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.

Morphine-3-glucuronide upregulates PD-L1 expression via TLR4 and promotes the immune escape of non-small cell lung cancer.

Objective: Patients with cancer pain are highly dependent on morphine analgesia, but studies have shown a negative correlation between morphine demand and patient outcomes. The long-term use of morphine may result in abnormally elevated serum morphine-3-glucuronide (M3G) levels. Hence, the effects of M3G on tumor progression are worth studying. Methods: The effects of M3G on PD-L1 expressions in human non-small cell lung cancer (NSCLC) cell lines were first evaluated. Activation of TLR4 downstream pathways after M3G treatment was then determined by Western blot. The effects of M3G on human cytotoxic T lymphocytes (CTL) cytotoxicity and INF-γ release was also detected. Finally, the LLC murine lung adenocarcinoma cell line were used to establish a murine lung cancer model, and the effects of M3G on tumor growth and metastasis were determined. Results: M3G promoted the expressions of PD-L1 in the A549 and H1299 cell lines in a TLR4-dependent manner (P < 0.05). M3G activated the PI3K and the NFκB signaling pathways, and this effect was antagonized by a TLR4 pathway inhibitor. A PI3K pathway inhibitor reversed the M3G-mediated PD-L1 upregulation. M3G inhibited the cytotoxicity of CTL on A549 cells and decreased the level of INF-γ. Repeated M3G intraperitoneal injections promoted LLC tumor growth and lung metastasis through the upregulation of tumor expressed PD-L1 and the reduction of CTL in the tumor microenvironment. Conclusions: M3G specifically activated TLR4 in NSCLC cells and upregulated PD-L1 expression through the PI3K signaling pathway, thereby inhibiting CTL cytotoxicity and finally promoting tumor immune escape.

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.

Screening genes associated with elevated neutrophil­to­lymphocyte ratio in chronic heart failure.

Neutrophil­to­lymphocyte ratio (NLR) is commonly considered a useful prognostic index for many cardiovascular diseases; however, it has limited sensitivity and specificity. Factors associated with elevated NLR may aid in the prediction of prognosis with heart failure (HF) in combination with NLR. The present study sought to identify decisive factors associated with NLR in HF patients and investigate their association with elevated NLR. The gene expression profile for blood samples from 197 individuals with chronic heart failure (CHF), with corresponding hematological parameters and clinical data were obtained from the public database, GSE77343. Differentially expressed genes (DEGs) were identified, and Gene Ontology and pathway enrichment analyses were performed. The protein­protein interaction network was constructed with the Search Tool for the Retrieval of Interacting Genes along with Cytoscape. Receiver operating characteristic curves for predictive power, sensitivity and specificity were constructed. The present study identified specific associated DEGs by using Pearson linear correlation and logistic regression analysis. A mean NLR of 3.96 was determined as the cutoff value in the analysis. In total, 31 genes were initially identified as DEGs associated with elevated NLR. They were mainly enriched in neutrophil activation and neutrophil mediated immunity, in fluid shear stress and atherosclerosis, and transcriptional misregulation in cancer. Three focused DEGs, solute carrier family 22 member 4 (SLC22A4), interleukin­1 receptor 2 (IL1R2) and vanin 3 (VNN3), were finally revealed to be independently associated with elevated NLR in CHF patients. The present study demonstrated that the three genes SLC22A4, IL1R2 and VNN3 may be independently associated with elevated NLR in CHF patients as potential decisive factors of NLR.

Magneto-optical properties of one-dimensional orderly nanocorrugation made from magnetic quadrilayer films.

Magneto-optical (MO) Kerr effect and optical reflectance are investigated in the visible light region for one-dimensional orderly nanocorrugation of magnetic quadrilayer films. We find that the MO enhancement originates from the combined action between cavity effect and surface plasmon resonance. The coupling between surface plasmon polaritions and localized surface plasmons cannot only enhance the magnitude of Kerr angle, but also alter the sign of Kerr rotation. In addition, the MO properties on the nanocomposite films can be tuned by the thickness of the intermediate HfO2 layer due to the cavity effect in multilayer.

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.

The effect of SYT-SSX and extracellular signal-regulated kinase (ERK) on cell proliferation in synovial sarcoma.

The character of Synovial sarcoma is the chromosomal translocation t(X; 18)(p11.2;q11.2), which results in the fusion of the SYT gene with a SSX gene. There is little study that could fully elucidate the mechanism of pathogenesis of this fusion transcript. This study is designed to gain more insight into the function of this fusion gene. We evaluated the whole genome expression in SYO-1 cells inhibited as a result of specific small interfering RNA for SYT-SSX. Cell proliferation and apoptosis were analyzed by flow cytometer and MTT. The proteins correlated with proliferation were also detected using western blot. TUNEL and Immunohistochemical stain assessment were also carried out on TMA of SS tissues. The mRNA level reduced over 90% caused by SYT-SSX specific siRNA. Five pathways were employed, that ERK1/2 pathway was differential significantly (p = 0.043218). Meanwhile, down-regulation of SYT-SSX fusion gene expression would inhibit the proliferation of SS cell and the survival rate decreased (34.1%), while apoptotic rate increased (10.92%). After transfected with SYT-SSX-specific siRNA it caused a block in G1/G0 phase (31.99%) of SYO-1 cells compared with control cells. The protein level of ERK1/2, p-ERK, and cyclin D1 altered in same trend with expression of SYT-SSX. In TMA stain assessment, SYT-SSX positive group with high ki-67 LI expressed more cyclin D1and CDK4 than the SYT-SSX negative group. High ki-67 LI was detected in cases with p-ERK expression. Meanwhile, cyclin D1 and CDK4 were shown to be more expressed in tumor cells with p-ERK expression. Our results suggest that the fusion gene SYT-SSX should be considered to play important role on SS cell growth via ERK pathway. This study may be valuable for understanding the pathogenic role and molecular mechanism of the fusion gene SYT-SSX in synovial sarcoma through the proposed genome-wide approach. Furthermore, the research would open up the possibility of using SYT-SSX and ERK as a therapeutic target.

Application of EDTA decontamination on soils affected by mining activities and impact of treatment on the geochemical partition of metal contaminants.

Two soil samples were collected at mining areas located in southern Hunan Province, China. EDTA extraction of Pb, Zn, Cu and Cd from these two tailing soils was studied using column leaching experiments. The redistributions of heavy metals (HMs) were determined using the modified BCR (Community Bureau of Reference) sequential extraction procedure, before and after EDTA extraction. The results indicated that EDTA was an effective extractant because of its strong chelating ability for various HMs. The proportions of Pb, Zn, Cu and Cd in the four fractions varied largely after EDTA extraction. The extraction efficiency of EDTA of the acid-extractable fraction (AEX) was significant in shallow soil column, while in deeper soil column, decrease of the extraction efficiency of reduced (RED), oxidizable (OX) and residual fractions (RES) was obtained, which was mainly due to the decrease of EDTA concentration.

Characterization of Cr(VI) removal from aqueous solutions by a surplus agricultural waste--rice straw.

The removal of Cr(VI) from aqueous solution by rice straw, a surplus agricultural byproduct was investigated. The optimal pH was 2.0 and Cr(VI) removal rate increased with decreased Cr(VI) concentration and with increased temperature. Decrease in straw particle size led to an increase in Cr(VI) removal. Equilibrium was achieved in about 48 h under standard conditions, and Cr(III), which appeared in the solution and remained stable thereafter, indicating that both reduction and adsorption played a part in the Cr(VI) removal. The increase of the solution pH suggested that protons were needed for the Cr(VI) removal. A relatively high level of NO(3)(-) notably restrained the reduction of Cr(VI) to Cr(III), while high level of SO(4)(2-) supported it. The promotion of the tartaric acid modified rice straw (TARS) and the slight inhibition of the esterified rice straw (ERS) on Cr(VI) removal indicated that carboxyl groups present on the biomass played an important role in chromium remediation even though were not fully responsible for it. Isotherm tests showed that equilibrium sorption data were better represented by Langmuir model and the sorption capacity of rice straw was found to be 3.15 mg/g.

[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.