Snail-type transcription factors (TFs) are found in numerous metazoan organisms and function in a plethora of cellular and developmental processes including mesoderm and neuronal development, apoptosis and cancer. So far, Snail-type TFs are exclusively known as transcriptional repressors. They repress gene expression by recruiting transcriptional co-repressors and/or by preventing DNA binding of activators from the basic helix-loop-helix (bHLH) family of TFs to CAGGTG E-box sequences. Here we report that the Caenorhabditis elegans Snail-type TF CES-1 can activate transcription in vivo. Moreover, we provide results that suggest that CES-1 can share its binding site with bHLH TFs, in different tissues, rather than only occluding bHLH DNA binding. Together, our data indicate that there are at least two types of CES-1 target genes and, therefore, that the molecular function of Snail-type TFs is more plastic than previously appreciated.
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http://dx.doi.org/10.1093/nar/gkp232 | DOI Listing |
Drug Metab Dispos
October 2024
Departments of Pharmaceutical Sciences (S.M.J.) and Clinical Pharmacy (H.-J.Z.), University of Michigan, Ann Arbor, Michigan
Hydrolases represent an essential class of enzymes indispensable for the metabolism of various clinically essential medications. Individuals exhibit marked differences in the expression and activation of hydrolases, resulting in significant variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by these enzymes. The regulation of hydrolase expression and activity involves both genetic polymorphisms and nongenetic factors.
View Article and Find Full Text PDFJ Pharmacol Exp Ther
February 2024
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (B.H.K., M.N., J.N.S.); Nodthera, Seattle Washington (P.S., C.D., H.W., J.R.D., K.S., C.A.G.); Nodthera, Cambridge, United Kingdom (D.H., A.P.W.); and Nodthera, Boston, Massachusetts (M.G.B.)
The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a central regulator of innate immunity, essential for processing and release of interleukin-1 and pyroptotic cell death. As endogenous NLRP3 activating triggers are hallmarks of many human chronic inflammatory diseases, inhibition of NLRP3 has emerged as a therapeutic target. Here we identify NDT-19795 as a novel carboxylic acid-containing NLRP3 activation inhibitor in both human and mouse monocytes and macrophages.
View Article and Find Full Text PDFDrug Metab Dispos
August 2023
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University (K.H., T.F., Ma.N., Mi.N.) and WPI Nano Life Science Institute, Kanazawa, Japan (T.F., Ma.N., Mi.N.).
Drug-drug interactions (DDI) have a significant impact on drug efficacy and safety. It has been reported that orlistat, an anti-obesity drug, inhibits the hydrolysis of -nitrophenol acetate, a common substrate of the major drug-metabolizing hydrolases, carboxylesterase (CES) 1, CES2, and arylacetamide deacetylase (AADAC), in vitro. The aim of this study was to examine whether orlistat affects the pharmacokinetics of drug(s) metabolized by hydrolases in vivo after evaluating its inhibitory potencies against CES1, CES2, and AADAC in vitro.
View Article and Find Full Text PDFDrug Metab Dispos
May 2023
Drug Metabolism and Pharmacokinetics, Drug Safety and Pharmacokinetics Laboratories, Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
TP0473292 is an adamantane carboxylic acid (ACA) ester prodrug for enhancing the oral bioavailability of the hydrophilic glutamate analog TP0178894, a novel metabotropic glutamate 2 and 3 receptor antagonist, and being developed as an antidepressant. TP0473292 showed high membrane permeability and rapid hydrolysis to TP0178894 in rat, monkey, and human liver S9 fractions, with a conversion rate of such that complete conversion by first-pass metabolism was expected. TP0473292 was also hydrolyzed in the intestinal, renal, and lung S9 fractions, coinciding with the result that TP0473292 was activated by carboxylesterase (CES) 1 and more efficiently by CES2.
View Article and Find Full Text PDFPharmaceutics
April 2022
Department of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany.
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