytes
#5
Julie Anne Côté, Julie Lessard, Mélissa Pelletier, Simon Marceau, Odette Lescelleur, Julie Fradette, André Tchernof
Dedifferentiation of adipocytes contributes to the generation of a proliferative cell population that could be useful in cellular therapy or tissue engineering. Adipocytes can dedifferentiate into precursor cells to acquire a fibroblast-like phenotype using ceiling culture, in which the buoyancy of fat cells is exploited to allow them to adhere to the inner surface of a container. Ceiling culture is usually performed in flasks, which limits the ability to test various culture conditions. Using a new six-well plate ceiling culture approach, we examined the relevance of TGF-β signaling during dedifferentiation...
August 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/28779848/tgf-%C3%AE-1-stimulates-cyclooxygenase-2-expression-and-pge2-production-of-human-dental-pulp-cells-role-of-alk5-smad2-and-mek-erk-signal-transduction-pathways
#6
Po-Shuen Lin, Ru-Hsiu Cheng, Mei-Chi Chang, Jang-Jaer Lee, Hsiao-Hua Chang, Wei-Ling Huang, Sin-Yuet Yeung, Ya-Ching Chang, Jiiang-Huei Jeng
BACKGROUND/PURPOSES: TGF-β1 is an important growth factor that may influence the odontoblast differentiation and matrix deposition in the reactionary/reparative dentinogenesis to dental caries or other tooth injuries. TGF-β1 exerts its effects through various signaling pathways, such as Smads and MAPKs. Cyclooxygenase-2 (COX-2) is a membrane-associated enzyme that produces prostaglandin E2 (PGE2) at sites of pulpal injury and inflammation, which leads to tissue swelling, redness and pain...
August 2, 2017: Journal of the Formosan Medical Association, Taiwan Yi Zhi
https://www.readbyqxmd.com/read/28767427/mir-338-3p-inhibits-the-invasion-of-renal-cell-carcinoma-by-downregulation-of-alk5
#7
Xiaoqian Zhang, Chunxia Wang, Hui Li, Xiaobin Niu, Xinwei Liu, Dongxu Pei, Xiaolan Guo, Xiaona Xu, Yongwei Li
BACKGROUND: The current study aims to elucidate the role of miRNA-338-3p (miR-338-3p) in the invasion of renal cell carcinoma (RCC). METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to detect the expression of miR-338-3p in human RCC cell lines with high metastatic potential (Caki-1) and low metastatic potential (786-O), respectively. The Caki-1 and 786-O cells were transfected with miR-338-3p mimic or inhibitor. Wound healing assay, Transwell assay and western blotting were performed to analyze the invasive ability and expression of activin receptor-like kinase 5 (ALK5) in the RCC cell lines...
July 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28716756/cartilage-specific-deletion-of-alk5-gene-results-in-a-progressive-osteoarthritis-like-phenotype-in-mice
#8
Q Wang, Q Y Tan, W Xu, H B Qi, D Chen, S Zhou, Z H Ni, L Kuang, J Y Guo, J L Huang, X X Wang, Z Q Wang, N Su, L Chen, B Chen, W L Jiang, Y Gao, H G Chen, X L Du, Y L Xie, L Chen
OBJECTIVE: Previous studies have shown that Transforming growth factor-β (TGF-β)/TGFβRII-Smad3 signaling is involved in articular cartilage homeostasis. However, the role of TGF-β/ALK5 signaling in articular cartilage homeostasis has not been fully defined. In this study, a combination of in vitro and in vivo approaches was used to elucidate the role of ALK5 signaling in articular cartilage homeostasis and the development of osteoarthritis (OA). DESIGN: Mice with inducible cartilage-specific deletion of Alk5 were generated to assess the role of ALK5 in OA development...
July 14, 2017: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/28694529/the-production-of-fibroblast-growth-factor-23-is-controlled-by-tgf-%C3%AE-2
#9
Martina Feger, Philipp Hase, Bingbing Zhang, Frank Hirche, Philipp Glosse, Florian Lang, Michael Föller
Transforming growth factor-β (TGF-β) is a cytokine produced by many cell types and implicated in cell growth, differentiation, apoptosis, and inflammation. It stimulates store-operated calcium entry (SOCE) through the calcium release-activated calcium (CRAC) channel Orai1/Stim1 in endometrial Ishikawa cells. Bone cells generate fibroblast growth factor (FGF) 23, which inhibits renal phosphate reabsorption and 1,25(OH)2D3 formation in concert with its co-receptor Klotho. Moreover, Klotho and FGF23 counteract aging and age-related clinical conditions...
July 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28632033/overexpression-of-alk5-induces-human-tenon-s-capsule-fibroblasts-transdifferentiation-and-fibrosis-in-vitro
#10
Shu-Hao Fu, Hui-Ying Wang, Jia-Ying Zhang, Hui-Min Shi, Nan Zhang, Wen Ye, Yi-Qin Xiao
PURPOSE: To investigate the involvement of activin receptor-like kinase 5 (ALK5) in human Tenon's capsule fibroblasts (HTFs) transdifferentiation and fibrosis. METHODS: (1) Cultured HTFs were treated with transforming growth factor beta 1 (TGF-β1) at different concentrations for different durations, mRNA expression of ALK5 and plasminogen activator inhibitor-1 (PAI-1) was measured by quantitative polymerase chain reaction (PCR) while protein expression of ALK5, α-smooth muscle actin (α-SMA), and extracellular matrix deposition including fibronectin (FN) and collagen I (Col1) was assessed by western blot...
February 28, 2017: Current Eye Research
https://www.readbyqxmd.com/read/28569204/tgf%C3%AE-1-induced-smad2-3-and-smad1-5-phosphorylation-are-both-alk5-kinase-dependent-in-primary-chondrocytes-and-mediated-by-tak1-kinase-activity
#11
Arjan van Caam, Wojciech Madej, Amaya Garcia de Vinuesa, Marie-José Goumans, Peter Ten Dijke, Esmeralda Blaney Davidson, Peter van der Kraan
BACKGROUND: Dysregulated transforming growth factor β (TGFβ) signaling is implicated in osteoarthritis development, making normalizing TGFβ signaling a possible therapy. Theoretically, this can be achieved with small molecule inhibitors specifically targeting the various TGFβ receptors and downstream mediators. In this study we explore in primary chondrocytes the use of small molecule inhibitors to target TGFβ-induced pSmad1/5/9-, pSmad2/3- and TGFβ-activated kinase 1 (TAK1)-dependent signaling...
May 31, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28489883/bmp-7-induces-apoptosis-in-human-germinal-center-b-cells-and-is-influenced-by-tgf-%C3%AE-receptor-type-i-alk5
#12
Lise K Bollum, Kanutte Huse, Morten P Oksvold, Baoyan Bai, Vera I Hilden, Lise Forfang, Sun Ok Yoon, Sébastien Wälchli, Erlend B Smeland, June H Myklebust
Selection and maturation of B cells into plasma cells producing high-affinity antibodies occur in germinal centers (GC). GCs form transiently in secondary lymphoid organs upon antigen challenge, and the GC reaction is a highly regulated process. TGF-β is a potent negative regulator, but the influence of other family members including bone morphogenetic proteins (BMPs) is less known. Studies of human peripheral blood B lymphocytes showed that BMP-6 suppressed plasmablast differentiation, whereas BMP-7 induced apoptosis...
2017: PloS One
https://www.readbyqxmd.com/read/28436712/disposition-and-metabolism-of-14-c-galunisertib-a-tgf-%C3%AE-ri-kinase-alk5-inhibitor-following-oral-administration-in-healthy-subjects-and-mechanistic-prediction-of-the-effect-of-itraconazole-on-galunisertib-pharmacokinetics
#13
Kenneth C Cassidy, Ivelina Gueorguieva, Colin Miles, Jessica Rehmel, Ping Yi, William J Ehlhardt
1. The disposition and metabolism of galunisertib (LY2157299 monohydrate, a TGF-βRI Kinase/ALK5 Inhibitor) was characterized following a single oral dose of 150 mg of [(14)C]-galunisertib (100 µCi) to six healthy human subjects. 2. The galunisertib plasma half-life was 8.6 h, while the (14)C half-life was 10.0 h. Galunisertib was abundant in circulation (40.3% of the (14)C AUC024 h), with 7 additional metabolites detected in plasma. Two metabolites LSN3199597 (M5, mono-oxidation), and M4 (glucuronide of M3) were the most abundant circulating metabolites (10...
May 16, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28405618/efficacy-of-alk5-inhibition-in-myelofibrosis
#14
Lanzhu Yue, Matthias Bartenstein, Wanke Zhao, Wanting Tina Ho, Ying Han, Cem Murdun, Adam W Mailloux, Ling Zhang, Xuefeng Wang, Anjali Budhathoki, Kith Pradhan, Franck Rapaport, Huaquan Wang, Zonghong Shao, Xiubao Ren, Ulrich Steidl, Ross L Levine, Zhizhuang Joe Zhao, Amit Verma, Pearlie K Epling-Burnette
Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples...
April 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28360109/focal-adhesion-kinase-signaling-determines-the-fate-of-lung-epithelial-cells-in-response-to-tgf-%C3%AE
#15
Qiang Ding, Indhu Subramanian, Tracy R Luckhardt, Pulin Che, Meghna Waghray, Xue-Ke Zhao, Nathaniel Bone, Ashish R Kurundkar, Louise Hecker, Meng Hu, Yong Zhou, Jeffrey C Horowitz, Ragini Vittal, Victor J Thannickal
Alveolar epithelial cell (AEC) injury and apoptosis are prominent pathological features of idiopathic pulmonary fibrosis (IPF). There is evidence of AEC plasticity in lung injury repair response and in IPF. In this report, we explore the role of focal adhesion kinase (FAK) signaling in determining the fate of lung epithelial cells in response to transforming growth factor-β1 (TGF-β1). Rat type II alveolar epithelial cells (RLE-6TN) were treated with or without TGF-β1, and the expressions of mesenchymal markers, phenotype, and function were analyzed...
June 1, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28359790/design-synthesis-and-optimization-of-7-substituted-pyrazolo-4-3-b-pyridine-alk5-activin-receptor-like-kinase-5-inhibitors
#16
Mark Sabat, Haixia Wang, Nick Scorah, J David Lawson, Joy Atienza, Ruhi Kamran, Mark S Hixon, Douglas R Dougan
A series of potent ALK5 inhibitors were designed using a SBDD approach and subsequently optimized to improve drug likeness. Starting with a 4-substituted quinoline screening hit, SAR was conducted using a ALK5 binding model to understand the binding site and optimize activity. The resulting inhibitors displayed excellent potency but were limited by high in vitro clearance in rat and human microsomes. Using a scaffold morphing strategy, these analogs were transformed into a related pyrazolo[4,3-b]pyridine series with improved ADME properties...
May 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28337662/a83-01-inhibits-tgf-%C3%AE-induced-upregulation-of-wnt3-and-epithelial-to-mesenchymal-transition-in-her2-overexpressing-breast-cancer-cells
#17
Yanyuan Wu, Trinh Tran, Sami Dwabe, Marianna Sarkissyan, Juri Kim, Miguel Nava, Sheilah Clayton, Richard Pietras, Robin Farias-Eisner, Jaydutt V Vadgama
PURPOSE: The aim of this study is to investigate the mechanisms of interactions between TGF-β and Wnt/β-catenin pathways that induce and regulate EMT and promote breast cancer cells to become resistant to treatment. METHODS: The effect of TGF-β on Wnt/β-catenin signaling pathway was examined by using a human Wnt/β-catenin-regulated cDNA plate array and western blot analysis. The interaction of Twist at promoter of Wnt3 was examined by chromatin immunoprecipitation (ChIP) assay...
June 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28324846/novel-alk5-inhibitor-tp0427736-reduces-tgf-%C3%AE-%C3%A3-induced-growth-inhibition-in-human-outer-root-sheath-cells-and-elongates-anagen-phase-in-mouse-hair-follicles
#18
Takumi Naruse, Mari Aoki, Natsuko Fujimoto, Seiji Arase, Hajimu Oura, Yasuji Ueda, Akiko Ikeda
BACKGROUND: Androgenic alopecia (AGA) occurs as a result of the contraction of the anagen phase because of the action of androgens on hair follicles. TGF-β production from dermal papillae is enhanced by androgens, and growth inhibition of hair-follicle cells is induced by TGF-β, and the hair cycle progresses from the anagen phase to the catagen phase. We investigated both the in vitro and in vivo potency of the newly identified ALK5 inhibitor TP0427736 {6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole}...
June 2017: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/28250236/tgfb1-represses-the-expression-of-sf1-and-lrh1-to-inhibit-e2-production-in-rat-lcs
#19
Qianqian Yang, Binfang Ma, Huilian Qiao, He Ma, Yuhang Dong, Liang Cao, Jing Ma, Zhen Li
Leydig cells (LCs) in the adult testis have been identified as the major sites of oestrogen production, which is crucial for mammalian germ cell differentiation. Our previous work showed that transforming growth factor beta 1 (TGFB1) inhibits estradiol (E2) secretion via down-regulating Cyp19 gene expression in mature rat (LCs). However, the mechanism remains unclear. In the present study, the effects of TGFB1 on the expression levels of steroidogenic factor 1 (SF1), liver receptor homolog 1 (LRH1), cAMP response element-binding protein (CREB) and cAMP responsive element modulator (CREM) were evaluated by Western blotting and immunofluorescence staining both in primary cultured LCs and in rat testis...
March 1, 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/28168444/fluid-shear-stress-induced-tgf-%C3%AE-alk5-signaling-in-renal-epithelial-cells-is-modulated-by-mek1-2
#20
Steven J Kunnen, Wouter N Leonhard, Cor Semeins, Lukas J A C Hawinkels, Christian Poelma, Peter Ten Dijke, Astrid Bakker, Beerend P Hierck, Dorien J M Peters
Renal tubular epithelial cells are exposed to mechanical forces due to fluid flow shear stress within the lumen of the nephron. These cells respond by activation of mechano-sensors located at the plasma membrane or the primary cilium, having crucial roles in maintenance of cellular homeostasis and signaling. In this paper, we applied fluid shear stress to study TGF-β signaling in renal epithelial cells with and without expression of the Pkd1-gene, encoding a mechano-sensor mutated in polycystic kidney disease...
June 2017: Cellular and Molecular Life Sciences: CMLS
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