Inhibitory effect of resveratrol on the pharmacokinetics of ticagrelor in vivo and in vitro.

This study was to evaluate the effect of resveratrol on the pharmacokinetics of ticagrelor in rats and the metabolism of ticagrelor in human cytochrome P450 (CYP) 3A4 (CYP3A4) and liver microsomes. Eighteen Sprague-Dawley rats were randomly divided into three groups: group A (control group), group B (50 mg/kg resveratrol), and group C (150 mg/kg resveratrol). After 30 min administration of resveratrol, a single dose of ticagrelor (18 mg/kg) was administered orally. The in vitro experiment was performed to examine the influence of resveratrol on ticagrelor metabolism in CYP3A4*1, human, and rat liver microsomes. Serial biological samples were assayed by validated ultra high-performance liquid chromatography - tandem mass spectrometer methods. For the in vivo study, the area under the concentration-time curve and mean peak plasma concentrations of ticagrelor in group B and C appeared to be significantly higher than the control group, while volume of distribution in terminal phase and apparent clearance of ticagrelor in group B and C were significantly decreased. For the in vitro study, resveratrol exhibited an inhibitory effect on CYP3A4*1, human and rat liver microsomes. The half-maximal inhibitory concentration values of resveratrol were 56.75 µM, 69.07 µM, and 14.22 µM, respectively. Our results indicated that resveratrol had an inhibitory effect on the metabolism of ticagrelor in vitro and in vivo. Further research should focus on the clinical combination of resveratrol with ticagrelor, and ticagrelor plasma concentration should be monitored to avoid the occurrence of adverse reaction.

[On-line detection of concentration process of Ganmaoling granules by near infrared spectroscopy combined with automatic control system].

Our research was designed for on-line detection of multi-index in the concentration process of Ganmaoling granules by integration of near infrared spectroscopy and automatic control system. First, on-line detection system was set up in the concentration tank for Ganmaoling granules production. Spectra were scanned and values of chlorogenic acid, linarin, solid content and relative density were measured. Models of partial least squares regression were built and imported into near infrared workstation. By connecting the control system, real-time multi-index values were determined automatically in the concentration process. Results showed that correlation coefficients of chlorogenic acid, linarin, solid content and relative density models were 0.963, 0.989, 0.993 and 0.918, respectively. Relative standard errors of prediction were 3.71%, 4.28%, 4.17% and 0.24%, respectively, indicating a good performance and high accuracy of the models. Real-time data collection during the whole process was measured by the near infrared detecting system in the control system. In conclusion, the near infrared detection system is able to perform real-time automatic determination of multiindex in the concentration process of Ganmaoling granules with significant advantages.

[On-line monitoring of extraction of coldrine by near-infrared spectrum].

Extraction of the four Chinese herbals is the beginning step of the production process of coldrine granules and influences on drug quality significantly. In this paper, the on-line near infrared spectrum was collected during the extraction process of coldrine and then pre-processed by the first derivative. Partial least square regression (PLSR) model was developed for the quantity indicators of linarin, chlorogenic acid and solid content, according to results of both HPLC and weight-loss as reference methods. The correlation coefficient, root mean square error of cross-validation (RMSECV), root mean square error of calibration (RMSEC) and root mean square error of prediction (RMSEP) were used to optimize model parameters and confirm their performance. Correlation coefficients of three quality control indicator models reached more than 0.95.Values of RMSEC of linarin, chloroenic acid and solid content were 0.010 4, 0.009 34 and 0.055 5, respectively. And the values of RMSEP were 0.009 47, 0.142 and 0.008 42, respectively. The models, built on-line analyze data, revealed that the correlation coefficients of predicted values and measured values were greater than 0.97 and values of RSEP of linarin, chloroenic acid and solid content were 8.14%, 8.17% and 9.86%, respectively. The results showed that the NIR method could achieve the on-line detection and real-time monitoring of multi-indexes during the extraction process of coldrine. The technology could be used for drug quality control in the process of practical production, reducing the batch differences and ensuring pharmaceutical quality stability. In addition, it could provide real-time production data for subsequent product quality backtracking.

Arterial Spin Labeling for Glioma Grade Discrimination: Correlations with IDH1 Genotype and 1p/19q Status.

Since accurate grading of gliomas has important clinical value, the aim of this study is to evaluate the diagnostic efficacy of perfusion values derived from arterial spin labeling (ASL) to grade gliomas. In addition, the correlation between perfusion and isocitrate dehydrogenase 1 (IDH1) genotypes and chromosome arms 1p and 19q (1p/19q) status of gliomas was assessed. A total of 52 cases of supratentorial gliomas in adults who received ASL imaging were enrolled in this retrospective study. The cerebral blood flow (CBF) images derived from ASL and anatomical maps were normalized to the Montreal Neurological Institute coordinate system and matched. The mean CBF (meanCBF), the maximum CBF (maxCBF), and their relative values (rmeanCBF and rmaxCBF, respectively) were assessed in each case. The tumor grades, IDH1 genotypes, and 1p/19q status were diagnosed according to the 2016 WHO criteria. Receiver operating characteristic curves were performed to assess the efficacy of perfusion parameters for grading. Qualitatively, all gliomas were divided into high- and low-perfusion groups. The crosstabs chi-square test of independence was performed to calculate contingency coefficient (C) and Cramer V coefficient to assess the correlation between perfusion and IDH1 genotypes and 1p/19q status of gliomas. The rmaxCBF showed the best diagnostic efficacy; meanwhile, rmeanCBF had the best specificity for grade discrimination. In astrocytoma, there was a mild correlation between IDH1 genotypes and tumor perfusion with the Cramer's V coefficient of 0.378. There was no significant association between 1p/19q codeletion and perfusion in grade II and III gliomas.

Nicotine modulates the effects of retinoids on growth inhibition and RAR beta expression in lung cancer cells.

Epidemiological and animal studies have demonstrated that vitamin A and its natural and synthetic derivatives, retinoids, are effective agents in preventing the development of tobacco-associated cancers. Unfortunately, clinical trials of retinoids on cigarette smokers have shown lack of efficacy in preventing lung cancer. In our study, we investigated the effect of nicotine on the anti-cancer activity of all trans-retinoic acid (trans-RA) in human lung cancer cells. Our results demonstrated that nicotine could abrogate the growth inhibitory effect of trans-RA by suppressing its ability to induce the expression of RA receptor beta (RAR beta), a tumor suppressor. The inhibitory effect of nicotine was accompanied with induction of orphan receptor TR3. Inhibition of TR3 expression by overexpression of TR3 anti-sense RNA in H460 lung cancer cells strongly prevented the suppressive effect of nicotine on trans-RA activity. Treatment with nicotine or the cotransfection of TR3 expression vector inhibited the induction of RAR beta promoter activity by trans-RA in transient transfection assays. The inhibition of RAR beta promoter activity was due to the interaction of TR3 with orphan receptor COUP-TF, resulting in inhibition of COUP-TF DNA binding and transactivation on the RAR beta promoter. Furthermore, we found that nicotine failed to suppress the effect of a retinoid X receptor (RXR)-selective retinoid SR11237 on inducing both growth inhibition and RAR beta promoter activity, due to the ability of SR11237 to activate the RAR beta promoter through the RXR/TR3 heterodimer. Together, our results demonstrate that nicotine suppresses the growth inhibitory effects of trans-RA by inhibiting RAR beta expression through its induction of TR3 expression and suggest that RXR-selective retinoids may be more effective than classical retinoids for preventing and treating tobacco-associated cancers.

Regulation of retinoic acid-induced inhibition of AP-1 activity by orphan receptor chicken ovalbumin upstream promoter-transcription factor.

Retinoids are therapeutically effective in the treatment of various cancers, and some of the therapeutic action of retinoids can be ascribed to their potent inhibition of AP-1 activity that regulates transcription of genes associated with cell growth. We recently reported that the expression of orphan receptor chicken ovalbumin upstream promoter-transcription factor (COUP-TF) plays a role in mediating the growth inhibitory effect of trans-retinoic acid (trans-RA) in cancer cells. To gain insight into the molecular mechanism by which COUP-TF regulates trans-RA activity, we evaluated the effect of COUP-TF on antagonism of AP-1 activity by trans-RA. Our results demonstrated a positive correlation between COUP-TF expression and the ability of trans-RA to inhibit AP-1 activity in various cancer cell lines. In transient transfection assay, expression of COUP-TF strongly inhibited tumor promoter 12-O-tetradecanoylphorbol-13-acetate-induced AP-1 transactivation activity and transactivation of c-Jun/c-Fos in both a trans-RA-dependent and -independent manner. In vitro studies demonstrated that the addition of COUP-TF inhibited c-Jun DNA binding through a direct protein-protein interaction that is mediated by the DNA binding domain of COUP-TF and the leucine zipper of c-Jun. Stable expression of COUP-TF in COUP-TF-negative MDA-MB231 breast cancer cells restored the ability of trans-RA to inhibit 12-O-tetradecanoylphorbol-13-acetate-induced c-Jun expression. The effect of COUP-TF in enhancing the trans-RA-induced antagonism of AP-1 activity required expression of retinoic acid receptors (RARs), since stable expression of COUP-TF in COUP-TF-negative HT-1376 bladder cancer cells, which do not express RARalpha and RARbeta, failed to restore trans-RA-induced AP-1 repression. Thus, COUP-TF, through its physical interaction with AP-1, promotes anticancer effects of retinoids by potentiating their anti-AP-1 activity.