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Identification and Profiling of Environmental Chemicals That Inhibit the TGF?/SMAD Signaling Pathway.

ABSTRACT: The transforming growth factor beta (TGF?) superfamily of secreted signaling molecules and their cognate receptors regulate cell fate and behaviors relevant to many developmental and disease processes. Disruption of TGF? signaling during embryonic development can, for example, affect morphogenesis and differentiation through complex pathways that may be SMAD (Small Mothers Against Decapentaplegic) dependent or SMAD independent. In the present study, the SMAD Binding Element (SBE)-beta lactamase (bla) HEK 293T cell line, which responds to the activation of the SMAD2/3/4 complex, was used in a quantitative high-throughput screening (qHTS) assay to identify potential TGF? disruptors in the Tox21 10K compound library. From the primary screening we identified several kinase inhibitors, organometallic compounds, and dithiocarbamates (DTCs) that inhibited TGF?1-induced SMAD signaling of reporter gene activation independent of cytotoxicity. Counterscreen of SBE antagonists on human embryonic neural stem cells demonstrated cytotoxicity, providing additional evidence to support evaluation of these compounds for developmental toxicity. We profiled the inhibitory patterns of putative SBE antagonists toward other developmental signaling pathways, including wingless-related integration site (WNT), retinoic acid ? receptor (RAR), and sonic hedgehog (SHH). The profiling results from SBE-bla assay identify chemicals that disrupt TGF?/SMAD signaling as part of an integrated qHTS approach for prioritizing putative developmental toxicants.

SUBMITTER: Wei Z

PROVIDER: S-EPMC7341485 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Identification and Profiling of Environmental Chemicals That Inhibit the TGFβ/SMAD Signaling Pathway.

Wei Zhengxi Z Sakamuru Srilatha S Zhang Li L Zhao Jinghua J Huang Ruili R Kleinstreuer Nicole C NC Chen Yanling Y Shu Yan Y Knudsen Thomas B TB Xia Menghang M

Chemical research in toxicology 20191111 12

The transforming growth factor beta (TGFβ) superfamily of secreted signaling molecules and their cognate receptors regulate cell fate and behaviors relevant to many developmental and disease processes. Disruption of TGFβ signaling during embryonic development can, for example, affect morphogenesis and differentiation through complex pathways that may be SMAD (Small Mothers Against Decapentaplegic) dependent or SMAD independent. In the present study, the SMAD Binding Element (SBE)-beta lactamase ...[more]

PMID: 31652400

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Project description:BackgroundKangquan Recipe (KQR) is a traditional Chinese medicine compound made by our research group for the treatment of benign prostatic hyperplasia (BPH). Whether KQR can treat BPH as a single drug or play a role in the treatment of BPH in combination therapy needs further study.Aim of the studyTo investigate the effect of KQR on the expression of TGF-β/Smad signaling pathway-related factors in rats with BPH. In-depth analysis revealed the relevant signal transduction mechanism by which KQR acts to treat BPH.Materials and methodsForty-eight male Sprague-Dawley rats were randomly divided into six groups of 8 rats each. In addition to the control group, 40 rats were castrated and then injected with testosterone propionate to form a prostatic hyperplasia model. After 30 days, three groups received different concentrations of KQR (14 g/kg, 7 g/kg, and 3.5 g/kg), and the finasteride group received 0.5 mg/kg finasteride. The BPH group and the control group received the same volume of saline. All groups were treated for a total of 30 days. Rat body weight, prostate volume, wet weight, index, histology, and the mRNA and protein levels of TGF-β, TGF-βR1, TGF-βR2, p-Smad2, p-Smad3, BAMBI, E-cadherin, and N-cadherin in the prostate tissue were measured after the end of treatment.ResultsCompared with the control group, the BPH group had increased prostate wet weight, volume, and index, and the histology showed significant BPH. Compared with the BPH group, the three KQR groups and the finasteride group all had varying levels of reduction in the prostate wet weight, volume, and index of the prostate and varying degrees of improvement in the histological manifestations of BPH. KQR downregulates the mRNA and/or protein expression of TGF-β, TGF-βR1, TGF-βR2, p-Smad2, p-Smad3, and N-cadherin protein in prostate tissue and increases the mRNA and protein expression of BAMBI and E-cadherin protein.ConclusionsIn the model of BPH induced by testosterone propionate after castration, KQR can inhibit the conduction of the TGF-β/Smad signaling pathway by upregulating the expression of BAMBI protein and reversing EMT in rat prostate tissue.

Dataset Information

Identification and Profiling of Environmental Chemicals That Inhibit the TGF?/SMAD Signaling Pathway.

Publications

Identification and Profiling of Environmental Chemicals That Inhibit the TGFβ/SMAD Signaling Pathway.

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