Helicobacter pylori (H. pylori) infection leads to the massive apoptosis of the gastric epithelial cells, causing gastric ulcers, gastritis, and gastric adenocarcinoma. Autophagy is a cellular recycling process that plays important roles in cell death decisions and can protect cells by preventing apoptosis. Upon the induction of autophagy, the level of the autophagy substrate p62 is reduced and the autophagy-related ratio of microtubule-associated proteins 1A/1B light chain 3B (LC3B)-II/LC3B-I is heightened. AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are involved in the regulation of autophagy. Astaxanthin (AST) is a potent anti-oxidant that plays anti-inflammatory and anti-cancer roles in various cells. In the present study, we examined whether AST inhibits H. pylori-induced apoptosis through AMPK-mediated autophagy in the human gastric epithelial cell line AGS (adenocarcinoma gastric) in vitro. In this study, H. pylori induced apoptosis. Compound C, an AMPK inhibitor, enhanced the H. pylori-induced apoptosis of AGS cells. In contrast, metformin, an AMPK activator, suppressed H. pylori-induced apoptosis, showing that AMPK activation inhibits H. pylori-induced apoptosis. AST inhibited H. pylori-induced apoptosis by increasing the phosphorylation of AMPK and decreasing the phosphorylation of RAC-alpha serine/threonine-protein kinase (Akt) and mTOR in H. pylori-stimulated cells. The number of LC3B puncta in H. pylori-stimulated cells increased with AST. These results suggest that AST suppresses the H. pylori-induced apoptosis of AGS cells by inducing autophagy through the activation of AMPK and the downregulation of its downstream target, mTOR. In conclusion, AST may inhibit gastric diseases associated with H. pylori infection by increasing autophagy through the activation of the AMPK pathway.
Helicobacter pylori infection causes the hyper-proliferation of gastric epithelial cells that leads to the development of gastric cancer. Overexpression of tumor necrosis factor receptor associated factor (TRAF) is shown in gastric cancer cells. The dietary antioxidant β-carotene has been shown to counter hyper-proliferation in H. pylori-infected gastric epithelial cells. The present study was carried out to examine the β-carotene mechanism of action. We first showed that H. pylori infection decreases cellular IκBα levels while increasing cell viability, NADPH oxidase activity, reactive oxygen species production, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, and TRAF1 and TRAF2 gene expression, as well as protein-protein interaction in gastric epithelial AGS cells. We then demonstrated that pretreatment of cells with β-carotene significantly attenuates these effects. Our findings support the proposal that β-carotene has anti-cancer activity by reducing NADPH oxidase-mediated production of ROS, NF-κB activation and NF-κB-regulated TRAF1 and TRAF2 gene expression, and hyper-proliferation in AGS cells. We suggest that the consumption of β-carotene-enriched foods could decrease the incidence of H. pylori-associated gastric disorders. from its complex with cytoplasmic IκBα and translocation to the nucleus, a process that is triggered by reactive oxygen species (ROS) and involves ubiquitin-mediated IκBα degradation [17].Previous studies have implicated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and specifically, the reactive oxygen species (ROS) generated by NADPH oxidase, as potential causative factors in H. pylori-induced gastric injury [18][19][20]. It has been shown that gastric epithelial cells infected with H. pylori contain higher levels of NADPH oxidase activity and consequently, higher levels of ROS, leading to the degradation of IκBα and activation of 21].The antioxidant β-carotene-which is responsible for the orange color of many fruits and vegetables, such as carrots and sweet potatoes-inhibits cell growth and also induces apoptosis and cell cycle arrest in various cancers, such as breast cancer and colon cancer [22,23]. β-Carotene is known to reduce ROS levels in H. pylori-infected gastric epithelial cells [5]. Therefore, we hypothesized that β-carotene might inhibit H. pylori-induced up-regulation of TRAF1 and TRAF2 and thereby inhibit NF-κB activation in gastric epithelial cells.
Astaxanthin (ASX), a red-colored xanthophyll carotenoid, functions as an antioxidant or pro-oxidant. ASX displays anticancer effects by reducing or increasing oxidative stress. Reactive oxygen species (ROS) promote cancer cell death by necroptosis mediated by receptor-interacting protein kinase 1 (RIP1) and RIP3. NADPH oxidase is a major source of ROS that may promote necroptosis in some cancer cells. The present study aimed to investigate whether ASX induces necroptosis by increasing NADPH oxidase activity and ROS levels in gastric cancer AGS cells. AGS cells were treated with ASX with or without ML171 (NADPH oxidase 1 specific inhibitor), N-acetyl cysteine (NAC; antioxidant), z-VAD (pan-caspase inhibitor) or Necrostatin-1 (Nec-1; a specific inhibitor of RIP1). As a result, ASX increased NADPH oxidase activity, ROS levels and cell death, and these effects were suppressed by ML171 and NAC. Furthermore, ASX induced RIP1 and RIP3 activation, ultimately inducing mixed lineage kinase domain-like protein (MLKL) activation, lactate dehydrogenase (LDH) release and cell death. Moreover, the ASX-induced decrease in cell viability was reversed by Nec-1 treatment and RIP1 siRNA transfection, but not by z-VAD. ASX did not increase the ratio of apoptotic Bax/anti-apoptotic Bcl-2, the number of Annexin V-positive cells, or caspase-9 activation, which are apoptosis indices. In conclusion, ASX induced necroptotic cell death by increasing NADPH oxidase activity, ROS levels, LDH release and the number of propidium iodide-positive cells, as well as activating necroptosis-regulating proteins, RIP1/RIP3/MLKL, in gastric cancer AGS cells. The results of this study demonstrated the necroptotic effect of ASX on gastric cancer AGS cells, which required NADPH oxidase activation and RIP1/RIP3/MLKL signaling in vitro.
Recent works have shown that generative data augmentation, where synthetic samples generated from deep generative models complement the training dataset, benefit NLP tasks. In this work, we extend this approach to the task of dialog state tracking for goaloriented dialogs. Due to the inherent hierarchical structure of goal-oriented dialogs over utterances and related annotations, the deep generative model must be capable of capturing the coherence among different hierarchies and types of dialog features. We propose the Variational Hierarchical Dialog Autoencoder (VHDA) for modeling the complete aspects of goal-oriented dialogs, including linguistic features and underlying structured annotations, namely speaker information, dialog acts, and goals. The proposed architecture is designed to model each aspect of goal-oriented dialogs using inter-connected latent variables and learns to generate coherent goal-oriented dialogs from the latent spaces. To overcome training issues that arise from training complex variational models, we propose appropriate training strategies. Experiments on various dialog datasets show that our model improves the downstream dialog trackers' robustness via generative data augmentation. We also discover additional benefits of our unified approach to modeling goal-oriented dialogsdialog response generation and user simulation, where our model outperforms previous strong baselines.
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