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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, 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 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., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Scope: Hyperglycemia-induced vascular inflammation resulting in the adhesion of monocytes to endothelium is a key event in the pathogenesis of atherosclerosis in diabetes. We investigated whether epigallocatechin gallate (EGCG), a major catechin found in green tea, reduces vascular inflammation in diabetes., Methods and Results: Human aortic endothelial cells (HAEC) were pretreated with green tea catechins before the addition of high glucose (25 mM) for 72 h. EGCG at physiologically achievable concentration (1 μM) significantly inhibited high glucose induced adhesion of monocytes to HAEC both in static and under flow conditions. EGCG also reduced nuclear factor κB (NF-κB) regulated transcriptional activity in ECs. Six-week-old diabetic db/db mice were fed a diet containing 0% or 0.1% EGCG for 8 weeks. ECs were isolated from aortic vessels of db/db, db/db-EGCG, and control db/+ mice. EGCG supplementation greatly suppressed diabetes-increased monocytes adhesion to ECs, which is associated with reduced circulating levels of chemokines, and reduced secretions of chemokines and adhesion molecules by aortic ECs from db/db-EGCG mice. EGCG treatment reduced nuclear translocation of NF-κB p65 in aortic vessels, decreased blood pressure and serum concentrations of cholesterol and triglycerides in db/db-EGCG mice., Conclusion: EGCG may have a direct protective effect against vascular inflammation in diabetes., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Abscisic acid (ABA) is a natural phytohormone and peroxisome proliferator-activated receptor gamma (PPARgamma) agonist that significantly improves insulin sensitivity in db/db mice. Although it has become clear that obesity is associated with macrophage infiltration into white adipose tissue (WAT), the phenotype of adipose tissue macrophages (ATMs) and the mechanisms by which insulin-sensitizing compounds modulate their infiltration remain unknown. We used a loss-of-function approach to investigate whether ABA ameliorates insulin resistance through a mechanism dependent on immune cell PPARgamma. We characterized two phenotypically distinct ATM subsets in db/db mice based on their surface expression of F4/80. F4/80(hi) ATMs were more abundant and expressed greater concentrations of chemokine receptor (CCR) 2 and CCR5 when compared to F4/80(lo) ATMs. ABA significantly decreased CCR2(+) F4/80(hi) infiltration into WAT and suppressed monocyte chemoattractant protein-1 (MCP-1) expression in WAT and plasma. Furthermore, the deficiency of PPARgamma in immune cells, including macrophages, impaired the ability of ABA to suppress the infiltration of F4/80(hi) ATMs into WAT, to repress WAT MCP-1 expression and to improve glucose tolerance. We provide molecular evidence in vivo demonstrating that ABA improves insulin sensitivity and obesity-related inflammation by inhibiting MCP-1 expression and F4/80(hi) ATM infiltration through a PPARgamma-dependent mechanism.

Background & Aims: Despite their efficacy in improving insulin sensitivity, thiazolidinediones (TZDs) are associated with a number of side effects (i.e. weight gain, hepatotoxicity, congestive heart failure) that have limited their use by millions of diabetic patients. We have investigated whether abscisic acid (ABA), a naturally occurring phytochemical with structural similarities to TZDs, could be used as an alternative to TZDs to improve glucose homeostasis., Methods: We first examined whether ABA, similar to TZDs, activates PPARgamma in vitro. We next determined the lowest effective dose of dietary ABA (100 mg/kg) and assessed its effect on glucose tolerance, obesity-related inflammation, and mRNA expression of PPARgamma and its responsive genes in white adipose tissue (WAT) of db/db mice fed high-fat diets., Results: We found that ABA induced transactivation of PPARgamma in 3T3-L1 pre-adipocytes in vitro. Dietary ABA-supplementation for 36 days decreased fasting blood glucose concentrations, ameliorated glucose tolerance, and increased mRNA expression of PPARgamma and its responsive genes (i.e., adiponectin, aP2, and CD36) in WAT. We also found that adipocyte hypertrophy, tumor necrosis factor-alpha (TNF-alpha) expression, and macrophage infiltration in WAT were significantly attenuated in ABA-fed mice., Conclusions: These findings suggest that ABA could be used as a nutritional intervention against type II diabetes and obesity-related inflammation.

Abstract: Aging is well-known an inevitable process that is influenced by genetic, lifestyle and environmental factors. However, the exact mechanisms underlying the aging process are not well understood. Increasing evidence shows that aging is highly associated with chronic increase in reactive oxygen species (ROS), accumulation of a low-grade proinflammatory phenotype and reduction in age-related autophagy, suggesting that these factors may play important roles in promoting aging. Indeed, reduction of ROS and low-grade inflammation and promotion of autophagy by calorie restriction or other dietary manipulation can extend lifespan in a wide spectrum of model organisms. Interestingly, recent studies show that some food-derived small molecules, also called phytochemicals, can extend lifespan in various animal species. In this paper, we review several recently identified potential antiaging phytochemicals that have been studied in cells, animals and humans and further highlight the cellular and molecular mechanisms underlying the antiaging actions by these molecules. [Copyright &y& Elsevier]

The anti-inflammatory effects of phytochemicals, bioactive components from plants having health benefits, have been heavily investigated in the last several decades. However, the gap between the high dosage demands (μM) of phytochemicals in vitro studies and the low bioavailability (nM) of most phytochemicals after consuming relevant foods/supplements in humans undermines the application of these phytochemicals in the prevention of chronic inflammation and its related chronic diseases in humans. One of the approaches to bridging this gap is to combine two or more phytochemicals/foods to synergistically prevent chronic inflammation. While increasing combinations of phytochemicals on anti-inflammation studies have been reported, there is no report dedicating why combining two or more phytochemicals synergistically attenuates chronic inflammation. In the present review, we summarized different types of combinations exerting synergistic anti-inflammatory effects such as the combination of phytochemicals from the same foods, and the combination of phytochemicals from different foods/plants. Particularly, we proposed five mechanisms including enhancing the bioavailability of phytochemicals, increasing antioxidant capacity, interacting with gut microbiome and targeting same and different signaling pathways, to understand how the combination of phytochemicals exerts synergistic anti-inflammatory effects in cells, animals, and humans. This review provides clues to boost more studies to combine several phytochemicals/foods to reduce chronic inflammation and prevent chronic diseases in humans. [ABSTRACT FROM AUTHOR]

Chronic increased pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) play critical roles in the development of endothelial dysfunction and therefore induce cardiovascular disease. Although phytochemicals have the potential ability to reduce the risk of CVD, the big gap between required high concentration in cells and the low bioavailability in the blood of phytochemicals compromise their therapeutic potentials. This study aims to investigate if combined phytochemicals at low levels exert a synergistic anti-inflammatory effect and to define relevant molecular mechanisms. Our results found that combined curcumin (5 µM) and resveratrol (5 µM) synergistically (combination index is 0.78) inhibited TNF-α-induced monocytes adhesion to human endothelial EA.hy 926 cells while the individual chemicals did not have such effect at the selected concentrations. The concentrations of curcumin (5 µM) and resveratrol (5 µM) are very close to the maximum level of curcumin (3.56 µM) and resveratrol (2 µM) in human blood. Dietary supplementation of combined curcumin (500mg/kg) and resveratrol (200mg/kg) synergistically reduced TNF-α-induced vascular inflammation in C57BL/6 mice with a similar pattern in cells. Moreover, the combination ameliorated the TNF-α-induced protein expressions and circulating levels of vascular cell adhesion molecule 1 and monocyte chemotactic protein-1 in EA.hy 926 cells, mice aorta and serum. Furthermore, combined curcumin and resveratrol significantly inhibited TNF-α-induced nuclear factor-kappaB (NF-κB) p65 nuclear protein expression than that by the individual chemical alone in EA.hy 926 cells, indicating that the synergistic effect of the combination may result from that curcumin reduces the required minimum concentration for resveratrol to inhibit the nuclear translocation of NF-κB. In conclusion, the combination of curcumin and resveratrol protects against TNF-α-induced vascular inflammation by suppressing NF-κB signaling in vitro and in vivo models. This study suggests that dietary intake of a combination of curcumin and resveratrol or its foods may be a practical, safe approach to prevent vascular inflammation and therefore prevent/treat vascular diseases in humans. [ABSTRACT FROM AUTHOR]

Vascular inflammation plays a significant role in the pathogenesis of atherosclerosis. Luteolin, a naturally occurring flavonoid present in many medicinal plants and some commonly consumed fruits and vegetables, has received wide attention for its potential to improve vascular function in vitro . However, its effect in vivo and the molecular mechanism of luteolin at physiological concentrations remain unclear. Here, we report that luteolin as low as 0.5 μM significantly inhibited tumor necrosis factor (TNF)-α-induced adhesion of monocytes to human EA.hy 926 endothelial cells, a key event in triggering vascular inflammation. Luteolin potently suppressed TNF-α-induced expression of the chemokine monocyte chemotactic protein-1 (MCP-1) and adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), key mediators involved in enhancing endothelial cell–monocyte interaction. Furthermore, luteolin inhibited TNF-α-induced nuclear factor (NF)-κB transcriptional activity, IκBα degradation, expression of IκB kinase β and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that luteolin can inhibit inflammation by suppressing NF-κB signaling. In an animal study, C57BL/6 mice were fed a diet containing 0% or 0.6% luteolin for 3 weeks, and luteolin supplementation greatly suppressed TNF-α-induced increase in circulating levels of MCP-1/JE, CXCL1/KC and sICAM-1 in C57BL/6 mice. Consistently, dietary intake of luteolin significantly reduced TNF-α-stimulated adhesion of monocytes to aortic endothelial cells ex vivo . Histology shows that luteolin treatment prevented the eruption of endothelial lining in the intima layer of the aorta and preserved elastin fibers' delicate organization as shown by Verhoeff–Van Gieson staining. Immunohistochemistry studies further show that luteolin treatment also reduced VCAM-1 and monocyte-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, luteolin protects against TNF-α-induced vascular inflammation in both in vitro and in vivo models. This anti-inflammatory effect of luteolin may be mediated via inhibition of the NF-κB-mediated pathway. [ABSTRACT FROM AUTHOR]

Abstract: Abscisic acid (ABA) is a natural phytohormone which improves insulin sensitivity and reduces adipose tissue inflammation when supplemented into diets of obese mice. The objective of this study was to investigate the mechanisms by which ABA prevents or ameliorates atherosclerosis. apolipoprotein E-deficient (ApoE−/−) mice were fed high-fat diets with or without ABA for 84 days. Systolic blood pressure was assessed on Days 0, 28, 56 and 72. Gene expression, immune cell infiltration and histological lesions were evaluated in the aortic root wall. Human aortic endothelial cells were used to examine the effect of ABA on 3′,5′-cyclic adenosine monophosphate (cAMP) and nitric oxide (NO) production in vitro. We report that ABA-treated mice had significantly improved systolic blood pressure and decreased accumulation of F4/80+CD11b+ macrophages and CD4+ T cells in aortic root walls. At the molecular level, ABA significantly enhanced aortic endothelial nitric oxide synthase (eNOS) and tended to suppress aortic vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) expression and plasma MCP-1 concentrations. ABA also caused a dose-dependent increase in intracellular concentrations of cAMP and NO and up-regulated eNOS mRNA expression in human aortic endothelial cells. This is the first report showing that ABA prevents or ameliorates atherosclerosis-induced hypertension, immune cell recruitment into the aortic root wall and up-regulates aortic eNOS expression in ApoE−/− mice. [ABSTRACT FROM AUTHOR]