Search

Pyrogallol (1,2,3‐trihydroxybenzene), a polyphenolic natural compound, has attracted considerable attention with regard to its potential anticancer activity. However, further study is needed to elucidate the underlying mechanism related to the antiNSCLC activity of pyrogallol and provide a comprehensive theoretical basis for better clinical utilization of pyrogallol. Our current study aims to investigate the effects and potential underlying mechanisms of pyrogallol on the inhibition of NSCLC growth. Our results showed that pyrogallol treatment induced cell cycle arrest at the G2/M phase and apoptosis in two different NSCLC cell lines. Mechanistically, we found that the induction of cell cycle arrest in NSCLC cells at the G2/M phase by pyrogallol was due to the upregulation of p21 in a p53‐dependent manner. And blockade of p53 and p21 effectively abolished the cell cycle arrest at the G2/M phase. Meanwhile, p53 inhibition has been found to abrogate the pyrogallol‐induced apoptosis of the two NSCLC cells. Moreover, we revealed that the inhibitory effects of pyrogallol on β‐catenin signaling resulted from autophagy initiation depending on p53 activation, accompanied by an increase in p62/SQSTM1 expression, thus p62 subsequently interacting with ubiquitinated β‐catenin and facilitating autophagic destruction of β‐catenin. Furthermore, in vivo experiments demonstrated that pyrogallol exerted growth inhibition on NSCLC with low toxicity through the same molecular mechanism as observed in vitro. Our findings could contribute to the understanding of the mechanism by which pyrogallol negatively regulates NSCLC growth, which could be effective in treating NSCLC. [ABSTRACT FROM AUTHOR]

Background: Rosmarinic acid (RosA) is a natural phenolic compound that possesses a wide-range of pharmacological properties. However, the effects of RosA on influenza A virus-mediated acute lung injury remain unknown. In this study, we aimed to explore whether RosA could protect against H1N1 virus-mediated lung injury and elucidate the underlying mechanisms. Methods: Mice were intragastrically administered with RosA for 2 days before intranasal inoculation of the H1N1 virus (5LD50) for the establishment of an acute lung injury model. At day 7 post-infection (p.i.), gross anatomic lung pathology, lung histopathologic, and lung index (lung weight/body weight) were examined. Luminex assay, multiple immunofluorescence and flow cytometry were performed to detect the levels of pro-inflammatory cytokines and apoptosis, respectively. Western blotting and plasmid transfection with hematopoietic-type PGD2 synthase (h-PGDS) overexpression were conducted to elucidate the mechanisms. Results: RosA effectively attenuated H1N1 virus-triggered deterioration of gross anatomical morphology, worsened lung histopathology, and elevated lung index. Excessive pro-inflammatory reactions, aberrant alveolar epithelial cell apoptosis, and cytotoxic CD8+ T lung recruitment in the lung tissues induced by H1N1 virus infection were observed to be reduced by RosA treatment. In vitro experiments demonstrated that RosA treatment dose-dependently suppressed the increased levels of pro-inflammatory mediators and apoptosis through inhibition of nuclear factor kappa B (NF-κB) and P38 MAPK signaling pathways in H1N1 virus-infected A549 cells, which was accompanied by promoting activation of the h-PGDS-PGD2-HO-1 signal axis. Furthermore, we strikingly found that h-PGDS inhibition significantly abrogated the inhibitory effects of RosA on H1N1 virus-mediated activation of NF-κB and P38 MAPK signaling pathways, resulting in diminishing the suppressive effects on the increased levels of pro-inflammatory cytokines and chemokines as well as apoptosis. Finally, suppressing h-PGDS prominently abolished the protective effects of RosA on H1N1 virus-mediated severe pneumonia and lung injury. Conclusions: Taken together, our study demonstrates that RosA is a promising compound to alleviate H1N1 virus-induced severe lung injury through prompting the h-PGDS-PGD2-HO-1 signal axis. [ABSTRACT FROM AUTHOR]

Objective: Natriuretic peptides (NPs) are hormones with cardioprotective effects. NP levels vary by race; however, the pathophysiological consequences of lower NP levels are not well understood. We aimed to quantify the association between NPs and endothelial function as measured by flow-mediated dilation (FMD) and the contribution of NP levels to racial differences in endothelial function.Methods: In this cross-sectional study of 2938 Multi-Ethnic Study of Atherosclerosis participants (34% Caucasian, 20% African-American, 20% Asian-American and 26% Hispanic) without cardiovascular disease at baseline, multivariable linear regression models were used to examine the association between serum N-terminal pro-B-type NP (NT-proBNP) and natural log-transformed FMD. We also tested whether NT-proBNP mediated the relationship between race and FMD using the product of coefficients method.Results: Among African-American and Chinese-American individuals, lower NT-proBNP levels were associated with lower FMD, β=0.06 (95% CI: 0.03 to 0.09; p<0.001) and β=0.06 (95% CI: 0.02 to 0.09; p=0.002), respectively. Non-significant associations between NT-proBNP and FMD were found in Hispanic and Caucasian individuals. In multivariable models, endothelial function differed by race, with African-American individuals having the lowest FMD compared with Caucasians, p<0.001. Racial differences in FMD among African-Americans and Chinese-Americans were mediated in part by NT-proBNP levels (African-Americans, mediation effect: -0.03(95% CI: -0.05 to -0.01); Chinese-Americans, mediation effect: -0.03(95% CI: -0.05 to -0.01)).Conclusions: Lower NP levels are associated with worse endothelial function among African-Americans and Chinese-Americans. A relative NP deficiency in some racial/ethnic groups may contribute to differences in vascular function. [ABSTRACT FROM AUTHOR]

The severity of a viral respiratory illness was greatly exacerbated after exposure to a contaminant containing benzo[ a ]pyrene (B[ a ]P). Flavonoid-rich fruit intake has gained intense interest due to their health-promoting benefits for viral respiratory diseases, including influenza viruses. In our study, diosmetin (3',5,7-trihydroxy-4'-methoxyflavone), a naturally occurring hydroxylated methoxyflavone that is abundant in Citrus fruits, was explored for its effects on B[ a ]P-exacerbated H1N1 influenza virus-mediated inflammation and lung injury. Initially, in vivo results demonstrated that diosmetin protected against H1N1 virus-elicited acute lung injury. Simultaneously, H1N1 virus or B[ a ]P-stimulated A549 cells treated with diosmetin inhibited NF-κB and P-P38 activation, resulting in suppression of pro-inflammatory cytokines and apoptosis. Interestingly, diosmetin obviously promoted the expression of PPAR-γ as well as nuclear translocation of PPAR-γ, whereas, PPAR-γ inhibition by GW9662 weakened the inhibitory effects of diosmetin on H1N1 virus or B[ a ]P-mediated activation of NF-κB and P-P38, elevated expression of pro-inflammatory mediators as well as apoptosis. Furthermore, it was surprising to discover that mice exposed to both B[ a ]P and H1N1 viruses contributed to exacerbated acute lung injury, which were significantly ameliorated by diosmetin administration. In vitro studies showed that A549 cells with the combination of B[ a ]P and H1N1 virus augmented NF-κB and P-P38 activation, accompanied by higher levels of pro-inflammatory mediators and apoptosis, all of which were also significantly reduced by diosmetin treatment. Repressing PPAR-γ abrogated the inhibitory effects of diosmetin on B[ a ]P-exacerbated H1N1 virus-mediated NF-κB and P-P38 activation, inflammation, and apoptosis in A549 cells. Our findings suggest that diosmetin protected against B[ a ]P-exacerbated H1N1 virus-mediated lung injury by suppressing the exacerbation of NF-κB and P38 kinase activation in a PPAR-γ-dependent manner, suggesting potential benefits for B[ a ]P-exacerbated influenza-related illness therapeutics.