Ellagic acid, a natural polyphenol found in certain fruits, nuts and vegetables, has in recent years been the subject of intense research within the fields of cancer and inflammation. Pain, fever and swelling, all typical symptoms of inflammation, are ascribed to elevated levels of PGE2. In the present study, we have investigated the effects of ellagic acid on PGE2 release and on prostaglandin-synthesising enzymes in human monocytes. Ellagic acid was found to inhibit Ca ionophore A23187-, phorbol myristate acetate- and opsonised zymosan-induced release of PGE2 from monocytes pre-treated with the inflammatory agent lipopolysaccharide. Ellagic acid suppressed the lipopolysaccharide-induced increase in protein expression of cyclo-oxygenase-2 (COX-2), microsomal PGE synthase-1 (mPGEs-1) and cytosolic phospholipase A2α (cPLA2α), while it had no effect on the constitutively expressed COX-1 protein. Ellagic acid had no apparent inhibitory effect on these enzymes when the activities were determined in cell-free assays. We conclude that the inhibitory effect of ellagic acid on PGE2 release from monocytes is due to a suppressed expression of COX-2, mPGEs-1 and cPLA2α, rather than a direct effect on the activities of these enzymes.

Proliferation of intimal vascular smooth muscle cells is an important component in the development of atherosclerosis. Ellagic acid is a phenolic compound present in fruits (raspberries, blueberries, strawberries) and walnuts. The present study investigated the effect of ellagic acid on the oxidised LDL (ox-LDL)-induced proliferation of rat aortic smooth muscle cells (RASMC). The study found that ellagic acid significantly inhibited ox-LDL-induced proliferation of RASMC and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2.Furthermore, ellagic acid also blocked the ox-LDL-induced (inducible) cell-cycle progression and down regulation of the expression of proliferating cell nuclear antigen (PCNA) in RASMC. Therefore, ellagic acid reduced the amount of ox-LDL-induced proliferation of RASMC via inactivation of the ERK pathway and suppression of PCNA expression. These results may significantly advance the understanding of the role that antioxidants play in the prevention of atherosclerosis.

Epidemiological studies suggest that the incidence of CVD and postmenopausal osteoporosis is low in the Mediterranean area, where herbs and nuts, among others, play an important role in nutrition. In the present study, we sought a role of walnuts (Juglans regia L.) in endothelial and bone-cell function. As the endothelial cell expression of adhesion molecules has been recognised as an early step in inflammation and atherogenesis, we examined the effect of walnut methanolic extract and ellagic acid, one of its major polyphenolic components (as shown by HPLC analysis), on the expression of vascular cell adhesion molecule (VCAM)-1 and intracellular adhesion molecule (ICAM)-1 in human aortic endothelial cells. After incubating the cells with TNF-α (1 ng/ml) in the absence and in the presence of walnut extract (10–200 μg/ml) or ellagic acid (10− 7–10− 5 m), the VCAM-1 and ICAM-1 expression was quantified by cell-ELISA. We further evaluated the effect of walnut extract (10–50 μg/ml), in comparison with ellagic acid (10− 9–10− 6m), on nodule formation in the osteoblastic cell line KS483.Walnut extract and ellagic acid decreased significantly the TNF-α-induced endothelial expression of both VCAM-1 and ICAM-1 (P < 0·01; P < 0·001). Both walnut extract (at 10–25 μg/ml) and ellagic acid (at 10− 9–10− 8 m) induced nodule formation in KS483 osteoblasts. The present results suggest that the walnut extract has a high anti-atherogenic potential and a remarkable osteoblastic activity, an effect mediated, at least in part, by its major component ellagic acid. Such findings implicate the beneficial effect of a walnut-enriched diet on cardioprotection and bone loss.

Expression of cell adhesion molecules by endothelium and the attachment of monocytes to endothelium may play a major role in atherosclerosis. Ellagic acid (EA) is a phenolic compound found in fruits and nuts including raspberries, strawberries, grapes and walnuts. Previous studies have indicated that EA possesses antioxidant activity in vitro. In the present study, we investigated the effects of EA on the formation of intracellular reactive oxygen species, the translocation of NFκB and expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 and endothelial leucocyte adhesion molecule (E-selectin) induced by IL-1β in human umbilical vein endothelial cells (HUVEC). We found that EA significantly reduced the binding of human monocytic cell line, U937, to IL-1β-treated HUVEC. The production of reactive oxygen species by IL-1β was dose-dependently suppressed by EA. Supplementation with increasing doses of EA up to 50 μmol/l was most effective in inhibiting the expression of VCAM-1 and E-selectin. Furthermore, the inhibition of IL-1β-induced adhesion molecule expression by EA was manifested by the suppression of nuclear translocation of p65 and p50. In conclusion, EA inhibits IL-1β-induced nuclear translocation of p65 and p50, thereby suppressing the expression of VCAM-1 and E-selectin, resulting in decreased monocyte adhesion. Thus, EA has anti-inflammatory properties and may play an important role in the prevention of atherosclerosis.