Biology subjects

Oltean, M.

Publications and source records attributed to Oltean, M..

3 recordsLinked to original sources

bioRxiv2025

Pre-implantation non-steroidal anti-inflammatory drug treatment disrupts mouse embryo spacing and post-implantation chamber morphogenesis

Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit the prostaglandin synthase (PTGS) enzymes PTGS1 and PTGS2, may present a risk when consumed during early pregnancy. The impact of PTGS enzyme inhibition by NSAIDS on the three-dimensional organization and function of uterine compartments in context of implantation success is not well known. Here we show that pre-implantation treatment of mouse pregnancy with indomethacin, an NSAID that inhibits both PTGS1 and PTGS2, results in embryo crowding, delayed embryo implantation, defective implantation chamber formation that eventually results in significant pregnancy loss. These effects are dose dependent as lower doses of indomethacin do not show these effects on pregnancy. When embryo spacing defects were observed, a significant proportion of embryos that showed delayed growth or resorption were located in distinct decidual sites, suggesting that additional mechanisms beyond spatial distribution are at play. These findings highlight the potential risks associated with NSAID use during early pregnancy and underscore the need for further research into the underlying molecular mechanisms and the development of safer pain management strategies during pregnancy.

physiology↗

bioRxiv2025

Cryo-EM structure of CLCA1 identifies CLCA1 as a founding member of a novel metzincin family.

Calcium-activated chloride channel regulator 1 (CLCA1) is implicated in several diseases, especially mucus-associated airway diseases, but its molecular function and regulation have remained unclear. By determining the structure of CLCA1 by negative stain electron microscopy and cryo-EM, we could confirm that CLCA1 forms large oligomeric complexes which adopts a compact domain organization comprising a metallohydrolase (MH), von Willebrand type A (VWA), {beta}-sheet-rich (BSR), inhibitory (ID), and fibronectin type III-like (FnIII-l) domains. The unusually large MH domain bears hallmarks of metzincins but is distinguished by several unique features including an atypical active site zinc-coordination environment and a second Zn2+ -coordination site. Unlike classical metzincins, CLCA1 lacks a pro-domain; instead, a C-terminal inhibitory loop occludes the MH active site, providing an alternative mechanism of autoinhibition. The adjacent VWA domain, resolved in its closed state, is poised for conformational change upon ligand binding, suggesting a route for allosteric regulation of protease activity. Structural and functional assays support a role for CLCA1 in cleaving glycosylated substrates, leading to alterations in mucin architecture consistent with a regulated function in mucus remodeling. Together, these data establish CLCA1 as the founding member of a new eukaryotic metzincin family, here termed CLCAsins, with unique regulatory mechanisms.

molecular biology↗

bioRxiv2025

The role of Akkermansia muciniphila sulfatases in colonic mucinutilisation

Akkermansia muciniphila, an obligate mucin degrader, is a major member of the human colonic microbiota and has been associated positive health outcomes. Mucins are complex glycoproteins that contain heavily sulfated O-glycans and form the protective colonic mucus layer. Bacterial carbohydrate sulfatases are required to metabolise these heavily sulfated mucin glycans and excessive bacterial foraging has been associated with several diseases. Sulfatases have been linked with inflammatory bowel disease, making these microbiota enzymes potential drug targets. A. muciniphila expresses carbohydrate sulfatases that can act on colonic mucins yet their roles in its metabolism remain opaque. Our data reveal that A. muciniphila requires glycopeptides/protein forms of colonic mucin for metabolism and its sulfatases have unique adaptations compared to Bacteroides species. Localisation studies reveal that desulfation of N-acetyl-D-glucosamine, but not D-galactose, is exclusively periplasmic. A cell surface sulfatase has a novel carbohydrate binding module that binds to colonic mucin. This paints a contrasting picture of sulfated mucin metabolism by Akkermansia muciniphila versus Bacteroides species. These data will be important for understanding the contexts for Akkermansia muciniphilas positive health correlations.

biochemistry↗