The role of aquaporin-4 (AQP4) in the regulation of astrocytes function has been widely investigated. However, there is little information about its contribution to the drug metabolism enzymes such as Cytochrome P4502E1. In the present study, we investigated whether AQP4 is involved in the process of the cell damage caused by MPP + and LPS through regulating the expression of CYP2E1 in astrocytes. Compared to the wild-type, in primary astrocytes, AQP4 knockout increased the cell damage and the reactive oxygen species (ROS) production which were induced by MPP + , LPS and ethanol. Notably, AQP4 knockout enhanced the up-regulation of the expression of CYP2E1 in astrocytes exposed to MPP + , LPS and ethanol. Furthermore, Diallylsulphide (DAS), a CYP2E1 inhibitor, partially or almost abolished the cell injury and the ROS production of the astrocytes induced by MPP + and LPS. These findings indicate AQP4 protects astrocytes from the damage caused by MPP + and LPS through reducing the ROS production correlation to the diminished expression of CYP2E1.

Carboxylesterases constitute a class of enzymes that hydrolyze drugs containing such functional groups as carboxylic acid ester, amide, and thioester. Hydrolysis of many drugs is reduced in liver diseases such as hepatitis and cirrhosis. In this study, we have demonstrated, in vitro and in vivo, treatment with LPS decreased the expression of HCE1 and HCE2 and the capacity of hydrolytic activity. In HepG2 cells, the decreased expression by LPS occurred at both mRNA and protein levels. Both HCE1 and HCE2 promoters were significantly repressed by LPS, and the repression was comparable with the decrease in HCE1 and HCE2 mRNA, suggesting the transrepression is responsible for suppressed expression. Further study showed that both PDTC, a NF-κB inhibitor, and SB203580, a p38MAPK inhibitor, could abolish the repression of HCE1 and HCE2 mediated by LPS, but U0126, a selective ERK1/2 inhibitor, could not do so, suggesting the repression of HCE1 and HCE2 by LPS through the p38MAPK-NF-κB pathway. In addition, being pretreated with LPS, HepG2 cells altered the cellular responsiveness to ester therapeutic agents, including clopidogrel (hydrolyzed by HCE1) and irinotecan (hydrolyzed by HCE2). The altered cellular responsiveness occurred at low micromolar concentrations, suggesting that suppressed expression of carboxylesterases by LPS has profound pharmacological and toxicological consequences, particularly with those that are hydrolyzed in an isoform-specific manner. This study provides new insight into the understanding of the pharmacological and toxicological effects and the mechanisms for repressing drug metabolism enzymes in inflammation.

BACKGROUND AND PURPOSEByakangelicin is found in extracts of the root of Angelica dahurica, used in Korea and China as a traditional medicine to treat colds, headache and toothache. As byakangelicin can inhibit the effects of sex hormones, it may increase the catabolism of endogenous hormones. Therefore, this study investigated the effects of byakangelicin on the cytochrome P450 isoform cytochrome (CY) P3A4 in human hepatocytes. EXPERIMENTAL APPROACHCultures of human hepatocytes and a hepatoma cell line (Huh7 cells) were used. mRNA and protein levels were measured by quantitative reverse transcription-polymerase chain reaction and Western blot. Plasmid constructs and mutants were prepared by cloning and site-directed mutagenesis. Reporter (luciferase) activity was determined by transient co-transfection experiments. KEY RESULTSIn human primary hepatocytes, byakangelicin markedly induced the expression of CYP3A4 both at the mRNA level (approximately fivefold) and the protein level (approximately threefold) but did not affect expression of human pregnane X receptor (hPXR). In reporter assays, byakangelicin activated CYP3A4 promoter in a concentration-dependent manner (EC50 = 5 mM), and this activation was enhanced by co-transfection with hPXR. Further reporter assays demonstrated that the eNR4 binding element in the CYP3A4 promoter was required for the transcriptional activation of CYP3A4 by byakangelicin. CONCLUSIONS AND IMPLICATIONSByakangelicin induced expression and activity of CYP3A4 in human hepatocytes. This induction was achieved by the transactivation of PXR and not by increased expression of PXR. Therefore, byakangelicin is likely to increase the expression of all PXR target genes (such as MDR1) and induce a wide range of drug-drug interactions. Abbreviations

Curcumin is extracted from the rhizomes of the ginger family plant Curcuma longa L., which has a good protection for liver, kidney, and immune system. However, there is little information about its contribution in protection of astrocytes recently. The present study was undertaken to elucidate the protective effect of curcumin, an herbal antioxidant, on 1-methyl-4-phenylpyridinium ion- (MPP+-) and lipopolysaccharide- (LPS-) induced cytotoxicities, as well as the underlying mechanisms by using primary mouse mesencephalic astrocytes. The results showed that curcumin protected the mesencephalic astrocytes from MPP+- and LPS-induced toxicities along with reducing reactive oxygen species (P < 0.05) and maleic dialdehyde (P < 0.05) sufficiently. Moreover, curcumin significantly inhibited the cytochrome P450 2E1 (CYP2E1) expression (P < 0.01 at mRNA level, P < 0.05 at protein level) and its activity (P < 0.05) sufficiently induced by MPP+ and LPS in the mouse mesencephalic astrocytes. And curcumin as well as diallyl sulphide, a CYP2E1 positive inhibitor, ameliorated MPP+- and LPS-induced mouse mesencephalic astrocytes damage. Accordingly, curcumin protects against MPP+- and LPS-induced cytotoxicities in the mouse mesencephalic astrocyte via inhibiting the CYP2E1 expression and activity.

BACKGROUND Coronary artery stenosis (CAS) is the most common type of heart disease and the leading cause of death in both men and women globally. CAS occurs when the arteries that supply blood to the heart muscle harden and become narrower due to plaque buildup - cholesterol and other material - on their inner walls. As a result, the heart muscle cannot receive the blood or oxygen it needs. Most heart attacks happen when a blood clot suddenly cuts off the hearts' blood supply, causing permanent heart damage. AIM To analyze the relationship between the left ventricular ejection fraction (LVEF), left ventricular strain (LVS), and coronary stenosis. METHODS A total of 190 participants were enrolled in this trail. The control group comprised 93 healthy individuals, and observation group comprised 97 patients with coronary heart disease who were hospitalized between July 2020 and September 2021. Coronary lesions were assessed using the Gensini score, and the LVEF and LVS were measured using magnetic resonance imaging (MRI). The interaction between the LVEF and LVS was examined using a linear regression model. The relationship between LVEF and coronary stenosis was examined using Spearman’s correlation. RESULTS The LVEF of the observation group was lower than that of the control group. The left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) of the observation group were significantly higher than those of the control group ( P < 0.05). The longitudinal and circumferential strains (LS, CS) of the observation group were significantly higher than those of the control group; however, the radial strain (RS) of the observation group was significantly lower than that of the control group ( P < 0.05). LVS, LS, and CS were significantly negatively correlated with the LVEF, and RS was positively correlated with the LVEF. There were significant differences in the LVEF, LVESV, and LVEDV of patients with different Gensini scores; the LVEF significantly decreased and the LVESV and LVEDV increased with increasing Gensini scores ( P < 0.05). In the observation group, the LVEF was negatively correlated and the LVESV and LVEDV were positively correlated with coronary stenosis ( P < 0.05). CONCLUSION The LVEF measured using MRI is significantly linearly correlated with LVS and negatively correlated with coronary stenosis.

Gambogic acid (GA) was approved by the Chinese Food and Drug Administration for phase II clinical trials in patients with solid tumors. Recently, combinations of GA and chemotherapeutic agents have represented a promising therapeutic approach for cancer. However, little is known about the effect of GA on drug metabolism enzymes. In this study, we report for the first time that GA is a potent repressor of the cytochrome P450 3A4 (CYP3A4) enzyme, which is responsible for the oxidative metabolism of more than 60% of all pharmaceuticals. After HepG2 cells were treated with GA, the expression of CYP3A4 decreased at both the mRNA and protein levels, and CYP3A4 enzymatic activity was also reduced. Moreover, GAmediated repression of CYP3A4 occurred after the decrease of PXR. Knockdown of PXR decreased CYP3A4 at the mRNA and protein levels, whereas PXR overexpression increased the CYP3A4 mRNA and protein levels. GA markedly decreased CYP3A4 expression in both normal and PXR overexpressing cells.Meanwhile, differentiated embryonic chondrocyte gene 1 (DEC1) expression rapidly increased in response to GA treatment, and subsequently, CYP3A4 expression continuously decreased. Overexpression of DEC1 decreased CYP3A4 mRNA and protein levels, and knockdown of DEC1 partially abolished the GAmediated decrease in CYP3A4 expression. Taken together, our data suggest that two transcriptional factors, PXR and DEC1, are involved in the GA-mediated suppression of CYP3A4 in HepG2 cells.