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https://www.readbyqxmd.com/read/28081250/cutaneous-deficiency-of-filaggrin-and-stat3-exacerbates-vaccinia-disease-in-vivo
#1
Yong He, Ishrat Sultana, Kazuyo Takeda, Jennifer L Reed
RATIONALE: Defects in filaggrin and STAT3 are associated with atopic dermatitis (AD) and susceptibility to severe skin infection. METHODS: We evaluated skin infection with the current smallpox vaccine, ACAM-2000, in immunosuppressed mice with combined cutaneous deficiency in filaggrin and STAT3. In parallel, early events post-infection with ACAM-2000 were investigated in cultured keratinocytes in which filaggrin expression was knocked down via siRNA. RESULTS: Immunosuppressed, filaggrin-deficient mice, treated with the topical STAT3 inhibitor Stattic® prior to ACAM-2000 infection, demonstrated rapid weight loss, prolonged vaccinia burden in skin, and dermatitis...
2017: PloS One
https://www.readbyqxmd.com/read/28078713/the-novel-mtor-complex-1-2-inhibitor-p529-inhibits-human-lung-myofibroblast-differentiation
#2
Keith T Ferguson, Elizabeth E Torr, Ksenija Bernau, Jonathan Leet, Davis Sherris, Nathan Sandbo
Idiopathic pulmonary fibrosis is a progressive and deadly disorder with very few therapeutic options. Palomid 529 (8-(1-hydroxyethyl)-2-methoxy-3-(4-methoxybenzyloxy)-benzo[c]chromen-6-one; P529) is a novel dual inhibitor of mechanistic target of rapamycin complex 1/2 (mTORC1/2). In these studies, we investigated the effect of P529 on TGF-β-dependent signaling and myofibroblast differentiation. TGF-β-induced phosphorylation of the mTORC1 targets, p70 S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), were both dose dependently inhibited by P529 in human lung fibroblasts with maximal inhibition occurring between 10-20 µM...
January 11, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28064471/vasohibin-2-is-required-for-epithelial-mesenchymal-transition-of-ovarian-cancer-cells-by-modulating-tgf-%C3%AE-signaling
#3
Rie Norita, Yasuhiro Suzuki, Yutaka Furutani, Kazuki Takahashi, Yasuhiro Yoshimatsu, Katarzyna A Podyma-Inoue, Tetsuro Watabe, Yasufumi Sato
Vasohibin-2 (VASH2) is a homologue of VASH1, an endothelium-derived angiogenesis inhibitor. VASH2 is mainly expressed in cancer cells, and has been implicated in the progression of cancer by inducing angiogenesis and tumor growth. While VASH2 has been recently reported to be involved in epithelial-mesenchymal transition (EMT), its precise roles are obscure. The aim of the present study was to clarify the role of VASH2 in the EMT of cancer cells in relation to TGF-β signaling, which is a major stimulator of the EMT...
January 8, 2017: Cancer Science
https://www.readbyqxmd.com/read/28046097/glucocorticoid-insensitivity-in-virally-infected-airway-epithelial-cells-is-dependent-on-transforming-growth-factor-%C3%AE-activity
#4
Yuxiu C Xia, Asmaa Radwan, Christine R Keenan, Shenna Y Langenbach, Meina Li, Danica Radojicic, Sarah L Londrigan, Rosa C Gualano, Alastair G Stewart
Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) and influenza A virus (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-β (TGF-β) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-β...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28019669/transforming-growth-factor-%C3%AE-1-modulates-the-expression-of-syndecan-4-in-cultured-vascular-endothelial-cells-in-a-biphasic-manner
#5
Takato Hara, Eiko Yoshida, Yasuyuki Fujiwara, Chika Yamamoto, Toshiyuki Kaji
Proteoglycans are macromolecules that consist of a core protein and one or more glycosaminoglycan side chains. Previously, we reported that transforming growth factor-β1 (TGF-β1 ) regulates the synthesis of a large heparan sulfate proteoglycan, perlecan, and a small leucine-rich dermatan sulfate proteoglycan, biglycan, in vascular endothelial cells depending on cell density. Recently, we found that TGF-β1 first upregulates and then downregulates the expression of syndecan-4, a transmembrane heparan sulfate proteoglycan, via the TGF-β receptor ALK5 in the cells...
December 26, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27934472/application-of-pd-catalyzed-cross-coupling-reactions-in-the-synthesis-of-5-5-dimethyl-5-6-dihydro-4h-pyrrolo-1-2-b-pyrazoles-that-inhibit-alk5-kinase
#6
Lukáš Tenora, Juraj Galeta, Eva Řezníčková, Vladimír Kryštof, Milan Potáček
C-H activation of position 3 of a substituted pyrazole ring catalyzed by palladium(II) was straightforward and convenient for arylated or heteroarylated 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles. Moreover, we introduced simple protection of the nitrogen in the pyridin-2-yl directing group, which otherwise does not allow a cross-coupling reaction, by transformation to the N-oxide. Selected final products were reasonably selective ALK5 kinase inhibitors.
December 2, 2016: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/27899163/human-fetal-and-adult-epicardial-derived-cells-a-novel-model-to-study-their-activation
#7
Asja T Moerkamp, Kirsten Lodder, Tessa van Herwaarden, Esther Dronkers, Calinda K E Dingenouts, Fredrik C Tengström, Thomas J van Brakel, Marie-José Goumans, Anke M Smits
BACKGROUND: The epicardium, a cell layer covering the heart, plays an important role during cardiogenesis providing cardiovascular cell types and instructive signals, but becomes quiescent during adulthood. Upon cardiac injury the epicardium is activated, which includes induction of a developmental gene program, epithelial-to-mesenchymal transition (EMT) and migration. However, the response of the adult epicardium is suboptimal compared to the active contribution of the fetal epicardium to heart development...
November 29, 2016: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/27866969/overexpression-of-cd109-in-the-epidermis-differentially-regulates-alk1-versus-alk5-signaling-and-modulates-extracellular-matrix-synthesis-in-the-skin
#8
Joshua Vorstenbosch, Christopher M Nguyen, Shufeng Zhou, You Jung Seo, Aya Siblini, Kenneth W Finnson, Albane A Bizet, Simon D Tran, Anie Philip
Transforming growth factor-beta (TGF-β) is a multifunctional growth factor involved in many physiological processes including wound healing and inflammation. Excessive TGF-β signaling in the skin has been implicated in fibrotic skin disorders such as keloids and scleroderma. We have previously identified CD109 as a TGF- β co-receptor and inhibitor of TGF-ß signaling, and have shown that transgenic mice overexpressing CD109 in the epidermis display decreased scarring. In certain cell types, in addition to the canonical type I receptor, ALK5 which activates Smad2/3, TGF-β can signal through another type I receptor ALK1 which activates Smad1/5...
November 17, 2016: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/27865758/bone-morphogenetic-protein-2-and-transforming-growth-factor-%C3%AE-1-inhibit-the-expression-of-the-proinflammatory-cytokine-il-34-in-rheumatoid-arthritis-synovial-fibroblasts
#9
Marguerite Chemel, Regis Brion, Aude-Isabelle Segaliny, Audrey Lamora, Celine Charrier, Benedicte Brulin, Yves Maugars, Benoit Le Goff, Dominique Heymann, Franck Verrecchia
IL-34 is a proinflammatory cytokine implicated in rheumatoid arthritis (RA). The current study aimed to assess the IL-34 expression in response to two members of the transforming growth factor (TGF)-β family, TGF-β1 and bone morphogenetic protein (BMP)-2, in synovial fibroblasts from RA patients. IL-34, TGF-β1, and BMP-2 productions were measured in patient synovial fluids by enzyme-linked immunosorbent assay. IL-34 mRNA levels were quantified by real-time quantitative PCR in human synovial fibroblasts and murine mesenchymal stem cells...
January 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/27723266/effects-of-tgf-%C3%AE-1-on-plasminogen-activation-in-human-dental-pulp-cells-role-of-alk5-smad2-tak1-and-mek-erk-signaling
#10
Mei-Chi Chang, Hsiao-Hua Chang, Po-Shuan Lin, Yu-An Huang, Chiu-Po Chan, Yi-Ling Tsai, Shen-Yang Lee, Po-Yuan Jeng, Han-Yueh Kuo, Sin-Yuet Yeung, Jiiang-Huei Jeng
Transforming growth factor-β1 (TGF-β1) plays an important role in the pulpal repair and dentinogenesis. Plasminogen activation (PA) system regulates extracellular matrix turnover. In this study, we investigated the effects of TGF-β1 on PA system of dental pulp cells and its signaling pathways. Dental pulp cells were treated with different concentrations of TGF-β1. MTT assay, reverse transcription-polymerase chain reaction (RT-PCR), western blotting and enzyme-linked immunosorbant assay (ELISA) were used to detect the effect of TGF-β1 on cell viability, mRNA and protein expression of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1) as well as their secretion...
October 9, 2016: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/27688842/expression-of-tgf-%C3%AE-signaling-regulator-rbpms-rna-binding-protein-with-multiple-splicing-is-regulated-by-il-1%C3%AE-and-tgf-%C3%AE-superfamily-members-and-decreased-in-aged-and-osteoarthritic-cartilage
#11
S Shanmugaapriya, A van Caam, L de Kroon, Elly L Vitters, B Walgreen, H van Beuningen, E Blaney Davidson, Peter M van der Kraan
OBJECTIVE: RNA-binding protein with multiple splicing (RBPMS) has been shown to physically interact with Smads and enhance transforming growth factor-β (TGF-β)-mediated Smad2/3 transcriptional activity in mammalian cells. Objective of this study was to examine whether expression of RBPMS is regulated by interleukin-1β (IL)-1β and TGF-β superfamily growth factors and whether expression of RBPMS is altered during aging and experimental osteoarthritis. METHODS: Expression of RBPMS protein was investigated in chondrocyte cell lines of murine (H4) and human (G6) origin using Western blot analysis...
October 2016: Cartilage
https://www.readbyqxmd.com/read/27460209/design-synthesis-and-optimization-of-novel-alk5-activin-like-kinase-5-inhibitors
#12
Haixia Wang, J David Lawson, Nick Scorah, Ruhi Kamran, Mark S Hixon, Joy Atienza, Douglas R Dougan, Mark Sabat
Using SBDD, a series of 4-amino-7-azaindoles were discovered as a novel class of Alk5 inhibitors that are potent in both Alk5 enzymatic and cellular assays. Subsequently a ring cyclization strategy was utilized to improve ADME properties leading to the discovery of a series of 1H-imidazo[4,5-c]pyridin-2(3H)-one drug like Alk5 inhibitors.
September 1, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27444351/mhp-1-inhibits-cancer-metastasis-and-restores-topotecan-sensitivity-via-regulating-epithelial-mesenchymal-transition-and-tgf-%C3%AE-signaling-in-human-breast-cancer-cells
#13
Sensen Lin, Xiaodan Lyu, Jun Yu, Li Sun, Danyu Du, Yanqi Lai, Hongyang Li, Ying Wang, Luyong Zhang, Hongping Yin, Shengtao Yuan
BACKGROUND: Cordyceps has long been used to treat cancer. However, its pharmacologically active components as well as the molecular mechanisms underlying its effects are still unclear. PURPOSE: To investigate the effect of MHP-1, a newly isolated polysaccharide from Mortierella hepialid (the asexual structure of C. sinensis), on breast cancer metastasis. STUDY DESIGN: The effect of MHP-1 on breast cancer cell migration, epithelial-mesenchymal transition (EMT) and TGF-β signaling were investigated in vitro and in vivo...
September 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/27248167/proteinase-activated-receptor-2-promotes-tgf-%C3%AE-dependent-cell-motility-in-pancreatic-cancer-cells-by-sustaining-expression-of-the-tgf-%C3%AE-type-i-receptor-alk5
#14
Franziska Zeeh, David Witte, Thomas Gädeken, Bernhard H Rauch, Evelin Grage-Griebenow, Nadja Leinung, Sofie Joline Fromm, Stephanie Stölting, Koichiro Mihara, Roland Kaufmann, Utz Settmacher, Hendrik Lehnert, Morley D Hollenberg, Hendrik Ungefroren
Pancreatic ductal adenocarcinoma (PDAC) is characterized by high expression of transforming growth factor (TGF)-β and the G protein-coupled receptor proteinase-activated receptor 2 (PAR2), the latter of which functions as a cell-surface sensor for serine proteinases asscociated with the tumour microenvironment. Since TGF-β and PAR2 affect tumourigenesis by regulating migration, invasion and metastasis, we hypothesized that there is signalling crosstalk between them. Depleting PDAC and non-PDAC cells of PAR2 by RNA interference strongly decreased TGF-β1-induced activation of Smad2/3 and p38 mitogen-activated protein kinase, Smad dependent transcriptional activity, expression of invasion associated genes, and cell migration/invasion in vitro...
July 5, 2016: Oncotarget
https://www.readbyqxmd.com/read/27182558/alk5-inhibition-increases-delivery-of-macromolecular-and-protein-bound-contrast-agents-to-tumors
#15
Heike E Daldrup-Link, Suchismita Mohanty, Celina Ansari, Olga Lenkov, Aubie Shaw, Ken Ito, Su Hyun Hong, Matthias Hoffmann, Laura Pisani, Nancy Boudreau, Sanjiv Sam Gambhir, Lisa M Coussens
Limited transendothelial permeability across tumor microvessels represents a significant bottleneck in the development of tumor-specific diagnostic agents and theranostic drugs. Here, we show an approach to increase transendothelial permeability of macromolecular and nanoparticle-based contrast agents via inhibition of the type I TGF-β receptor, activin-like kinase 5 (Alk5), in tumors. Alk5 inhibition significantly increased tumor contrast agent delivery and enhancement on imaging studies, while healthy organs remained relatively unaffected...
May 6, 2016: JCI Insight
https://www.readbyqxmd.com/read/27166254/transforming-growth-factor-%C3%AE-promotes-aggressiveness-and-invasion-of-clear-cell-renal-cell-carcinoma
#16
Raviprakash T Sitaram, Pramod Mallikarjuna, Maréne Landström, Börje Ljungberg
The molecular mechanisms whereby transforming growth factor-β (TGF-β) promotes clear cell renal cell carcinoma (ccRCC) progression is elusive. The cell membrane bound TGF-β type I receptor (ALK5), was recently found to undergo proteolytic cleavage in aggressive prostate cancer cells, resulting in liberation and subsequent nuclear translocation of its intracellular domain (ICD), suggesting that ALK5-ICD might be a useful cancer biomarker. Herein, the possible correlation between ALK5 full length (ALK5-FL) and ALK5-ICD protein, phosphorylated Smad2/3 (pSmad2/3), and expression of TGF-β target gene PAI-1, was investigated in a clinical ccRCC material, in relation to tumor grade, stage, size and cancer specific survival...
June 14, 2016: Oncotarget
https://www.readbyqxmd.com/read/27153151/a-small-dibromotyrosine-derivative-purified-from-pseudoceratina-sp-suppresses-tgf-%C3%AE-responsiveness-by-inhibiting-tgf-%C3%AE-type-i-receptor-serine-threonine-kinase-activity
#17
C-L Chen, Y-C Kao, P-H Yang, P-J Sung, J-H Wen, J-J Chen, P-Y Chen
For clinical application, there is a great need for small-molecule inhibitors (SMIs) that could control pathogenic effects of transforming growth factor (TGF-β) and/or modulate effects of TGF-β in normal responses. Selective SMIs of the TGF-β signaling pathway developed for therapeutics will also be powerful tools in experimentally dissecting this complex pathway, especially its cross-talk with other signaling pathways. In this study, we characterized (1'R,5'S,6'S)-2-(3',5'-dibromo-1',6'-dihydroxy-4'-oxocyclohex -2'-enyl) acetonitrile (DT), a member of a new class of small-molecule inhibitors related to bromotyrosine derivate from Pseudoceratina sp...
May 5, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27099352/calpain-2-activates-akt-via-tgf-%C3%AE-1-mtorc2-pathway-in-pulmonary-artery-smooth-muscle-cells
#18
Prasanna Abeyrathna, Laszlo Kovacs, Weihong Han, Yunchao Su
Calpain is a family of calcium-dependent nonlysosomal neutral cysteine endopeptidases. Akt is a serine/threonine kinase that belongs to AGC kinases and plays important roles in cell survival, growth, proliferation, angiogenesis, and cell metabolism. Both calpain and Akt are the downstream signaling molecules of platelet-derived growth factor (PDGF) and mediate PDGF-induced collagen synthesis and proliferation of pulmonary artery smooth muscle cells (PASMCs) in pulmonary vascular remodeling. We found that inhibitions of calpain-2 by using calpain inhibitor MDL28170 and calpain-2 small interfering RNA attenuated Akt phosphorylations at serine-473 (S473) and threonine-308 (T308), as well as collagen synthesis and cell proliferation of PASMCs induced by PDGF...
July 1, 2016: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/26588899/dasatinib-blocks-transcriptional-and-promigratory-responses-to-transforming-growth-factor-beta-in-pancreatic-adenocarcinoma-cells-through-inhibition-of-smad-signalling-implications-for-in-vivo-mode-of-action
#19
Tobias Bartscht, Benjamin Rosien, Dirk Rades, Roland Kaufmann, Harald Biersack, Hendrik Lehnert, Frank Gieseler, Hendrik Ungefroren
BACKGROUND: We have previously shown in pancreatic ductal adenocarcinoma (PDAC) cells that the SRC inhibitors PP2 and PP1 effectively inhibited TGF-β1-mediated cellular responses by blocking the kinase function of the TGF-β type I receptor ALK5 rather than SRC. Here, we investigated the ability of the clinically utilised SRC/ABL inhibitor dasatinib to mimic the PP2/PP1 effect. METHODS: The effect of dasatinib on TGF-β1-dependent Smad2/3 phosphorylation, general transcriptional activity, gene expression, cell motility, and the generation of tumour stem cells was measured in Panc-1 and Colo-357 cells using immunoblotting, reporter gene assays, RT-PCR, impedance-based real-time measurement of cell migration, and colony formation assays, respectively...
2015: Molecular Cancer
https://www.readbyqxmd.com/read/26524124/in-silico-studies-on-the-interaction-between-bioactive-ligands-and-alk5-a-biological-target-related-to-the-cancer-treatment
#20
Michell O Almeida, Gustavo H G Trossini, Vinícius G Maltarollo, Danielle da C Silva, Kathia M Honorio
Studies have showed that there are many biological targets related to the cancer treatment, for example, TGF type I receptor (TGF-βRI or ALK5). The ALK5 inhibition is a strategy to treat some types of cancer, such as breast, lung, and pancreas. Here, we performed CoMFA and CoMSIA studies for 70 ligands with ALK5 inhibition. The internal validation for both models (q(2)LOO = 0.887 and 0.822, respectively) showed their robustness, while the external validations showed their predictive power (CoMFA: r(2)test = 0...
September 2016: Journal of Biomolecular Structure & Dynamics
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