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Alk5 inhibitor

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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
#1
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}...
January 25, 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
#2
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
#3
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...
February 6, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28165490/generation-of-pdgfr%C3%AE-cardioblasts-from-pluripotent-stem-cells
#4
Seon Pyo Hong, Sukhyun Song, Sung Woo Cho, Seungjoo Lee, Bong Ihn Koh, Hosung Bae, Kyun Hoo Kim, Jin-Sung Park, Hyo-Sang Do, Ilkyun Im, Hye Jin Heo, Tae Hee Ko, Jae-Hyeong Park, Jae Boum Youm, Seong-Jin Kim, Injune Kim, Jin Han, Yong-Mahn Han, Gou Young Koh
Isolating actively proliferating cardioblasts is the first crucial step for cardiac regeneration through cell implantation. However, the origin and identity of putative cardioblasts are still unclear. Here, we uncover a novel class of cardiac lineage cells, PDGFRα(+)Flk1(-) cardioblasts (PCBs), from mouse and human pluripotent stem cells induced using CsAYTE, a combination of the small molecules Cyclosporin A, the rho-associated coiled-coil kinase inhibitor Y27632, the antioxidant Trolox, and the ALK5 inhibitor EW7197...
February 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28135685/alk5-kinase-inhibitory-activity-and-synthesis-of-2-3-4-substituted-5-5-dimethyl-5-6-dihydro-4h-pyrrolo-1-2-b-pyrazoles
#5
Eva Řezníčková, Lukáš Tenora, Pavlína Pospíšilová, Juraj Galeta, Radek Jorda, Karel Berka, Pavel Majer, Milan Potáček, Vladimír Kryštof
A series of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles (DPPs) was synthesized and evaluated for their ALK5 inhibition activity. The most potent compounds displayed submicromolar IC50 values for ALK5. Preliminary profiling of one of the most active compounds in a panel of 50 protein kinases revealed its selectivity for ALK5. In cells, the compounds caused dose-dependent dephosphorylation of SMAD2, a well-established substrate of ALK5. In addition, the compounds blocked translocation of SMAD2/3 to nuclei of cells stimulated with TGFβ and the protein remained predominantly in cytoplasm, further confirming their molecular target...
February 15, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28114966/tgf-%C3%AE-1-induced-differentiation-of-shed-into-functional-smooth-muscle-cells
#6
Jian Guang Xu, Shao Yue Zhu, Boon Chin Heng, Waruna Lakmal Dissanayaka, Cheng Fei Zhang
BACKGROUND: Adequate vascularization is crucial for supplying nutrition and discharging metabolic waste in freshly transplanted tissue-engineered constructs. Obtaining the appropriate building blocks for vascular tissue engineering (i.e. endothelial and mural cells) is a challenging task for tissue neovascularization. Hence, we investigated whether stem cells from human exfoliated deciduous teeth (SHED) could be induced to differentiate into functional vascular smooth muscle cells (vSMCs)...
January 23, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28081250/cutaneous-deficiency-of-filaggrin-and-stat3-exacerbates-vaccinia-disease-in-vivo
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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-β (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 previously identified CD109 as a TGF-β co-receptor and inhibitor of TGF-β 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...
March 2017: 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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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