Alantolactone triggers oxeiptosis in human ovarian cancer cells via Nrf2 signaling pathway.

Introduction: A growing body of evidence indicated that Alantolactone (ALT) promotes Reactive Oxygen Species (ROS) generation exclusively in cancer cells. Therefore, the aim of this study was to investigate the effect of ALT on the molecular mechanism of oxeiptosis, as a novel cell death pathway due to the high levels of intracellular ROS in ovarian cancer. Methods: MTT assay was used to evaluate the effect of ALT on SKOV3 cell viability. mRNA and protein expression levels of Nrf2 (nuclear factor erythroid 2-related factor 2), KEAP1 (Kelch-like ECH-associated protein 1), PGAM5 (phosphoglycerate mutase family member 5), AIFM1 (Mitochondrial Apoptosis-Inducing Factor), Glutathione synthetase (GSS) and glutathione peroxidase (GPX) were analyzed by real time PCR and western blotting methods respectively. Results: Our findings showed that ALT inhibits the proliferation of skov3 cells in a time and dose dependent manner and IC50 was 32 µM at 24h.A significant down-regulation of Nrf2, GSH and GPX mRNA levels was seen in skov3 cells incubated with 32 and 64 µM of ALT in comparison with control group, while, mRNA expression levels of PGAM5 and KEAP1 were increased.Western blot analysis showed that ALT significantly decreases protein levels of Nrf2 and increases PGAM5 and KEAP1.ALT dephosphorylated PS116-AIFM1 and total AIFM1 protein level was elevated. Conclusion: Our results provided evidence that ALT could be a potential option for ovarian cancer treatment by ROS-mediated oxeiptosis.

Correction to: Interaction of opioid with insulin/IGFs signaling in Alzheimer's disease.

The original version of this article unfortunately contained mistake in the Author Group section. Reza Rahbarghazi's family name was inadvertently spelled as "Rahbarghzi".

Interaction of opioid with insulin/IGFs signaling in Alzheimer's disease.

Alzheimer's disease is associated with biochemical and histopathological changes characterized by molecular abnormalities. Due to the lack of effective treatments for Alzheimer's disease, many attempts have been made to find potential therapies to reduce or even return neuronal loss after disease initiation. Alzheimer's disease is also touted as type III diabetes, showing an association with insulin signaling. The large distribution of the insulin receptor on the cell surface and its regulatory role in the central nervous system suggests that the pathogenesis of Alzheimer's disease could be ascribed to insulin signaling. The interference of opioids, such as morphine with insulin signaling pathways, is thought to occur via direct crosstalk between the signaling pathways of the insulin receptor and the mu-opioid receptor. In this review article, we discuss the possible crosstalk between the mu-opioid receptor and insulin signaling pathways. The association of these two signaling pathways with Alzheimer's disease is also debated.

Crocetin suppresses the growth and migration in HCT-116 human colorectal cancer cells by activating the p-38 MAPK signaling pathway.

BACKGROUND AND PURPOSE: Crocetin is a natural antioxidant that is found in the crocus flower and Gardenia jasminoides (fruit). Previous studies have reported its anticancer activity both in vivo and in vitro. In addition, crocetin suppresses the growth and migration of human colorectal cancer cells, however, its mechanism of action remains to be elucidated. Therefore, the present study investigated the molecular mechanism of crocetin effect on colorectal cancer cells (HCT-116) in vitro. EXPERIMENTAL APPROACH: HCT-116 cells were treated with different concentrations (0, 200, 400, 600, and 800 µM) of crocetin for 24 h. The cell survival rate was measured by MTT assay. Cell migration capacity was evaluated using the wound healing assay. The expression levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP-9) was monitored by RT-PCR. Phosphorylation of focal adhesion kinase (FAK) and p38 mitogen-activated protein kinase (MAPK) was determined using western blot. FINDINGS/RESULTS: The proliferation of HCT-116 was inhibited by crocetin at 800 µM (P < 0.001). Crocetin prevented migration of HCT-116 cells (P < 0.05) and suppressed VEGF and MMP-9 mRNA expression (P < 0.001) and increased phosphorylation of p38 (MAPK; P < 0.001). However, no significant change in the phosphorylation of FAK was observed. CONCLUSION AND IMPLICATION: These data suggested that crocetin-induced growth- and migration- suppressing effects on HCT-116 cells may partially depend on the regulation of the p38 (MAPK) signaling pathway.

Crocetin promotes angiogenesis in human endothelial cells through PI3K-Akt-eNOS signaling pathway.

Previous studies proved the pro-angiogenic effect of Crocetin, a natural carotenoid dicarboxylic acid, in both in vivo and in vitro models. However, the exact mechanism of Crocetin action has not completely been elucidated yet. The current experiment was designed to find the activity of PI3K-Akt-eNOS axis after the treatment of endothelial cells with Crocetin in vitro. Human Umbilical Vein Endothelial Cells (HUVECs) were incubated with various concentrations of Crocetin (1, 5, 25, 50, and 100 µM) over a period of 72 h. Crocetin significantly increased HUVECs viability after 72 h as compared with the control group. We also found that Crocetin promoted the formation of the capillary-like structure compared to the control (p<0.05). Moreover, an improved migration rate and increased MMP-9 activity were observed in HUVECs that received 50 µM Crocetin (p<0.05). Crocetin enhanced the uptake of Ac-LDL which is correlated with increased lipid metabolism. Based on the data from the current experiment, protein level of VEGFR-1, -2 and p-Akt/Akt, p-eNOS/eNOS ratios were increased 72 h after the treatment of HUVECs with Crocetin (p<0.05). In contrast, the transcription level of VEGF was reduced in Crocetin-treated cells. These data demonstrated that Crocetin promotes HUVECs angiogenesis potential by the modulation of VEGF signaling pathway and increased cell viability. The PI3K/Akt/eNOS axis is required for a Crocetin-associated activity in endothelial cells.