Identification and characterization of endogenous biomarkers for hepatic vectorial transport (OATP1B3-P-gp) function using metabolomics with serum pharmacology.

The organic anion-transporting polypeptide 1B3 and P-glycoprotein (P-gp) provide efficient directional transport (OATP1B3-P-gp) from the blood to the bile that serves as a key determinant of hepatic disposition of the drug. Unfortunately, there is still a lack of effective means to evaluate the disposal ability mediated by transporters. The present study was designed to identify a suitable endogenous biomarker for the assessment of OATP1B3-P-gp function in the liver. We established stably transfected HEK293T-OATP1B3 and HEK293T-P-gp cell lines. Results showed that azelaic acid (AzA) was an endogenous substrate for OATP1B3 and P-gp using serum pharmacology combined with metabolomics. There is a good correlation between the serum concentration of AzA and probe drugs of rOATP1B3 and rP-gp when rats were treated with their inhibitors. Importantly, after 5-fluorouracil-induced rat liver injury, the relative mRNA level and expression of rOATP1B3 and rP-gp were markedly down-regulated in the liver, and the serum concentration of AzA was significantly increased. These observations suggest that AzA is an endogenous substrate of both OATP1B3 and P-gp, and may serve as a potential endogenous biomarker for the assessment of the function of OATP1B3-P-gp for the prediction of changes in the pharmacokinetics of drugs transported by OATP1B3-P-gp in liver disease states.

Bioinformatics identification of potential candidate blood indicators for doxorubicin-induced heart failure.

The care of individual patients requiring anthracyclines remains challenging as uncertainty persists on predictors of cardiotoxicity. The aim of the present study was to identify potential candidate blood indicators of doxorubicin-induced heart failure. The gene expression profiles of GSE40447 and GSE9128 microarray data were downloaded from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) using the R/Limma package or GEO2R. Functional and pathway enrichment analysis on DEGs were performed using DAVID database. The cardiovascular disease (CVD)-related DEGs were screen out based on the CardioGenBase database. The protein-protein interaction (PPI) network was constructed with STRING database and visualized by using Cytoscape. Then, the CVD-related DEGs were validated by intersection analysis with DEGs in GSE9128. The overlapping DEGs with a consistent expression pattern in GSE40447 and GSE9128 were identified as candidate indicators for doxorubicin-induced heart failure. A total of 516 DEGs potentially associated with doxorubicin-induced heart failure in GSE40447 were identified, which were mainly enriched in the gene ontology terms related to B cells, leukocytes, lymphocyte activation and B cell receptor signaling pathway. Of the DEGs, 42 were screened out as CVD-related DEGs by using CardioGenBase. Seven genes with high connectivity degree were presented in the PPI network. Finally, 5/6 CVD-related DEGs revealed by the intersection analysis were validated by GSE9128 and highlighted as candidate indicators of doxorubicin-induced heart failure: CD163, CD28, SLC25A20, ANPEP and TLR5. Several genes, including the 5 previously mentioned, were proposed as potential candidate blood indicators for doxorubicin-induced heart failure. Further experimental validations are greatly warranted for future clinical application.

Triglyceride to high density lipoprotein cholesterol ratio may serve as a useful predictor of major adverse coronary event in female revascularized ST-elevation myocardial infarction.

BACKGROUND: Elevated triglyceride to high density lipoprotein cholesterol (TG/HDL-C) ratio has been identified as a surrogate marker of insulin resistance and an independent predictor for cardiovascular events in the general population. However, the prognostic value of TG/HDL-C ratio in revascularized ST-elevation myocardial infarction(STEMI) patients remains unclear. We examined the association between TG/HDL-C ratio and clinical outcome of revascularized STEMI patients in the Chinese population. METHODS: 464 STEMI patients who underwent successful revascularization were enrolled to determine the relationship between TG/HDL-C ratio and major adverse coronary events(MACEs) with a 30-month follow-up. The Kaplan-Meier analysis and Cox regression proportional hazard model were applied to assess the prognostic value of TG/HDL-C ratio. RESULTS: TG/HDL-C ratio was found to be significantly associated with age (p = 0.017), history of diabetes(p = 0.017), heart rate(p = 0.011), TG(p < 0.001), HDL-C(p < 0.001) and Gensini score(p = 0.034). The multivariate Cox regression analysis revealed that elevated TG/HDL-C ratio was an independent prognostic factor for MACE in female patients (HR = 2.624,95%CI = 1.211-5.687,p = 0.014) but not in male patients(HR = 0.756, 95%CI = 0.484-1.179,p = NS) after adjustment with other MACE-related prognostic factors. CONCLUSION: The TG/HDL-C ratio may be independently associated with MACEs in female revascularized STEMI patients in the Chinese population.

5-tert-Butyl 1-ethyl 3-amino-1,4,5,6-tetra-hydro-pyrrolo-[3,4-c]pyrazole-1,5-dicarboxyl-ate.

The asymmetric unit of the title compound, C(13)H(20)N(4)O(4), contains two crystallographically independent mol-ecules in which the dihedral angles between the fused pyrrole and pyrazole rings are 5.06 (8) and 1.12 (8)°. In the crystal, mol-ecules are linked by inter-molecular N-H⋯O and N-H⋯N hydrogen bonds into chains parallel to the b axis.

[Chemical constituents from tuber of Cremastra appendiculata].

OBJECTIVE: To investigate the chemical constituents from the tuber of the planted Cremastra appendiculata. METHOD: The compounds were isolated by column chromatography over silica gel, Sephadex LH-20 and RP-HPLC, and their structures were elucidated on the basis of spectroscopic analysis. RESULT: Eight compounds were isolated, and identified as cirrhopetalanthrin (I), 7-hydroxy-4-methoxyphenanthrene-2-O-beta-D-glucoside (II), 4-(2-hydroxyethyl)-2-methoxyphenyl-1-O-beta-D-glucopyranoside (III), tyrosol 8-O-beta-D-gluco-pyranoside (IV), vanilloloside (V), p-hydroxybenzaldehyde (VI), sucrose (VII), adenosine (VIII). CONCLUSION: These compounds are isolated from this plant for the first time. All compounds were evaluated against human colon cancer (HCT-8), human hepatoma (Bel7402), human stomach cancer(BGC-823), human lung adenocarcinoma (A549), human breast cancer (MCF-7), and human ovarian cancer (A2780) cell lines, and cirrhopetalanthrin (I) showed non-selective moderate cytotoxicity with IC50 values of 8.4-13.3 micromol x L(-1), and other compounds were inactive.