The reduction in cellular oxidative stress can result from PJ-induced increment in PON1, and/or from PJ-induced increment in paraoxonase 2 (PON2).43 PON2 is expressed in arterial wall cells including macrophages,44 and it protects the cells from oxidative stress and apoptosis.45 Figure 4. The anti-atherogenic effects of PJ consumption on HMDM from diabetic patients, and on carotid lesions from patients with CAS. PJ consumption by patients with type 2 diabetes mellitus significantly decreased the extent of

Ox-LDL cellular Inhibitors,research,lifescience,medical uptake by their HMDM (by 36%, Figure 4C), as was shown in vitro in J774A.1 macrophages.46 The carotid lesions from CAS patients who consumed PJ contained also less cholesterol (Figure 4D). This could be related to the reduction in the amount of Ox-LDL and thus in Ox-LDL uptake, and also to PJ-induced increment in PON1, since PON1 was shown in vitro to inhibit macrophage cholesterol biosynthesis.47 In addition, Inhibitors,research,lifescience,medical PJ can directly attenuate cholesterol biosynthesis by the cells, as was previously shown.46 The reduction in lesion cholesterol levels after Inhibitors,research,lifescience,medical PJ consumption could also result from stimulation of HDL-mediated cholesterol efflux by PON1.48 ANTI-ATHEROGENICITY OF STATIN TREATMENT IN COMBINATION WITH

POMEGRANATE Statins therapy made a significant health benefit, mainly in BVD-523 research buy cardiovascular protection,49 by improving the symptoms of atherosclerosis development.50 Statins are potent inhibitors of HMGCoA-reductase (the rate-limiting enzyme in cholesterol biosynthesis51),

and they possess Inhibitors,research,lifescience,medical minor antioxidative properties.52 However, statins have also deleterious side-effects when taken at high dosages for a long period of time.53 Phytosterols, which encompass plant sterols and stanols, are steroid compounds similar in their structure to cholesterol.54 The richest sources Inhibitors,research,lifescience,medical of phytosterols are vegetable oils and products made from them. The most commonly occurring phytosterols in human diet are β-sitosterol, campesterol, and stigmasterol.54 Phytosterols consumption decreased serum cholesterol levels in dyslipidemic patients, as well as their cardiovascular risk.55,56 Thus, phytosterols were suggested as an appropriate additional therapy to a low-dosage statin treatment. We have recently57 of analyzed in vitro the anti-atherogenic effects on macrophage cholesterol biosynthesis rate, and on cellular oxidative stress, of the combination of simvastatin with punicalagin, or with a phytosterol (β-sitosterol), or with PJ (that contains both of them58,59). Simvastatin (15μg/mL) decreased the J774A.1 macrophage cholesterol biosynthesis rate by 42% as compared to control cells. The addition to the statin of either punicalagin (15 or 30µM) or β-sitosterol (50 or 100µM) increased the inhibitory effect of the statin up to 62% or 57%, respectively.