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Alk5 inhibitor

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https://www.readbyqxmd.com/read/29456135/pericyte-alk5-timp3-axis-contributes-to-endothelial-morphogenesis-in-the-developing-brain
#1
Jui M Dave, Teodelinda Mirabella, Scott D Weatherbee, Daniel M Greif
The murine embryonic blood-brain barrier (BBB) consists of endothelial cells (ECs), pericytes (PCs), and basement membrane. Although PCs are critical for inducing vascular stability, signaling pathways in PCs that regulate EC morphogenesis during BBB development remain unexplored. Herein, we find that murine embryos lacking the transforming growth factor β (TGF-β) receptor activin receptor-like kinase 5 (Alk5) in brain PCs (mutants) develop gross germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH)...
February 8, 2018: Developmental Cell
https://www.readbyqxmd.com/read/29416020/bone-morphogenetic-protein-2-promotes-human-trophoblast-cell-invasion-by-upregulating-n-cadherin-via-non-canonical-smad2-3-signaling
#2
Hong-Jin Zhao, Christian Klausen, Yan Li, Hua Zhu, Yan-Ling Wang, Peter C K Leung
BMP2 expression is spatiotemporally correlated with embryo implantation and is crucial for endometrial decidualization and fertility in mice. BMP2 has been reported to increase the mesenchymal adhesion molecule N-cadherin and enhance cell invasion in cancer cells; moreover, studies suggest that N-cadherin promotes placental trophoblast invasion. However, whether BMP2 can promote trophoblast cell invasion during placentation remains unknown. The objective of our study was to investigate the effects of BMP2 on human trophoblast cell invasion and the involvement of N-cadherin and SMAD signaling...
February 7, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29405089/correction-to-cassidy-et-al-disposition-and-metabolism-of-14c-galunisertib-a-tgf-bri-kinase-alk5-inhibitor-following-oral-administration-in-healthy-subjects-and-mechanistic-prediction-of-the-effect-of-itraconazole-on-galunisertib-pharmacokinetics
#3
https://www.readbyqxmd.com/read/29279601/isolation-and-culture-of-primary-mouse-retinal-pigment-epithelial-rpe-cells-with-rho-kinase-and-tgf%C3%AE-r-1-alk5-inhibitor
#4
Junhui Shen, Jianfeng He, Fang Wang
BACKGROUND Primary RPE cells could be a reliable model for representing in vivo status of RPE compared with cell lines. We present a protocol for in vitro isolation and culture of primary RPE cells from C57BL mice. MATERIAL AND METHODS We used C57BL mice ages 7 days to 4 months. The RPE layer was separated from the neural retina layer by digestion with 2% Dispase for 45 min and scraped off from the choroid after 25-min incubation in 37°C. Collected RPE sheets were gently pipetted up into smaller sheets. RPE sheets were transferred into well plates and cultured in vitro for 2 weeks...
December 27, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29261154/the-role-of-par2-in-tgf-%C3%AE-1-induced-erk-activation-and-cell-motility
#5
Hendrik Ungefroren, David Witte, Christian Fiedler, Thomas Gädeken, Roland Kaufmann, Hendrik Lehnert, Frank Gieseler, Bernhard H Rauch
BACKGROUND: Recently, the expression of proteinase-activated receptor 2 (PAR2) has been shown to be essential for activin receptor-like kinase 5 (ALK5)/SMAD-mediated signaling and cell migration by transforming growth factor (TGF)-β1. However, it is not known whether activation of non-SMAD TGF-β signaling (e.g., RAS-RAF-MEK-extracellular signal-regulated kinase (ERK) signaling) is required for cell migration and whether it is also dependent on PAR2. METHODS: RNA interference was used to deplete cells of PAR2, followed by xCELLigence technology to measure cell migration, phospho-immunoblotting to assess ERK1/2 activation, and co-immunoprecipitation to detect a PAR2-ALK5 physical interaction...
December 20, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29235674/loss-of-cyld-promotes-cell-invasion-via-alk5-stabilization-in-oral-squamous-cell-carcinoma
#6
Satoru Shinriki, Hirofumi Jono, Manabu Maeshiro, Takuya Nakamura, Jianying Guo, Jian-Dong Li, Mitsuharu Ueda, Ryoji Yoshida, Masanori Shinohara, Hideki Nakayama, Hirotaka Matsui, Yukio Ando
Oral squamous cell carcinoma (OSCC) has a very poor prognosis because of its highly invasive nature, and the 5-year survival rate has not changed appreciably for the past 30 years. Although cylindromatosis (CYLD), a deubiquitinating enzyme, is thought to be a potent tumour suppressor, its biological and clinical significance in OSCC is largely unknown. This study aimed to clarify the roles of CYLD in OSCC progression. Our immunohistochemical analyses revealed significantly reduced CYLD expression in invasive areas in OSCC tissues, whereas CYLD expression was conserved in normal epithelium and carcinoma in situ...
December 13, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/29229918/negative-regulation-of-tgf-%C3%AE-1-induced-mkk6-p38-and-mek-erk-signalling-and-epithelial-mesenchymal-transition-by-rac1b
#7
David Witte, Hannah Otterbein, Maria Förster, Klaudia Giehl, Robert Zeiser, Hendrik Lehnert, Hendrik Ungefroren
Prompted by earlier findings that the Rac1-related isoform Rac1b inhibits transforming growth factor (TGF)-β1-induced canonical Smad signalling, we studied here whether Rac1b also impacts TGF-β1-dependent non-Smad signalling such as the MKK6-p38 and MEK-ERK mitogen-activated protein kinase (MAPK) pathways and epithelial-mesenchymal transition (EMT). Transient depletion of Rac1b protein in pancreatic cancer cells by RNA interference increased the extent and duration of TGF-β1-induced phosphorylation of p38 MAPK in a Smad4-independent manner...
December 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29191563/tgf-%C3%AE-1-p53-signaling-in-renal-fibrogenesis
#8
Stephen P Higgins, Yi Tang, Craig E Higgins, Badar Mian, Wenzheng Zhang, Ralf-Peter Czekay, Rohan Samarakoon, David J Conti, Paul J Higgins
Fibrotic disorders of the renal, pulmonary, cardiac, and hepatic systems are associated with significant morbidity and mortality. Effective therapies to prevent or curtail the advancement to organ failure, however, remain a major clinical challenge. Chronic kidney disease, in particular, constitutes an increasing medical burden affecting >15% of the US population. Regardless of etiology (diabetes, hypertension, ischemia, acute injury, urologic obstruction), persistently elevated TGF-β1 levels are causatively linked to the activation of profibrotic signaling networks and disease progression...
November 28, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/29190781/roles-of-cd34-cells-and-alk5-signaling-in-the-reconstruction-of-seminiferous-tubule-like-structures-in-3-d-re-aggregate-culture-of-dissociated-cells-from-neonatal-mouse-testes
#9
Shin-Ichi Abe, Kazuko Abe, Jidong Zhang, Tomoaki Harada, Go Mizumoto, Hiroki Oshikawa, Haruhiko Akiyama, Kenji Shimamura
Tissue reconstruction in vitro can provide, if successful, a refined and simple system to analyze the underlying mechanisms that drive the morphogenesis and maintain the ordered structure. We have recently succeeded in reconstruction of seminiferous cord-like and tubule-like structures using 3-D re-aggregate culture of dissociated testicular cells. In testis formation, endothelial cells that migrated from mesonephroi to embryonic gonads have been shown to be critical for development of testis cords, but how endothelial cells contribute to testis cord formation remains unknown...
2017: PloS One
https://www.readbyqxmd.com/read/29113082/tgf-%C3%AE-1-smad3-signaling-pathway-mediates-t-2-toxin-induced-decrease-of-type-ii-collagen-in-cultured-rat-chondrocytes
#10
Yang Li, Ning Zou, Jing Wang, Ke-Wei Wang, Fu-Yuan Li, Fu-Xun Chen, Bing-Yu Sun, Dian-Jun Sun
T-2 toxin can cause damage to the articular cartilage, but the molecular mechanism remains unclear. By employing the culture of rat chondrocytes, we investigated the effect of the TGF-β1/Smad3 signaling pathway on the damage to chondrocytes induced by T-2 toxin. It was found that T-2 toxin could reduce cell viability and increased the number of apoptotic cells when compared with the control group. After the addition of the T-2 toxin, the production of type II collagen was reduced at mRNA and protein levels, while the levels of TGF-β1, Smad3, ALK5, and MMP13 were upregulated...
November 5, 2017: Toxins
https://www.readbyqxmd.com/read/29064324/2d-qsar-study-molecular-docking-and-molecular-dynamics-simulation-studies-of-interaction-mechanism-between-inhibitors-and-transforming-growth-factor-beta-receptori-alk5
#11
Meng-Nan Jiang, Xiao-Ping Zhou, Dong-Ru Sun, Huan Gao, Qing-Chuan Zheng, Hong-Xing Zhang, Di Liang
Transforming growth factor type 1 receptor (ALK5) is kinase associated with a wide variety of pathological processes, and inhibition of ALK5 is a good strategy to treat many kinds of cancer and fibrotic diseases. Recently a series of compounds have been synthesized as ALK5 inhibitors. However, the study of their selectivity against other potential targets remains elusive. In this research, adataset of ALK5 inhibitors were collected and studied based on the combination of 2D-QSAR, molecular docking and molecular dynamics simulation...
October 24, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28969055/mir-338-3p-inhibits-the-invasion-of-renal-cell-carcinoma-by-downregulation-of-alk5
#12
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
#13
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...
November 15, 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
#14
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
#15
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...
November 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28781950/role-of-the-tgf-%C3%AE-pathway-in-dedifferentiation-of-human-mature-adipocytes
#16
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
#17
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
#18
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
#19
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...
November 2017: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/28694529/the-production-of-fibroblast-growth-factor-23-is-controlled-by-tgf-%C3%AE-2
#20
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
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