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Autophagy is a process of active programmed cell death, where a dying cell induces autophagosomes and subsequently regulated by degradative machinery. The aim of this study was to investigate the mechanism behind induction of autophagic cell death by Naringin flavonoid in AGS cancer cells. Growth inhibition of AGS cells showed downregulation of PI3K/Akt/mTOR signaling by Naringin treatment. Transmission electron microscopy observation showed swollen mitochondria and lysosome near peri-nuclear zone fused with autophagic vacuoles. Rapamycin pre-treatment with Naringin showed significant decrease in mTOR phosphorylation and increase in LC3B activation in AGS cells. Decrease in mTOR phosphorylation is associated with lysosomal function activation was observed by time-dependent treatment of Naringin. Induction of lysosomal membrane permeabilization (LMP) was observed by LAMP1 activation leading lysosomal cell death by releasing Cathepsin D from lysosomal lumen to cytosol. Naringin treated AGS cells showed up-regulating BH3 domain Bad, down-regulating Bcl-xL, and Bad phosphorylation and significant mitochondrial fluorescence intensity expression. Significant localization of mitochondria and LC3B activation was examined by person coefficient correlation. Activation of ERK1/2-p38 MAPKs and production of intracellular ROS has been observed over Naringin treatment. It has also been elucidated that pre-treatment with NAC inhibited mitochondria-LC3B colocalization, where ROS acted as upstream of ERK1/2-p38 MAPKs activation. Lysosomal cell death involvement has been evaluated by BAF A1 pre-treatment, inhibiting LAMP1, Cathepsin D, ROS, and blocking autophagolysosome in AGS cell death. Taken together, these findings show that, Naringin induced autophagy cell death involves LMP mediated lysosomal damage and BH3 protein Bad activation in AGS cancer cells. [ABSTRACT FROM AUTHOR]

Background: Hypertension is a common disease found in 1.13 billion adults worldwide. Several animal studies have provided evidence of the joint effect of alcohol drinking and cadmium exposure on hypertension. However, no epidemiologic study has examined the association between these 2 risk factors and hypertension. Therefore, we examined the individual effects of alcohol drinking and cadmium and the joint effect of their coexposure on hypertension in the general population. Methods: We analyzed data from 8,403 South Korean adults who had been randomly assigned to the Korea National Health and Nutrition Examination Survey from 2008 to 2013. Multiple linear and logistic regression analyses were conducted to estimate the association of alcohol drinking and blood cadmium concentration with blood pressure and the odds ratio (OR) for hypertension. Results: The weighted prevalence of hypertension and high‐risk drinking was 25.7 and 13.6%, respectively. The weighted geometric mean of blood cadmium levels was 0.94 μg/L (95% confidence interval [CI]: 0.93 to 0.96). After adjusting for demographic characteristics, anthropometric measurements, health‐related behaviors, and dietary and disease variables, the OR for hypertension in the group with the high‐risk alcohol drinking was 1.67 (95% CI: 1.34 to 2.06) compared with the group without high‐risk alcohol drinking. When the highest and the lowest blood cadmium quartiles were compared, the OR for hypertension was 1.46 (95% CI: 1.15 to 1.86). The positive joint effect of high‐risk drinking and blood cadmium levels was statistically significant for systolic blood pressure (SBP; p = 0.037) and diastolic blood pressure (DBP; p < 0.001). Conclusions: Our results show that heavy alcohol drinking had a joint effect with cadmium exposure to increase the risk of hypertension. Future efforts are needed to reduce alcohol drinking and environmental cadmium exposure to prevent hypertension in the general population. [ABSTRACT FROM AUTHOR]