Potent and Selective Human 5-HT Serotonin Receptor Antagonists: 4'-Cyano-(N)-methanocarba-adenosines by Synthetic Serendipity.

Rigidified nucleoside derivatives with (N)-methanocarba replacement of ribose have been repurposed as peripheral subtype-selective 5-HT serotonin receptor antagonists for heart and lung fibrosis and intestinal/vascular conditions. 4'-Cyano derivative (MRS8209; , 4.27 nM) was 47-fold (human binding, but not rat and mouse) and 724-fold (functionally) selective at 5-HTR, compared to antitarget 5-HTR, and predicted to form a stable receptor complex using docking and molecular dynamics.

Shorter vs. standard-duration antibiotic therapy for nocardiosis: a multi-center retrospective cohort study.

Purpose: The prolonged treatment recommended for nocardiosis does not rely on strong evidence. Consequently, some clinicians opt shorter therapy in certain circumstances. We assessed the effectiveness of shorter therapy.

Inhibition of TRPV1 by an antagonist in clinical trials is dependent on cholesterol binding.

TRP Vanilloid 1 (TRPV1) channel, one of the major members of the TRP family was discovered to play a critical role in pain sensation, particularly inflammatory pain, and is associated with hyperalgesia, an enhanced sensitivity to pain. A new study by Fanet al."Structural basis of TRPV1 inhibition by SAF312 and cholesterol" sheds new light on the mechanistic structural basis of TRPV1 inhibition by SAF312 (Libvatrep), a TRPV1 antagonist, currently in phase II clinical trials.

Impairment of microvascular endothelial Kir2.1 channels contributes to endothelial dysfunction in human hypertension.

Hypertension is associated with decreased endothelial function through reduced contributions of nitric oxide (NO). We previously discovered that flow-induced NO production in resistance arteries of mice and humans critically depends on endothelial inwardly rectifying K (Kir2.1) channels.

The glycolytic metabolite methylglyoxal covalently inactivates the NLRP3 inflammasome.

The NLRP3 inflammasome promotes inflammation in disease, yet the full repertoire of mechanisms regulating its activity is not well delineated. Among established regulatory mechanisms, covalent modification of NLRP3 has emerged as a common route for the pharmacological inactivation of this protein. Here, we show that inhibition of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) results in the accumulation of methylglyoxal, a reactive metabolite whose increased levels decrease NLRP3 assembly and inflammatory signaling in cells.