Suppressive effects of methylthiouracil on polyphosphate‐mediated vascular inflammatory responses

Abstract

Drug repositioning is used to discover drug candidates to treat human diseases, through the application of drugs or compounds that are approved for the treatment of other diseases. This method can significantly reduce the time required and cost of discovering new drug candidates for human diseases. Previous studies have reported pro‐inflammatory responses of endothelial cells to the release of polyphosphate (PolyP). In this study, we examined the anti‐inflammatory responses and mechanisms of methylthiouracil (MTU), which is an antithyroid drug, and its effects on PolyP‐induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behaviour of human neutrophils and vascular permeability were determined in PolyP‐activated HUVECs and mice. MTU suppressed the PolyP‐mediated vascular barrier permeability, up‐regulation of inflammatory biomarkers, adhesion/migration of leucocytes, and activation and/or production of nuclear factor‐κB, tumour necrosis factor‐α and interleukin‐6. Furthermore, MTU demonstrated protective effects on PolyP‐mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of MTU on various systemic inflammatory diseases, such as sepsis or septic shock.

Laminin-guided highly efficient endothelial commitment from human pluripotent stem cells

“…5a,b). As for specific gene expressions, some endothelial development-associated genes, such as LMO2, NOTCH1, HEY2, DLL4 and NRP1111516, are upregulated, while function-associated genes, such as IL8, IL6, IL18, NFKB1, EDN1 and CAV1171819, are downregulated in PSC-EPCs. However, representative common endothelial characteristic markers, such as CDH5, PECAM1 and MCAM, are expressed both on PSC-EPCs and primary ECs at comparable levels (Supplementary Fig.…”

Polyphosphate as a Target for Interference With Inflammation and Thrombosis

“…PolyP application activates NF-κb and β-catenin pathways via receptor for advanced glycation end products, P2Y 1 receptor signaling and Wnt signaling (61, 62). Vice versa , the anti-thyroid drug methylthiouracil interferes with polyP-mediated inflammation of the endothelium in vivo (82). On the other hand, probiotic-derived polyP improves epithelial barrier function and may contribute to immunomodulatory mechanisms against commensal bacteria in the gut via NF-κb inhibition (83).…”