Targeting PPARγ/ NF-κB Signaling Pathway by Britannin, a Sesquiterpene Lactone from Inula aucheriana DC., in Gastric Cancer.

BACKGROUND: Gastric cancer is one of the most common and deadliest malignancies in the world. Therefore, there is an urgent need to develop new and effective agents to reduce mortality. The plants of genus Inula have gained the attention of researchers worldwide as a rich source of potent medicinal compounds. OBJECTIVE: This study explores the anti-cancer activity of Britannin, a sesquiterpene lactone isolated from Inula aucheriana DC., and its molecular mechanism in gastric cancer cells, AGS and MKN45. METHODS: Cytotoxicity was evaluated through the MTT assay following 24 h, 48 h, and 72 h treatment with different concentrations of Britannin. Apoptosis rate and caspase-3 activity were measured 24 h after treatment by Britannin. . Western blotting was performed to determine the expression of the NF-κB, IκBα, and PPARγ proteins. Moreover, quantitative RT-PCR was applied to measure the expression of NF-κB target genes. RESULTS: We showed that Britannin induced cell growth inhibition and apoptosis in gastric cancer cells. Britannin caused an elevation in mRNA and protein levels of PPARγ. The involvement of PPARγ was more confirmed using GW9662, a PPARγ inhibitor. Suppression of NF-κB was demonstrated by western blot analysis. Down-regulation of MMP-9, TWIST-1, COX-2, and Bcl-2 and up-regulation of Bax were also observed in gastric cancer cells. CONCLUSION: These results imply that activation of the PPARγ signaling pathway through suppression of NF-κB underlies the anti-cancer properties of Britannin in gastric cancer. Therefore, Britannin could be considered as a promising anti-cancer candidate for further evaluation.

Gaillardin, a potent sesquiterpene lactone induces apoptosis via down-regulation of NF-κß in gastric cancer cells, AGS and MKN45.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Inula has been traditionally used as folk medicine in treating different illnesses such as kidney stones, urethra infection, jaundice, bronchitis, respiratory diseases and cancer. AIM OF THE STUDY: Gaillardin, a sesquiterpene lactone isolated from Inula oculus-christi, seems to have great potential as an anti-cancer agent. This study was carried out to evaluate the anti-cancer properties of Gaillardin in gastric cancer cells and also its possible underlying mechanism. METHODS: The colorimetric MTT assay was used to assess metabolic activity of cells as an indicator of viability and cytotoxicity. Flow cytometry using Annexin V-FITC/PI was applied to detect and quantify the level of apoptosis. Detection of activated caspase-3, as a biochemical marker of apoptosis, was done using caspase-3 assay kit. Activation of NF-κB pathway was determined by western blotting. The mRNA expression levels of NF-κB target genes were measured using quantitative RT-PCR. Moreover, intracellular reactive oxygen species (ROS) production was evaluated. RESULTS: Gaillardin significantly reduced cell viability in a time and dose-dependent manner. The inhibitory effect of Gaillardin was attributed to induction of apoptosis. Investigation about the underlying mechanism revealed that Gaillardin exerts its action through inhibition of NF-κB activation and subsequently down-regulation of genes (COX-2, MMP-9, TWIST-1, and BCl-2) regulated by NF-κB. Moreover, Gaillardin caused remarkable elevation in ROS production in AGS and MKN45 cells. CONCLUSION: We provided evidences about the role of NF-κB pathway in the induction of apoptosis by the sesquiterpene lactone Gaillardin in AGS and MKN45 cells for the first time, which suggest Gaillardin could be considered as a promising natural agent for further investigations to identify new potent anticancer drugs in the future.

Relationship between the number of hospitalized cardiovascular and respiratory disease and the average concentration of criteria air pollutants (CAP) in Ahvaz.

This study aims to investigate the relationship between the number of hospitalized cardiovascular and respiratory patients and the average concentration of criteria air pollutants, including NO2, SO2, CO, O3 and PM10 in Ahvaz in the period of 10 years (2007-2017). Data on referrals and the number of hospitalized cardiovascular and respiratory patients and also on air pollutants are obtained through Hospital Information System and air quality monitoring stations including Department of Environment Protection Station, Naderi Square Station, University Square Station and the Meteorological Organization Station. The data were analyzed by SPSS version 4 and Poisson distribution regression model to evaluate the effects of each pollutant and the rate of hospitalization. In this study, confidence interval and the significance level are considered at 95% and 5%, respectively. Changes in air pollution indices and number of patients with cardiovascular diseases were evaluated using Excel, Stata and ARIMA models. Based on the results of Poisson regression analysis, there was a significant relationship between the average concentration of NO2, O3, CO and SO2 and hospitalization of patients with cardiovascular disease, with a confidence level of less than 5%. This was the case with NO2 more than other pollutants. Furthermore, there was a significant relationship between the average concentrations of NO2, CO and O3 and the hospitalization rate of patients with respiratory problems and a confidence level of 5%. The effect of NO2 was also higher here. Due to the results, NO2, CO, and O3 had a significant direct correlation with cardiovascular and respiratory rates. The effect of NO2 has been higher than other pollutants. In the study of time intervals of patients with cardiovascular, the results of time-interval analysis indicate the relationship between cardiovascular clients with the "t" time of 7 days earlier and NO2 as a pollutant. The results of this analysis also revealed the relationship between respiratory patients at the time "t" up to 7 days before and O3.