Genistein inhibits TNF-α-induced endothelial inflammation through the protein kinase pathway A and improves vascular inflammation in C57BL/6 mice

Abstract

Genistein, a soy isoflavone, has received wide attention for its potential to improve vascular function, but the mechanism of this effect is unclear. Here, we report that genistein at physiological concentrations (0.1 µM–5 µM) significantly inhibited TNF-α-induced adhesion of monocytes to human umbilical vein endothelial cells (HUVECs), a key event in the pathogenesis of atherosclerosis. Genistein also significantly suppressed TNF-α-induced production of adhesion molecules and chemokines such as sICAM-1, sVCAM-1,sE-selectin, MCP-1 and IL-8, which play key role in the firm adhesion of monocytes to activated endothelial cells (ECs). Genistein at physiologically relevant concentrations didn’t significantly induce antioxidant enzyme activities or scavenge free radicals. Further, blocking the estrogen receptors (ERs) in ECs didn’t alter the preventive effect of genistein on endothelial inflammation. However, inhibition of protein kinase A (PKA) significantly attenuated the inhibitory effects of genistein on TNF-α-induced monocyte adhesion to ECs as well as the production of MCP-1 and IL-8. In animal study, dietary genistein (0.1% genistein in the diet) significantly suppressed TNF-α-induced increase in circulating chemokines and adhesion molecules in C57BL/6 mice. Genistein treatment also reduced VCAM-1 and monocytes-derived F4/80-positive macrophages in the aorta of TNF-α treated mice. In conclusion, genistein protects against TNF-α induced vascular endothelial inflammation both in vitro and in vivo models. This anti-inflammatory effect of genistein is independent of the ER-mediated signaling machinery or antioxidant activity, but mediated via the PKA signaling pathway.

TNF-α-mediated cardiorenal injury after rhabdomyolysis in rats

“…TNF-␣ is a potent chemoattractant to leucocytes and promotes the expression of adhesion molecules on endothelial cells (11). As expected, treated animals showed a reduction in macrophage infiltration (Fig.…”

Genistein inhibits glucocorticoid amplification in adipose tissue by suppression of 11β-hydroxysteroid dehydrogenase type 1

“…Our present findings that genistein prevents intracellular glucocorticoid reamplification by 11b-HSD1 and H6PD through a non-transcriptional pathway should be distinguished from the mechanisms reported in other studies [19,20].…”

“…Some of the potencies of genistein can be explained through its estrogenic activity [18] by binding to estrogen receptors (ERs) [19], while it also has a blocking action on a multitude of cell signaling pathways by inhibiting protein tyrosine kinases [20]. However, the mechanisms of the pleiotropic anti-obesity effects of genistein have not been fully clarified.…”

Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols

“…216 For example, genistein reduced the expression of TNF-a, IL-1b, 217 and IL-6 in T cells [53]. In endothelial cells, inflammation induced 218 by TNF-a was suppressed by genistein [54], while in macrophages, 219 LPS-induced overproduction of TNF-a andIL-6 and activation of 220 NF-jB was suppressed [55]. In another study, genistein down- Lowered the levels of TNF-a, NO, and IL-1b in mice [142].…”

“…While 51 acute inflammation is therapeutic, chronic inflammation causes 52 numerous chronic diseases. At the molecular level, inflammation 53 is regulated by numerous molecules and factors, including cyto- 54 kines [interleukin (IL)-1, IL-2, IL-6, IL-12, tumor necrosis factor 55 (TNF)-a, TNF-b], 1 chemokines (monocyte chemoattractant protein 56 1, IL-8), proinflammatory transcription factors [nuclear factor- 57 kappaB (NF-jB), signal transducer and activator of transcription 58 (STAT)-3], proinflammatory enzymes [cyclooxygenase (COX)-2, 59 5-lipoxygenase (LOX), 12-LOX, matrix metalloproteinases (MMPs), 60 prostate-specific antigen (PSA), C-reactive protein, adhesion http 62 adhesion molecule (VCAM)-1, endothelial-leukocyte adhesion mole- 63 cule (ELAM)-1), vascular endothelial growth factor (VEGF), and 64 TWIST [1]. Among all these mediators, NF-jB is the central regulator 65 of inflammation [1,2].…”