Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing IΚBα/NF-κB signaling pathway.

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 ß 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.

Sulforaphane reduces vascular inflammation in mice and prevents TNF-α-induced monocyte adhesion to primary endothelial cells through interfering with the NF-κB pathway.

Sulforaphane, a naturally occurring isothiocyanate present in cruciferous vegetables, has received wide attention for its potential to improve vascular function in vitro. However, its effect in vivo and the molecular mechanism of sulforaphane at physiological concentrations remain unclear. Here, we report that a sulforaphane concentration as low as 0.5 µM significantly inhibited tumor necrosis factor-α (TNF-α)-induced adhesion of monocytes to human umbilical vein endothelial cells, a key event in the pathogenesis of atherosclerosis both in static and under flow conditions. Such physiological concentrations of sulforaphane also significantly suppressed TNF-α-induced production of monocyte chemotactic protein-1 and adhesion molecules including soluble vascular adhesion molecule-1 and soluble E-selectin, key mediators in the regulation of enhanced endothelial cell-monocyte interaction. Furthermore, sulforaphane inhibited TNF-α-induced nuclear factor (NF)-κB transcriptional activity, Inhibitor of NF-κB alpha (IκBα) degradation and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that sulforaphane can inhibit inflammation by suppressing NF-κB signaling. In an animal study, sulforaphane (300 ppm) in a mouse diet significantly abolished TNF-α-increased ex vivo monocyte adhesion and circulating adhesion molecules and chemokines in C57BL/6 mice. Histology showed that sulforaphane treatment significantly 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 showed that sulforaphane treatment also reduced vascular adhesion molecule-1 and monocyte-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, sulforaphane at physiological concentrations protects against TNF-α-induced vascular endothelial inflammation, in both in vitro and in vivo models. This anti-inflammatory effect of sulforaphane may be, at least in part, associated with interfering with the NF-κB pathway.

Effects of cranberry juice consumption on vascular function in patients with coronary artery disease.

BACKGROUND: Cranberry juice contains polyphenolic compounds that could improve endothelial function and reduce cardiovascular disease risk. OBJECTIVE: The objective was to examine the effects of cranberry juice on vascular function in subjects with coronary artery disease. DESIGN: We completed an acute pilot study with no placebo (n = 15) and a chronic placebo-controlled crossover study (n = 44) that examined the effects of cranberry juice on vascular function in subjects with coronary artery disease. RESULTS: In the chronic crossover study, subjects with coronary heart disease consumed a research preparation of double-strength cranberry juice (54% juice, 835 mg total polyphenols, and 94 mg anthocyanins) or a matched placebo beverage (480 mL/d) for 4 wk each with a 2-wk rest period between beverages. Beverage order was randomly assigned, and participants refrained from consuming other flavonoid-containing beverages during the study. Vascular function was measured before and after each beverage, with follow-up testing ≥12 h after consumption of the last beverage. Mean (±SD) carotid-femoral pulse wave velocity, a measure of central aortic stiffness, decreased after cranberry juice (8.3 ± 2.3 to 7.8 ± 2.2 m/s) in contrast with an increase after placebo (8.0 ± 2.0 to 8.4 ± 2.8 m/s) (P = 0.003). Brachial artery flow-mediated dilation, digital pulse amplitude tonometry, blood pressure, and carotid-radial pulse wave velocity did not change. In the uncontrolled pilot study, we observed improved brachial artery flow-mediated dilation (7.7 ± 2.9% to 8.7 ± 3.1%, P = 0.01) and digital pulse amplitude tonometry ratio (0.10 ± 0.12 to 0.23 ± 0.16, P = 0.001) 4 h after consumption of a single 480-mL portion of cranberry juice. CONCLUSIONS: Chronic cranberry juice consumption reduced carotid femoral pulse wave velocity-a clinically relevant measure of arterial stiffness. The uncontrolled pilot study suggested an acute benefit; however, no chronic effect on measures of endothelial vasodilator function was found. This trial was registered at clinicaltrials.gov as NCT00553904.

Influence of specific nutrients on progression of atherosclerosis, vascular function, haemostasis and inflammation in coronary heart disease patients: a systematic review.

Epidemiological evidence suggests that the diet influences CHD risk, although the protective effects of dietary intervention for patients in diseased states has gained less attention. Secondary care prevention strategies for patients often involves drug therapy that is expensive and can result in undesirable side effects. Therefore, it is potentially beneficial to utilise other strategies, such as diet, in the management of CHD. A systematic review was conducted to examine the effects of specific nutrients on progression of atherosclerosis, vascular function, haemostasis and inflammation in CHD patients. Results show substantial evidence for the efficacy of n-3 oils in reducing cardiovascular mortality and one mechanism may be related to the stabilisation of vulnerable atherosclerotic plaques, although the effects on progression of atherosclerosis, haemostatic activity and vascular inflammation remain equivocal. Promising data also exist for the efficacy of flavonoid-rich foods for improving endothelial function, although strong clinical endpoint evidence is lacking. The variation in the efficacy of certain nutrients in CHD patients may be explained by genetics, existing risk factors, psychosocial factors and methodological issues, although these are often not adequately taken into consideration. We conclude that there is a need to undertake more appropriately designed trials in specific clinical populations, controlling for additional lifestyle and risk factors, examining potential interactions with medications, and also establishing methods to increase compliance to dietary recommendations before specific nutrients can be widely prescribed for secondary prevention. Future research should also utilise techniques that provide a direct measure of atherosclerosis.

Erythema elevatum diutinum associated with celiac disease: response to a gluten-free diet.

An 11-year-old girl with a history of insulin-dependent diabetes mellitus had erythema elevatum diutinum (EED) associated with a celiac disease related to a possible kidney disease. Dapsone did not improve the skin manifestations. However, the lesions disappeared after a gluten-free diet was begun. To our knowledge, this report describes the first case of EED in a patient with celiac disease.