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Costunolide-Induced Apoptosis via Promoting the Reactive Oxygen Species and Inhibiting AKT/GSK3β Pathway and Activating Autophagy in Gastric Cancer.

ABSTRACT: Objective: Costunolide (Cos) is a sesquiterpene lactone extracted from chicory. Although it possesses anti-tumor effects, the underlying molecular mechanism against gastric cancer cells remains unclear. This study aimed to explore the effect and potential mechanism of Cos on gastric cancer. Methods: The effect of Cos on HGC-27 and SNU-1 proliferation was detected by CCK-8 and clone formation assay. The changes in cell apoptosis were determined using Hoechst 33258 and tunel staining. The morphology of autophagy was analyzed by autophagosomes with the electron microscope and LC3-immunofluorescence with the confocal microscope. The related protein levels of the cell cycle, apoptosis, autophagy and AKT/GSK3β pathway were determined by Western blot. The anti-tumor activity of Cos was evaluated by subcutaneously xenotransplanting HGC-27 into Balb/c nude mice. The Ki67 and P-AKT levels were examined by immunohistochemistry. Results: Cos significantly inhibited HGC-27 and SNU-1 growth and induced cell cycle arrest in the G2/M phase. Cos activated intrinsic apoptosis and autophagy through promoting cellular reactive oxygen species (ROS) levels and inhibiting the ROS-AKT/GSK3β signaling pathway. Moreover, preincubating gastric carcinoma cells with 3-methyladenine (3-MA), a cell-autophagy inhibitor, significantly alleviated the effects of Cos in inducing cell apoptosis. Conclusion: Cos induced apoptosis of gastric carcinoma cells via promoting ROS and inhibiting AKT/GSK3β pathway and activating pro-death cell autophagy, which may be an effective strategy to treat gastric cancer.

SUBMITTER: Xu C

PROVIDER: S-EPMC8633576 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Apoptosis and autophagy are two important patterns of cell death in the process of heart failure. Qi-Li-Qiang-Xin (QLQX), a traditional Chinese medicine, has been frequently used in the treatment of chronic heart failure (CHF) in China. However, the potential effect of QLQX on autophagy has not been reported. In this study, we aimed to investigate whether QLQX alleviated isoproterenol (ISO)-induced myocardial injury through regulating autophagy. Methods: The rapid identification of chemical ingredients of QLQX was performed by UPLC-Q-TOF-MS, and the contents of major constituents in QLQX were also measured by UPLC-Q-TOF-MS. ISO was used to induce myocardial injury in H9c2 cardiomyocytes and SD rats. In vivo, cardiac function was evaluated by echocardiography and cardiac structure was observed by HE and Masson staining. Expressions of Bcl-2, Bax, LC3, P62, AKT, p-AKT, mTOR, and p-mTOR were detected by western blotting. In vitro, H9c2 cells were pretreated with QLQX for 3 h before ISO (80 µM, 48h) addressed. Cell viability, LDH and CK-MB release, apoptosis ratio, and the level of autophagy were measured. Western blotting was also performed to detected related protein expressions. Result: In vivo, treatment by QLQX significantly improved cardiac function and alleviated ISO-induced myocardial structural damage. In addition, QLQX markedly decreased apoptosis and inhibited autophagic activity, accompanied by activating the AKT/mTOR pathway. In vitro, the increased cell apoptosis induced by ISO was paralleling with the gradually increasing level of autophagy. Furthermore, 3-MA, an autophagic inhibitor, could block ISO-induced autophagy in H9c2 cells. Our results suggested that both QLQX and 3-MA treatment could decrease cell death induced by ISO, implying that QLQX protected against ISO-induced myocardial injury possibly by inhibiting excessive autophagy-mediated cell death. In addition, blockage of AKT signaling by an AKT inhibitor, capivasertib, could reduce the effect of QLQX on inhibiting ISO-induced apoptosis and autophagy-mediated cell death. Conclusion: QLQX could alleviate ISO-induced myocardial injury by inhibiting apoptosis and excessive autophagy-mediated cell death via activating the AKT/mTOR pathway.

Project description:Recently nanomaterials have received substantial attention in biotechnology areas for their innovative properties in physical and chemical function. One of the most arrestive properties of nanomaterials that has been reported is their bacteriostatic activity. Our previous research found that Fe3O4 magnetic nanoparticles (Fe3O4-NPs) could effectively reduce the viability of intracellular Salmonella Enteritidis in chicken cells. There is an essential need to explore whether the bacteriostatic activity of Fe3O4-NPs is available in vivo. As an extension of this research, we conducted the present study to investigate the potential effect of Fe3O4-NPs used for S. Enteritidis control in chickens and to extensively investigate the underlying mechanisms in the process. The overall study included the evaluation of pathological sections, antioxidant status, inflammation, and the autophagy status of chicken liver, including the signaling pathway involved in the process. Results indicated that Fe3O4-NPs pretreatment can effectively inhibit the invasion of S. Enteritidis in chicken liver. Fe3O4-NPs pretreatment significantly increased reactive oxygen species (ROS) generation in chickens, including antioxidant enzyme activities. S. Enteritidis infection significantly increased the protein expression of the autophagy marker LC3. Additionally, the inflammation response and pathological changes caused by S. Enteritidis infection were alleviated by Fe3O4-NPs pretreatment. Phosphorylated mTOR was significantly increased in S. Enteritidis infected chickens, but showed no difference in chickens pretreated with Fe3O4-NPs. In summary, the results demonstrated that ROS and autophagy were involved in the inhibition of S. Enteritidis in chickens by Fe3O4-NPs pretreatment. The redox balance and inflammation response appeared normal in the process, as did the expression of the PI3K/Akt/mTOR signaling pathways. Taken together, our research demonstrate that the bacteriostatic activity of Fe3O4-NPs in chickens is avaliable and safe, which can be an alternative to antibiotics for bacterial inhibition in poultry industry.

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Costunolide-Induced Apoptosis via Promoting the Reactive Oxygen Species and Inhibiting AKT/GSK3β Pathway and Activating Autophagy in Gastric Cancer.

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