Timosaponin Aâ ¢ induces drug-metabolizing enzymes by activating constitutive androstane receptor (CAR) via dephosphorylation of EGFR signaling pathway.

This study aims to assess the impact of Timosaponin AⅢ (T-AⅢ) on drug-metabolizing enzymes in anticancer treatment. In vivo experiments were conducted in nude mice and ICR mice. Following 24 days of T-AⅢ administration, nude mice exhibited induction of CYP2B10, MDR1, and CYP3A11 in the liver. In the liver of ICR mice, CYP2B10 and MDR1 were up-regulated after 3 days of T-AⅢ administration. In vitro assessments were conducted using HepG2 cells to ascertain the effects and underlying mechanisms. In HepG2 cells, T-AⅢ induced the expression of CYP2B6, MDR1, and CYP3A4, along with CAR activation. CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4. Furthermore, other CAR target genes displayed significant up-regulation. Up-regulation of mCAR was observed in the livers of nude mice and ICR mice. Subsequent findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation, partially reversed by the MAPK/MEK activator t-BHQ. Inhibition of the ERK1/2 signaling pathway was also observed in vivo. Lastly, T-AⅢ inhibited the phosphorylation of EGFR at Tyr1173 and Tyr845, and it suppressed EGF-induced phosphorylation of EGFR, ERK, and CAR. Additionally, T-AⅢ inhibited EGFR phosphorylation in nude mice. Our results demonstrated that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway.

Evaluation of diet as a risk factor in the development of childhood leukaemia: a case control study.

OBJECTIVE: To evaluate probable association of dietary risk factors with childhood leukaemia. METHODS: The case-control study was conducted at the Children Hospital, Pakistan Institute of Medical Sciences, Islamabad, Pakistan, from January to December 2017, and comprised children of either gender aged 2-12 years with recently diagnosed acute lymphocytic or acute myelocytic leukaemia An age and gender matched equal group of healthy children was taken as controls. Dietary-intake data was collected for six food groups, namely raw vegetables, fresh fruits, packed fruit juices, caffeinated drinks, junk foods, and processed/precooked food items. Frequency of the selected food group consumption was summarised in six categories: rarely/never, 1-3 days/week, 4-6 days/week, once daily, twice daily and thrice daily. Data was collected through interviews with the mothers using a pre-designed questionnaire, and was analysed using SPSS 21. RESULTS: Of the 90 subjects, 45(50%) were in each of the two groups. There were no differences in baseline characteristics between the two groups (p>0.05). Consumption of caffeinated drinks and junk food was significantly higher in cases (p=0.001) while controls showed significantly higher consumption of fresh fruits (p=0.0012). No significant difference was noted for consumption of vegetables, packed fruit juices and processed food between the groups (p> 0. 05 ). CONCLUSIONS: Higher consumption of caffeinated drinks and junk food was observed in cases compared to controls.

17ß-estradiol suppresses carboxylesterases by activating c-Jun/AP-1 pathway in primary human and mouse hepatocytes.

In order to study the influence of estrogen on carboxylesterases, we investigated the effects of 17ß-estradiol on CES1 (Ces1d) and CES2 (Ces1e) in human and mouse hepatocytes. After being treated with 17ß-estradiol, the mRNA levels of CES1 and CES2 decreased by 29-39% and 28-55%, respectively, in the human hepatocytes from four donors. Consistently, the hydrolysis of para-nitrophenylacetate decreased markedly by 32% induced by 17ß-estradiol. Moreover, 17ß-estradiol decreased CES1 and CES2 by 45% and 47% respectively at protein levels. The response of altered expression of Ces1d (CES1) and Ces1e (CES2) to 17ß-estradiolin in mouse hepatocytes was very similar to that in the human hepatocytes. Further, the decreased Ces1d and Ces1e expression induced by 17ß-estradiol could be abolished by SP600125, an inhibitor of AP-1, both at mRNA and protein levels. Likewise, the increased c-Jun expression induced by 17ß-estradiol could almost be abolished by SP600125. In vivo, the expression of Ces1d, Ces1e and the hydrolytic activity of liver were higher in the ovariectomized female mice(OVX) than those in control mice(SHAM). However, when 17ß-estradiol was administrated, the expression of Ces1d, Ces1e and the hydrolytic activity of liver in the ovariectomized female mice (OVX+E2) became restored to their normal levels. Taken together, 17ß-estradiol suppresses carboxylesterases by activating c-Jun/AP-1 pathway in primary human and mouse hepatocytes. The findings can offer the potential gains in the safety and efficacy of pharmacotherapy for women, especially for pregnant and menopausal women.