Siricilla, Shajila published the artcileComparative analysis of myometrial and vascular smooth muscle cells to determine optimal cells for use in drug discovery, Synthetic Route of 55981-09-4, the main research area is myometrial vascular smooth muscle cell drug discovery; Druggable transcriptome; High throughput; Intracellular calcium; Myometrium; Oxytocin; PHM1; Pregnancy; Preterm labor; RNA-sequencing; Tocolytic; Uterotonic; Vascular smooth muscle cells; hTERT-HM.
Novel therapeutic regulators of uterine contractility are needed to manage preterm labor, induce labor and control postpartum hemorrhage. Therefore, we previously developed a high-throughput assay for large-scale screening of small mol. compounds to regulate calcium-mobilization in primary mouse uterine myometrial cells. The goal of this study was to select the optimal myometrial cells for our high-throughput drug discovery assay, as well as determine the similarity or differences of myometrial cells to vascular smooth muscle cells (VSMCs)-the most common off-target of current myometrial therapeutics. Mol. and pharmacol. assays were used to compare myometrial cells from four sources: primary cells isolated from term pregnant human and murine myometrium, immortalized pregnant human myometrial (PHM-1) cells and immortalized non-pregnant human myometrial (hTERT-HM) cells. In addition, myometrial cells were compared to vascular SMCs. We found that the transcriptome profiles of hTERT-HM and PHM1 cells were most similar (r = 0.93 and 0.90, resp.) to human primary myometrial cells. Comparative transcriptome profiling of primary human myometrial transcriptome and VSMCs revealed 498 upregulated (p ≤ 0.01, log2FC≥1) genes, of which 142 can serve as uterine-selective druggable targets. In the high-throughput Ca2+-assay, PHM1 cells had the most similar response to primary human myometrial cells in OT-induced Ca2+-release (Emax = 195% and 143%, EC50 = 30 nM and 120 nM, resp.), while all sources of myometrial cells showed excellent and similar robustness and reproducibility (Z = 0.52 to 0.77). After testing a panel of 61 compounds, we found that the stimulatory and inhibitory responses of hTERT-HM cells were highly-correlated (r = 0.94 and 0.95, resp.) to human primary cells. Moreover, ten compounds were identified that displayed uterine-selectivity (≥5-fold Emax or EC50 compared to VSMCs). Collectively, this study found that hTERT-HM cells exhibited the most similarity to primary human myometrial cells and, therefore, is an optimal substitute for large-scale screening to identify novel therapeutic regulators of myometrial contractility. Moreover, VSMCs can serve as an important counter-screening tool to assess uterine-selectivity of targets and drugs given the similarity observed in the transcriptome and response to compounds
Pharmacological Research published new progress about Animal gene Role: BSU (Biological Study, Unclassified), BIOL (Biological Study) (CALD1). 55981-09-4 belongs to class esters-buliding-blocks, name is 2-((5-Nitrothiazol-2-yl)carbamoyl)phenyl acetate, and the molecular formula is C12H9N3O5S, Synthetic Route of 55981-09-4.
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