Gender Differences in the Hepatotoxicity and Toxicokinetics of Emodin: The Potential Mechanisms Mediated by UGT2B7 and MRP2.

Emodin is a main anthraquinone compound which exists in Chinese traditional medicines including Polygonum multiflorum and Rhubarb. It is documented to have obvious liver and kidney toxicity. This study aims to (a) estimate gender differences of the hepatotoxicity and toxicokinetics in rats after oral administration of emodin (60 and 150 mg/kg/d) for a consecutive 28 days and (b) clarify relative mechanisms caused by glucuronidation and disposition.

Molecular characteristics and clinical outcomes of exon 19 indel subtypes to EGFR TKIs in NSCLC patients.

Patients with non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor mutations (exon 19 deletions and L858R) benefit from EGFR tyrosine kinase inhibitors (TKIs). However, some researchers have reported that responses to TKIs differ by subtypes of exon 19 mutations. We retrospectively analyzed exon 19 deletion subtypes and their correlation with clinical outcomes of treatment with TKIs.

Simultaneous Determination of Rosuvastatin, Rosuvastatin-5 S-lactone, and N-desmethyl Rosuvastatin in Human Plasma by UPLC-MS/MS and Its Application to Clinical Study.

Objective: A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay was developed and validated for the simultaneous quantification of rosuvastatin (RST), rosuvastatin-5 S-lactone (RSTL), and N-desmethyl rosuvastatin (DM-RST) in human plasma.

Methods: Sample was prepared by liquid-liquid extraction with ethyl acetate from 100 μL acidulated buffered plasma. Then analytes were chromatographically separated using an Acquity UPLC HSS T3 column (3.

The bifunctional effect of propofol on thromboxane agonist (U46619)-induced vasoconstriction in isolated human pulmonary artery.

Propofol is known to cause vasorelaxation of several systemic vascular beds. However, its effect on the pulmonary vasculature remains controversial. In the present study, we investigated the effects of propofol on human pulmonary arteries obtained from patients who had undergone surgery.

The gut microbiome in atherosclerotic cardiovascular disease.

The gut microbiota has been linked to cardiovascular diseases. However, the composition and functional capacity of the gut microbiome in relation to cardiovascular diseases have not been systematically examined. Here, we perform a metagenome-wide association study on stools from 218 individuals with atherosclerotic cardiovascular disease (ACVD) and 187 healthy controls.

SLCO1B1 521T > C polymorphism associated with rosuvastatin-induced myotoxicity in Chinese coronary artery disease patients: a nested case-control study.

Purpose: This nested case-control study aimed to evaluate the association of candidate genetic variants with statin-induced myotoxicity in Chinese patients with coronary artery disease (CAD).

Methods: One hundred forty-eight Chinese patients experiencing statin-induced myotoxicity were included in our study, and 255 patients without muscular side effects served as controls. Five SNPs in CYP3A5, SLCO1B1, and APOE were genotyped.

EGFR T790M ctDNA testing platforms and their role as companion diagnostics: Correlation with clinical outcomes to EGFR-TKIs.

Somatic mutation in the epidermal growth factor receptor (EGFR) predict clinical response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) and is a promising target for personalised medicine. EGFR mutations have prognostic value. Initially patients respond well to tyrosine kinase inhibitors but finally they would develop resistance and about 50% of this resistance can be attributed to the emergence of EGFR resistant mutation, T790M.

DNA methyltransferase 1 rs16999593 genetic polymorphism decreases risk in patients with transposition of great arteries.

Complete transposition of the great arteries (TGA) is the most frequent cyanotic heart defect diagnosed in neonates. However, the exact etiology of TGA is unknown. The aim of the present study was to assess the association of TGA pathogenesis with single nucleotide polymorphisms (SNPs) in DNA methyltransferases (DNMTs)-1 and 3a- in Chinese children.

Hepatic and renal metabolism of genistein: An individual-based model to predict glucuronidation behavior of genistein in different organs.

The present study aims to develop an individual-based model to predict the glucuronidation characteristics of genistein in 45 human livers. The model was validated in 18 human kidneys. Ten UDP-glucuronosyltransferases (UGTs) were expressed in liver abundantly.

Genomewide Association Study Identifies Novel Genetic Loci That Modify Antiplatelet Effects and Pharmacokinetics of Clopidogrel.

Genetic variants in the pharmacokinetic (PK) mechanism are the main underlying factors affecting the antiplatelet response to clopidogrel. Using a genomewide association study (GWAS) to identify new genetic loci that modify antiplatelet effects in Chinese patients with coronary heart disease, we identified novel variants in two transporter genes (SLC14A2 rs12456693, ATP-binding cassette [ABC]A1 rs2487032) and in N6AMT1 (rs2254638) associated with P2Y12 reaction unit (PRU) and plasma active metabolite (H4) concentration. These new variants dramatically improved the predictability of PRU variability to 37.

Effects of epidermal growth factor receptor-tyrosine kinase inhibitors alone on EGFR-mutant non-small cell lung cancer with brain metastasis.

Background: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are remarkably effective for treating EGFR-mutant non-small cell lung cancer (NSCLC). However, the individual role of EGFR-TKIs in patients with brain metastasis (BM) arising from EGFR-mutant NSCLC remains unclear.

Methods: Patients with BM secondary to NSCLC and harboring EGFR-activating mutations were retrospectively screened.

An LC-MS based untargeted metabolomics study identified novel biomarkers for coronary heart disease.

This study performed untargeted metabolomics for plasma samples from 40 coronary heart disease patients and 43 healthy controls by high-performance liquid chromatography coupled with mass spectrometry technology to find a set of effective biomarkers for CHD diagnosis and prognosis. The discriminating metabolites were extracted and analyzed by univariate and multivariate analysis methods. We found five metabolites (1-naphthol, 2-naphthol, methylitaconate, N-acetyl-d-glucosamine 6-phosphate and l-carnitine) contributing to the separation of CHD patients from healthy controls, and a subset of two metabolites in these five were identified as potential plasma biomarkers for CHD diagnosis.

Relation of Transcriptional Factors to the Expression and Activity of Cytochrome P450 and UDP-Glucuronosyltransferases 1A in Human Liver: Co-Expression Network Analysis.

Cytochrome P450 (CYPs) and UDP-glucuronosyltransferases (UGTs) play important roles in the metabolism of exogenous and endogenous compounds. The gene transcription of CYPs and UGTs can be enhanced or reduced by transcription factors (TFs). This study aims to explore novel TFs involved in the regulatory network of human hepatic UGTs/CYPs.

Dexmedetomidine inhibits vasoconstriction via activation of endothelial nitric oxide synthase.

Despite the complex vascular effects of dexmedetomidine (DEX), its actions on human pulmonary resistance arteries remain unknown. The present study tested the hypothesis that DEX inhibits vascular tension in human pulmonary arteries through the endothelial nitric oxide synthase (eNOS) mediated production of nitric oxide (NO). Pulmonary artery segments were obtained from 62 patients who underwent lung resection.

Plasma miR-142 accounting for the missing heritability of CYP3A4/5 functionality is associated with pharmacokinetics of clopidogrel.

Aim: To investigate whether plasma miRNAs targeting CYP3A4/5 have an impact on the variance of pharmacokinetics of clopidogrel.

Materials & Methods: The contribution of 13 miRNAs to the CYP3A4/5 gene expression and activity was investigated in 55 liver tissues. The association between plasma miRNAs targeting CYP3A4/5 mRNA and clopidogrel pharmacokinetics was analyzed in 31 patients with coronary heart disease who received 300 mg loading dose of clopidogrel.

Simultaneous Determination of Ticagrelor and Its Metabolites in Human Plasma and Urine Using Liquid Chromatography-Tandem Mass Spectrometry.

We have developed and validated a rapid, selective and sensitive method using high-performance liquid chromatography-tandem mass spectrometry (MS) for the quantification of ticagrelor and all of its as-yet-identified metabolites in human plasma and urine. For the analysis of ticagrelor, its metabolites and the internal standard (IS) plasma samples were processed by liquid-liquid extraction using ethyl acetate and urine was processed by protein precipitation. Separations were performed on an Ultimate XB-C18 column (2.

Integrated metabolomics and metagenomics analysis of plasma and urine identified microbial metabolites associated with coronary heart disease.

Coronary heart disease (CHD) is top risk factor for health in modern society, causing high mortality rate each year. However, there is no reliable way for early diagnosis and prevention of CHD so far. So study the mechanism of CHD and development of novel biomarkers is urgently needed.

Macrophage migration inhibitory factor promotes expression of GLUT4 glucose transporter through MEF2 and Zac1 in cardiomyocytes.

Objective: Evidence shows that both macrophage migration inhibitory factor (MIF) and GLUT4 glucose transporter are involved in diabetic cardiomyopathy (DCM), but it remains largely unknown whether and how MIF regulates GLUT4 expression in cardiomyocytes. The present study aims to investigate the mechanism underlying the modulation of GLUT4 by MIF in cardiomyocytes.

Material And Methods: Activations of AKT and AMPK signaling, and expressions of MIF, GLUT4 and the candidate GLUT4 regulation associated transcription factors in the diabetic mouse myocardium were determined.

Over-expression of neurotrophin 3 in human aortic valves affected by calcific disease induces the osteogenic responses via the Trk-Akt pathway.

Unlabelled: Calcific aortic valve disease (CAVD) is a leading cardiovascular disorder in the elderly. While aortic valve interstitial cells (AVICs) are the main cells that express osteogenic mediators, the molecular mechanism that mediates AVIC osteogenic responses is incompletely understood. This study aims to identify pro-osteogenic factors in human AVICs affected by CAVD.

Human microsomal cyttrochrome P450-mediated reduction of oxysophocarpine, an active and highly toxic constituent derived from Sophora flavescens species, and its intestinal absorption and metabolism in rat.

Oxysophocarpine (OSC), an active and toxic quinolizidine alkaloid, is highly valued in Sophora flavescens Ait. and Subprostrate sophora Root. OSC is used to treat inflammation and hepatitis for thousands of years in China.

Activation of TLR3 induces osteogenic responses in human aortic valve interstitial cells through the NF-κB and ERK1/2 pathways.

Unlabelled: Calcific aortic valve disease (CAVD) is characterized by chronic inflammation and progressive calcification in valve leaflets. Aortic valve interstitial cells (AVICs) play a critical role in the pathogenesis of CAVD. Previous studies show that stimulation of Toll-like receptor (TLR) 2 or TLR4 in AVICs in vitro up-regulates the expression of osteogenic mediators.

Catheter ablation restores decreased plasma miR-409-3p and miR-432 in atrial fibrillation patients.

Aims: Despite numerous studies identifying specific microRNA (miRNA) expression profiles associated with atrial fibrillation (AF), changes in plasma miRNA expression in pre- and post-operative AF patients who have received catheter ablation, remain poorly characterized. This study aimed to reveal disease-related biomarkers by detecting plasma miRNA expression in AF patients, and examining the levels of AF-specific miRNAs in patients after catheter ablation, in order to help gauge therapeutic effects and assess prognosis.

Methods And Results: A total of 100 Han Chinese patients with AF who had received catheter ablation, and 100 healthy individuals, were sequentially recruited to the study.

Upregulation of 5-hydroxytryptamine receptor signaling in coronary arteries after organ culture.

Background: 5-Hydroxytryptamine (5-HT) is a powerful constrictor of coronary arteries and is considered to be involved in the pathophysiological mechanisms of coronary-artery spasm. However, the mechanism of enhancement of coronary-artery constriction to 5-HT during the development of coronary artery disease remains to be elucidated. Organ culture of intact blood-vessel segments has been suggested as a model for the phenotypic changes of smooth muscle cells in cardiovascular disease.