Inhibition of UGT1A1*1 and UGT1A1*6 catalyzed glucuronidation of SN-38 by silybins.

UGT1A1 is the main enzyme that catalyzes the metabolic elimination and detoxification of SN-38, the active form of the drug irinotecan. Milk thistle products have been used widely to protect the liver from injury associated with the use of chemotherapeutic agents. To evaluate whether SN-38 metabolism can be affected by milk thistle products, the inhibitory effects of silybins on UGT1A1*1 and UGT1A1*6 were evaluated in the present investigation. Both silybin A and silybin B potently inhibited SN-38 glucuronidation catalyzed by UGT1A1*1 or UGT1A1*6. It was noteworthy that silybin A and silybin B showed synergistic effect in UGT1A1*1 microsomes at concentration around IC50, while additive effect in UGT1A1*6. According to the predicted AUCi/AUC ratios (the ratio of the area under the plasma concentration-time curve of SN-38 in the presence and absence of silybins), the coadministration of irinotecan and several milk thistle products, including silybin-phosphatidylcholine complex, two Legalon capsules, four Silymarin tablets or four Liverman capsules, may lead to clinically significant herb-drug interactions (HDI) via UGT1A1 inhibition. Meanwhile, Rgut values were much higher than 11 in all the groups, indicating potential HDI due to intestinal UGT1A1 inhibition.

Association between ABCB1 C3435T polymorphism and antiepileptic drug resistance in epilepsy: An updated meta-analysis based on 62 studies.

OBJECTIVE: Previous clinical studies and meta-analyses have shown controversial results on the association between C3435T polymorphism of the ABCB1 gene and anti-epileptic drug (AED) resistance. Based on the fact that sample size and confounding factors could contribute to the inconsistency, we performed an updated meta-analysis by including the most recent studies, and subgroup analysis was conducted to evaluate the effect of confounding factors on the association. MATERIALS AND METHODS: We searched articles in 6 electronic databases including PubMed, Medline, Embase, Web of science, Cochrane Library, CNKI (China National Knowledge Infrastructure) for relevant articles up to June 2020. RESULTS: The current analysis showed that the C allele of C3435T variant was a risk factor for drug resistance in the overall populations (C allele vs. T allele, OR: 1.13; 95% CI: 1.02 - 1.25; p = 0.02) and in the Caucasians (C allele vs. T allele, OR: 1.09; 95% CI: 1.09 - 1.43; p = 0.002), while no association was observed in Asians and Indians. Particularly, our study reported for the first time that the 3435T allele was more common in epilepsy patients with drug resistance in the Tunisian population (C allele vs. T allele, OR: 0.31; 95% CI: 0.15 - 0.65; p = 0.002). In addition, our present analysis suggested an association between C3435T and AED resistance in cryptogenic, symptomatic, but not in idiopathic patients. Subgroup studies based on age and gender showed no association. CONCLUSION: AED resistance in Caucasian and Tunisian populations may benefit from ABCB1 C3435T genotyping. We recommend that more details, such as gender and etiology of epilepsy, should be taken into account to draw a reliable conclusion in future studies.

The second type of transglutaminase regulates immune and stress responses in white shrimp, Litopenaeus vannamei.

The total haemocyte count (THC), differential haemocyte count (DHC), phenoloxidase activity, respiratory bursts (release of superoxide anion), superoxide dismutase activity, and phagocytic activity and clearance efficiency to the pathogen Vibrio alginolyticus were measured when white shrimp, Litopenaeus vannamei, (7.5 ± 0.5 g) were individually injected with diethyl pyrocarbonate-water (DEPC-H2O) or different dsRNA at 3 days of injection. In addition, haemolymph glucose and lactate, and haemocytes crustacean hyperglycemic hormone (CHH), transglutaminase I (TGI), transglutaminase II (TGII) and clottable protein (CP) mRNA expression were determined for the shrimp that received DEPC-H2O and different dsRNA after 3 days, and then transferred to 22 and 28 °C from 28 °C. Results showed that respiratory burst, phagocytic activity and clearance efficiency significantly decreased, but hyaline cells significantly increased in the shrimp received LvTGII dsRNA after 3 days. In hypothermal stress studies, LvTGI and CHH were significantly up-regulated in LvTGII-depleted shrimp following exposure to 28 and 22 °C, and haemolymph glucose and lactate were significantly enhanced in LvTGII-depleted shrimp. The injection of LvTGII dsRNA also significantly increased the mortality of L. vannamei challenged with the pathogen V. alginolyticus. These results suggest that LvTGII is an important component on the immune resistance of shrimp, and is involved in the regulation of some immune parameters and carbohydrate metabolites, as well as has a complementary effect with LvTGI in immunological and physiological response of shrimp.