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The pathogenesis of high altitude-related gastric mucosal injury remains poorly understood, this study aimed to investigate the role of autophagy in hypoxia-induced apoptosis of rat gastric mucosal cells. Rats were randomized into four groups which were maintained at an altitude of 400 m (P) or received no treatment (H), autophagy inducer rapamycin (H+AI) or autophagy inhibitor 3-MA (H+AB) at an altitude of 4,300 m for 1, 7, 14 and 21 days, respectively, and the morphology, ultrastructure, autophagy, and apoptosis of gastric mucosal tissues were examined. Gastric mucosal epithelial cells CC-R039 were cultured under conditions of normoxia, 2% O2 (hypoxia), or 2% O2+anti-mTORC1 for 0, 24, 48, and 72 h, respectively, and the autophagy and apoptosis were analyzed. CC-R039 cells were transfected with siHIF-1α, siTERT, or siRNA and the autophagy was examined. The results showed that the exposure to hypoxia increased the autophagy and apoptosis of gastric mucosal cells in rats, and apoptosis was aggravated by rapamycin treatment but alleviated by 3-MA treatment. Increased duration of hypoxia from 0 to 72 h could increase the autophagy and apoptosis but decrease the proliferation of gastric mucosal cells. Inhibition of mTORC1 with rapamycin led to further increase in apoptosis and even substantial cell death, and inhibition of HIF- 1a and TERT increased mTORC1 expression and reduced autophagy. Moreover, the inhibition of HIF-1a reduced TERT expression. In conclusion, hypoxia could induce apoptosis of rat gastric mucosal cells by activating autophagy through HIF-1a/TERT/mTORC1 pathway. [ABSTRACT FROM AUTHOR]

YGY-E is an active ingredient in traditional Chinese medical herbs which have antiischemic activity. The present work was designed to study its therapeutic time window in cerebral ischemic injury as well as its effect on neuronal apoptosis. Animals received an intravenous injection of YGY-E at 1, 3, and 6 h, respectively, after permanent focal cerebral ischemia induced by electrocoagulation of the middle cerebral artery. Infarct ratio and neurological function were employed to assess the effects of YGY-E on the therapeutic time window in this animal model. Furthermore, we evaluated effects of this compound on neuronal apoptosis and synthesis of Bcl-2 and Bax in ischemic brain tissue with in situ DNA end labeling (TUNEL), immunohistochemistry assay, and Western blot analysis. YGY-E (2-8 mg/kg) delivered at all the three time points dosedependently decreased infarct ratio, neurological deficits, percentage of TUNEL-positive cells (p < 0.01) and Bax-positive cells (p < 0.01 or p < 0.05). In contrast, it increased the percentage of Bcl-2 positive cells (p < 0.01 or p < 0.05). These data demonstrated that YGY-E had protective effects against cerebral ischemia injuries in rats. But more importantly, they indicate that YGY-E has an unusually long (up to 6 h) therapeutic time window relative to classical drugs in treating cerebral ischemia. In addition, our results suggest that the anti-apoptotic effects of YGY-E are due to its regulation of the balance between Bcl-2 and Bax protein levels. [ABSTRACT FROM AUTHOR]

Context: Formononetin, an isoflavone, can inhibit the proliferation of cancer cells, including those of the prostate. However, its antitumor mechanism remains unclear. Aim: To investigate whether the insulin-like growth factor 1 (IGF-1)/insulin-like growth factor 1 receptor (IGF-1 R) signaling pathway mediates the formononetin antitumor effect on prostate cancer cells. Materials and methods: The viability of PC-3 cells was measured by MTT assay 48 h after formononetin treatment (25, 50 and 100 μM). Formononetin-induced cell apoptosis was measured by Hoechst 33258 staining and flow cytometry. Expression of Bax mRNA was detected by real-time PCR, and the expression levels of Bax and IGF-1 R proteins were detected by western blots. Results: At concentrations >12.5 μM, formononetin significantly inhibited the proliferation of human prostate cancer cells. Formononetin increased Bax mRNA and protein expression levels and decreased the expression levels of pIGF-1 R protein in a dose-dependent manner. Conclusion: High concentrations of formononetin-induced apoptosis in androgen-independent prostate cancer cells through inhibition of the IGF-1/IGF-1 R pathway. [ABSTRACT FROM AUTHOR]

Gastric cancer remains a major health problem worldwide. Natural products, with stronger antitumor activity and fewer side effects, are potential candidates for pharmaceutical development as anticancer agents. In this study, quercetin and curcumin were chosen for testing and were applied separately and in combination to human gastric cancer MGC-803 cells. The MTT assay was used to evaluate cell growth inhibition. Annexin V-FITC/PI was carried out to measure apoptosis rate. Flow cytometry was performed to analyze mitochondrial membrane potential levels. Western blots were applied to detect expression of cytochrome c, total and phosphorylated ERK and AKT. Combined treatment with curcumin and quercetin resulted in significant inhibition of cell proliferation, accompanied by loss of mitochondrial membrane potential (ΔΨm), release of cytochrome c and decreased phosphorylation of AKT and ERK. These results indicate that the combination of curcumin and quercetin induces apoptosis through the mitochondrial pathway. Notably, effect of combined treatment with curcumin and quercetin on gastric cancer MGC-803 cells is stronger than that of individual treatment, indicating that curcumin and quercetin combinations have potential as anti-gastric cancer drugs for further development. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate the efficacy of picosecond pulsed electric fields (psPEF) on a cervical cancer xenograft. Human cervical cancer xenografts were established in nude mice by transplantation of HeLa cells, and the tumors were then treated with psPEF. The histological changes were observed by hematoxylin-eosin staining and transmission electron microscopy. The rate of tumor cell apoptosis was determined using a terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling assay. The mitochondrial transmembrane potential of the tumor cells was detected by laser scanning confocal microscopy, and the activity of caspase-3, -8, -9 and -12 was determined. The inhibitory rate seven days post-psPEF treatment was also calculated. The results showed that exposure to psPEF led to an increased rate of apoptosis, collapse of mitochondrial transmembrane potential, and activation of caspases. The inhibitory rate was 9.11% at day 7. The results of the present study indicate that psPEF may induce apoptosis in a cervical cancer xenograft through the endoplasmic reticulum stress and caspase-dependent signaling pathways. [ABSTRACT FROM AUTHOR]

In this article, reversal activities of Euphorbia factor L1 (EFL1) against ABCB1-mediated multidrug resistance (MDR) and apoptosis sensitization in K562/ADR cells are reported. EFL1 decreased the IC50 values of anticancer agents in K562/ADR cells over-expressing ABCB1. However, EFL1 did not affect the IC50 values of anticancer agents in sensitive K562 cells. Additionally, EFL1 increased the intracellular accumulation of rhodamine 123 and doxorubicin in K562/ADR cells without affecting their accumulation in K562 cells. Furthermore, EFL1 sensitized the apoptosis triggered by vincristine in K562/ADR cells via mitochondrial pathway, as confirmed by Annexin V-FITC/PI detection and western blot. At the same time, EFL1 did not influence the apoptosis induced by vincristine in K562 cells. Western blot results showed that EFL1 did not affect the phosphorylation level of AKT and ERK in K562 and K562/ADR cells. Finally, EFL1 did not down-regulate protein expression of ABCB1. [ABSTRACT FROM AUTHOR]