Stress can alter immunological, neurochemical and endocrinological functions, but its role in cancer progression is not well understood. Here, we show that chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model. These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway by the beta(2) adrenergic receptor (encoded by ADRB2). Tumors in stressed animals showed markedly increased vascularization and enhanced expression of VEGF, MMP2 and MMP9, and we found that angiogenic processes mediated the effects of stress on tumor growth in vivo. These data identify beta-adrenergic activation of the cAMP-PKA signaling pathway as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth. These data also suggest that blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer.
BACKGROUND: MicroRNAs (miRNAs) are endogenous small RNAs of 21-25 nucleotides that can pair with sites in 3Ј untranslated regions in mRNAs of proteincoding genes to downregulate their expression. Recently, circulating miRNAs have been reported as promising biomarkers for various pathologic conditions. We assessed the hypothesis that miRNAs may leak into the circulating blood from injured cells and thereby serve as biomarkers for identifying the injured cell type.
To identify genetic factors that interact with social environments to impact human health, we used a bioinformatic strategy that couples expression array-based detection of environmentally responsive transcription factors with in silico discovery of regulatory polymorphisms to predict genetic loci that modulate transcriptional responses to stressful environments. Tests of one predicted interaction locus in the human IL6 promoter (SNP rs1800795) verified that it modulates transcriptional response to β-adrenergic activation of the GATA1 transcription factor in vitro. In vivo validation studies confirmed links between adverse social conditions and increased transcription of GATA1 target genes in primary neural, immune, and cancer cells. Epidemiologic analyses verified the health significance of those molecular interactions by documenting increased 10-year mortality risk associated with late-life depressive symptoms that occurred solely for homozygous carriers of the GATA1-sensitive G allele of rs1800795. Gating of depression-related mortality risk by IL6 genotype pertained only to inflammation-related causes of death and was associated with increased chronic inflammation as indexed by plasma C-reactive protein. Computational modeling of molecular interactions, in vitro biochemical analyses, in vivo animal modeling, and human molecular epidemiologic analyses thus converge in identifying β-adrenergic activation of GATA1 as a molecular pathway by which social adversity can alter human health risk selectively depending on individual genetic status at the IL6 locus.gene-environment interaction | inflammation | social epidemiology | stress | transcription
Several studies have demonstrated that the daily intakes of soy foods were associated with a reduced cardiovascular risk. The aim of our study was to investigate the inhibitory effect of black soybeans on low density lipoprotein (LDL) oxidation in comparison to yellow soybeans. The extract from black soybean had a longer LDL oxidation lag time than that from yellow soybean (205 +/- 16 and 65 +/- 3 min, respectively). When both soybeans were divided into the seed coat and the mixture of the germ and cotyledon, the diluted extract solution from the black soybean seed coat prolonged the lag time significantly more than the original extract of the yellow soybean seed coat. On the other hand, antioxidant effects of the extract from the mixture of germs and cotyledons were similar in both soybeans. Regarding total polyphenol contents, the seed coat of black soybean had a higher polyphenol content than that of yellow soybean (29.0 +/- 0.56 and 0.45 +/- 0.02 mg/g, respectively). Interestingly, the mixture of the germ and cotyledon hydrolyzed by beta-glucosidase in both soybeans showed a stronger inhibitory effect on LDL oxidation than that before being hydrolyzed by beta-glucosidase. These results suggest that black soybeans may be more effective in inhibiting LDL oxidation than yellow soybeans because of total polyphenols contents in its seed coat. In addition, aglycones, which are rich in soybeans fermented or hydrolyzed by beta-glucosidase, may play a crucial role in the prevention of oxidation-related diseases.
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