Docosahexaenoic Acid Reverses Epithelial-Mesenchymal Transition and Drug Resistance by Impairing the PI3K/AKT/ Nrf2/GPX4 Signalling Pathway in Docetaxel-Resistant PC3 Prostate Cancer Cells.

Drug resistance is a serious problem in cancer therapy. Growing evidence has shown that docosahexaenoic acid has anti-inflammatory and chemopreventive abilities. Studies have shown that autophagy inhibition and ferroptosis are promising therapeutic strategies for overcoming multidrug resistance. This study was aimed to examine whether docosahexaenoic acid (DHA) could reverse docetaxel resistance in prostate cancer cells. Cell survival was examined by MTT and colony formation. Protein expression was determined by Western blot. Reactive oxygen species (ROS) production was measured by flow cytometry. DHA displayed anti-cancer effects on proliferation, colony formation, migration, apoptosis, autophagy and epithelial mesenchymal transition. Glutathione-S-transferase π is an enzyme that plays an important role in drug resistance. DHA inhibited GSTπ protein expression and induced cytoprotective autophagy by regulating the PI3K/AKT signalling pathway in PC3R cells. DHA combined with PI3K inhibitor (LY294002) enhanced apoptosis by alleviating the expression of LC3B, (pro-) caspase- 3 and (uncleaved) PARP. DHA induced ferroptosis by attenuating the expression of glutathione peroxidase 4 (GPX4) and nuclear erythroid 2-related factor 2 (Nrf2). DHA-treated PC3R cells produced ROS. The ROS and cytotoxicity were reversed by treatment with ferrostatin-1. DHA combined with docetaxel inhibited EMT by regulating the expression of E-cadhein and N-cadherin. In summary, DHA reversed drug resistance and induced cytoprotective autophagy and ferroptosis by regulating the PI3K/AKT/Nrf2/GPX4 signalling pathway in PC3R cells. We propose that DHA could be developed as a chemosensitizer and that the PI3K/AKT /Nrf2/GPX4 signalling pathway might be a promising therapeutic target for overcoming cancer drug resistance.

Epidemiology, species distribution, antifungal susceptibility, and ERG11 mutations of Candida species isolated from pregnant Chinese Han women.

The widespread use of antifungal agents has led to increasing azole resistance in Candida species. A major azole-resistance mechanism involves point mutations in the ERG11 gene, which encodes cytochrome P450 lanosterol 14a-demethylase. In this study, vaginal swabs were obtained from 657 pregnant Chinese Han women and cultured appropriately. The open reading frame of the obtained fungal species were amplified by PCR and sequenced; additionally, the ERG11 gene of the isolated Candida species was amplified and sequenced, and the antifungal susceptibility of the isolated species was determined. The vaginal swabs of 124 women produced fungal cultures; five species of Candida were isolated from the patients, among which Candida albicans was predominant. Twelve C. albicans isolates (13.8%) were resistant to fluconazole and 2 (2.2%) were resistant to itraconazole. Seventeen mutations, including 9 silent and 8 missense mutations, were identified in the ERG11 gene of 31 C. albicans isolates. Our findings suggest that infection caused by C. albicans and non-C. albicansis common in Chinese Han women of reproductive age. Moreover, the relationship between Candida infection and certain epidemiological factors emphasizes the need to educate women about the precise diagnosis and punctual treatment of vaginitis.

Effects of methylmercury on hypnotic action of hexobarbital, liver hydroxylase and cytochrome P-450 in mice.

The effects of methylmercury hydroxide (MeHgOH) on the hypnotic action of hexobarbital was investigated in adult 129/SvSl mice of both sexes. It was found that there was no sex difference in the response to MeHgOH treatment. The action of MeHgOH was intimately related to the interval between MeHgOH administration and the test of hexobarbital hypnosis. A biphasic effect was observed. An initial dose-dependent prolongation of hexobarbital hypnosis was observed in animals pretreated with MeHgOH 24 h earlier. If the interval was extended from 24 h to 1 week, a shortening of sleeping time was observed in MeHgOH treated animals. The animals recovered from the effects of MeHgOH in 3 weeks. The initial effect of MeHgOH was found closely related to the decrease in the rate of hexobarbital metabolism in the liver through lowering of cytochrome P-450 concentration. On the other hand, the delayed shortening of hexobarbital hypnosis was not related to the rate of hexobarbital metabolism. It is assumed that the delayed effect of MeHgOH on the hexobarbital hypnosis is due to MeHgOH acting on the central nervous system to decrease its sensitivity to hexobarbital via interaction with the barbiturate receptors on the GABA-chloride ionophore complex. In animals exposed in utero to MeHgOH, it was found that the duration of hexobarbital-induced sleeping time was significantly longer in the offsprings tested for hexobarbital hypnosis 3.5 months after birth following prenatal exposure to MeHgOH. Repeated administration of hexobarbital to adult offsprings prenatally exposed to MeHgOH and to control mice shortened hexobarbital sleeping time, however, the maximum shortening capacity was smaller in the treated group. It is concluded that the hypnotic action of hexobarbital in mice can be altered by MeHgOH exposure both prenatally and postnatally. The effects of prenatal exposure to MeHg were observed in adult offsprings, indicating that MeHg may have a functional teratogenic effect on barbiturate-induced hypnosis in the absence of gross anomalies.

Pharmacokinetics, tissue distribution and excretion study of dl-praeruptorin A of Peucedanum praeruptorum in rats by liquid chromatography tandem mass spectrometry.

dl-Praeruptorin A (Pd-Ia), isolated from Chinese traditional herbal medicine Peucedanum praeruptorum Dunn, has been proved to be a novel Ca²+-influx blocker and K+-channel opener, and displayed bright prospects in prevention and therapy of cardiac diseases. The aim of this study was to investigate the pharmacokinetics, tissue distribution and excretion of Pd-Ia in rats following a single intravenous (i.v.) administration. The levels of Pd-Ia in plasma, tissues, bile, urine and feces were measured by a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The results showed that Pd-Ia was rapidly distributed and then eliminated from rat plasma and manifested linear dynamics in dose range of 5-20 mg/kg. The mean elimination half-life (t(½) of Pd-Ia for 5, 10 and 20 mg/kg dose were 57.46, 60.87 and 59.01 min, respectively. The major distribution tissues of Pd-Ia in rats were spleen, heart and lung, and low polarity enabled Pd-Ia to cross the blood-brain barrier. There was no long-term accumulation of Pd-Ia in rat tissues. Total recoveries of Pd-Ia within 24 h were low (0.097% in bile, 0.120% in urine and 0.009% in feces), which might be resulted from liver first pass effect.

Maternal diazepam exposure on brain ornithine decarboxylase and growth of offspring.

The prenatal treatment of diazepam on the developmental pattern of brain ornithine decarboxylase and the general growth of offspring were studied. Diazepam (120 mg/kg/day) was administered orally to pregnant Sprague-Dawley rats from day 14 to day 20 of gestation. The activity of brain ornithine decarboxylase and body weight of the offspring were measured from the late fetal stage to the early postnatal stage. It was found that diazepam inhibited both the prenatal and 4-hour postnatal ornithine decarboxylase activities, though the general maturation pattern of the enzyme in the brain was not much altered. It may indicate that diazepam inhibits early brain development. The enzyme activity fell off as it reached maturation. Prenatal treated neonates of 6-hour or older age group had the normal activities of brain ornithine decarboxylase. The general growth of the treated offspring was substantially retarded. Their body weights were very much lower than the control offspring. The results of the present study is an additional evidence that diazepam and other benzodiazepines should be used with great care in pregnant women.