Overcoming the Pregnane X Receptor Liability: Rational Design to Eliminate PXR-Mediated CYP Induction.

The pregnane X receptor (PXR) regulates expression of proteins responsible for all three phases required for the detoxification mechanism, which include CYP450 enzymes, phase II enzymes, and multidrug efflux pumps. Therefore, PXR is a prominent receptor that is responsible for xenobiotic excretion and drug-drug interactions. Pyrimidinone is an antagonist of the calcium sensing receptor (CaSR) and a strong activator of PXR.

Mitochondrial tRNA Mutation and Regulation of the Adiponectin Pathway in Maternally Inherited Hypertension in Chinese Han.

Some essential hypertension (EH) patients show maternal inheritance, which is the mode of mitochondrial DNA inheritance. This study examines the mechanisms by which mitochondrial mutations cause EH characterized by maternal inheritance. The study enrolled 115 volunteers, who were divided into maternally inherited EH (group A, = 17), non-maternally inherited EH (group B, = 65), and normal control (group C, = 33) groups.

Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases.

RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis.

Association between cardiac changes and stress, and the effect of peroxisome proliferator-activated receptor-γ on stress-induced myocardial injury in mice.

This study was aimed to investigate the effect of stress induced by high-intensity exercises on the cardiovascular system. In the epidemiological investigation, 200 subjects (test group) engaged in special high-intensity exercises, and 97 who lived and worked in the same environment and conditions as those in the test group, but did not participate in the exercises served as controls. In the second part of the study, 50 mice were randomly divided into control group, exhaustive swimming group, white noise group, exhaustive swimming plus white noise group, and pioglitazone intervention group.

[Mitochondrial DNA mutation associated with hypertension in tRNA(Ile) and tRNA(Gln) genes].

Objective: To study the relationship between mitochondrial DNA (mtDNA) mutations and hypertension.

Methods: Clinical data of two pedigrees with maternally transmitted hypertension was collected. Whole mtDNA sequence was analyzed.

Hypoxia training attenuates left ventricular remodeling in rabbit with myocardial infarction.

Objective: Previous studies showed that hypoxia preconditioning could protect cardiac function against subsequent myocardial infarction injury. However, the effect of hypoxia on left ventricular after myocardial infarction is still unclear. This study therefore aims to investigate the effects of hypoxia training on left ventricular remodeling in rabbits post myocardial infarction.

Molecular characterization of a Chinese family carrying a novel C4329A mutation in mitochondrial tRNAIle and tRNAGln genes.

Background: Hypertension is a very common cardiovascular disease influenced by multiple genetic and environmental factors. More recently, there are some studies showed that mutations in mitochondrial DNA have been involved in its pathogenesis. In this study we did further investigations on this relationship.

Effects of nerve growth factor on the action potential duration and repolarizing currents in a rabbit model of myocardial infarction.

Objectives: To investigate the effect of nerve growth factor (NGF) on the action potential and potassium currents of non-infarcted myocardium in the myocardial infarcted rabbit model.

Methods: Rabbits with occlusion of the left anterior descending coronary artery were prepared and allowed to recover for eight weeks (healed myocardial infarction, HMI). During ligation surgery of the left coronary artery, a polyethylene tube was placed near the left stellate ganglion in the subcutis of the neck for the purpose of administering NGF 400 U/d for eight weeks (HMI + NGF group).

[Effect of carvedilol on T-type calcium current in myocytes of non-infarcted area of the rabbit healed myocardial infarction].

This article reports the investigation of the effect of carvedilol (Car) on T-type calcium current (I(Ca,T)) of noninfarcted ventricular myocytes in rabbit models of healed myocardial infarction (HMI). Rabbits with left anterior descending artery ligation were prepared and allowed to recover for 8 weeks, as HMI group. Animals undergoing an identical surgical procedure without coronary ligation were served as the sham-operated group (sham group).

Electrophysiological study of V535M hERG mutation of LQT2.

This study examined the current changes of human ether-a-go-go-related gene (hERG) mutation derived from a LQT2 Chinese family with a highly penetrating phenotype. Mutation was identified and site-directed mutagenesis was performed to induce the mutation in wild-type (WT) hERG. WT hERG and mutated V535M were cloned and transiently expressed in HEK293 cells.

Titanium(IV) isopropoxide mediated synthesis of pyrimidin-4-ones.

A novel, one-step method for the synthesis of tri- and tetrasubstituted pyrimidin-4-ones is reported. This method involves a titanium(IV)-mediated cyclization involving two sequential condensations of primary and beta-ketoamides. The reaction is operationally facile, readily scalable, and offers rapid entry into differentially substituted pyrimidin-4-one scaffolds.

Functionalization of monofluoroallene and the synthesis of aryl-substituted conjugated fluorodienes.

[reaction: see text] 4-Fluoroallenol 3a, prepared from 1, cyclized easily to 4 but preserved its fluoroallenyl integrity under oxidation and S(N)2 displacement to yield aldehyde, amine, mesylate, and halide 6. Allylic isomerization yielded 2-halo-1-fluoro-1,3-butadiene 7, which underwent a Suzuki coupling to give aryl-substituted conjugated diene 8.