EFFECTS OF OXIDISED LDL ON NITRIC OXIDE AND ENDOTHELIN-1 PRODUCTION IN HUMAN MICROVASCULAR ENDOTHELIUM: ROLE OF THROMBOXANE A2 RECEPTOR

LDL particles modulate the release of NO and endothelin-1 by the endothelium. To what extent these effects depend on LDL concentration and degree of oxidation and eventually what is the role of tromboxane A2 receptor is unknown. HMEC-1 were exposed for 24-h to a) 3 concentrations (50, 100 and 200 ?g/ml) of either native, low- or medium-oxidised LDL, b) 8-epi-PGF2? (F2?IP, 10-11, 10-10, 10-9, and 10-8 M) either alone or with TXA2 receptor blocker SQ 29.548 (10-6 M), c) native, low- and medium-oxidised LDL either alone or with SQ 29.548 (10-6 M). In all experiments intracellular eNOS, and NO2/NO3, endothelin-1 and interleukin-6 concentration in the medium were measured. Both native and oxidised LDL induced a NO2/NO3 accumulation with dose and degree of oxidation acting synergistically; eNOS was stimulated only by oxidised LDL. F2?IP, NO2/NO3 and eNOS with SQ 29.548 completely preventing these effects but only partially the effect of LDL. IL-6 was also synergistically stimulated by LDL dose and degree of oxidation but not by direct exposure to F2?IP nor was affected by SQ 29.548. Both native and oxidised LDL stimulated endothelin-1 production independently of dose or degree of oxidation. F2?IP had a modest stimulatory effect while the effect of SQ 29.548 was evident only with oxidised LDL. In HMEC-1 LDL dose and degree of oxidation synergistically stimulate NO and IL-6 production and the effect on NO is largely mediated through the TXA2 receptor. LDL simultaneously facilitate endothelin-1 production independently of the dose and degree of oxidation

Effect of Vitamin K Supplementation on Insulin Resistance in Older Men and Women

OBJECTIVE—Vitamin K has a potentially beneficial role in insulin resistance, but evidence is limited in humans. We tested the hypothesis that vitamin K supplementation for 36 months will improve insulin resistance in older men and women

Effect of resveratrol on mitochondrial function: Implications in parkin-associated familiar Parkinson's disease

Mitochondrial dysfunction and oxidative stress occur in Parkinson's disease (PD), but the molecular mechanisms controlling these events are not completely understood. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) is a transcriptional coactivator known as master regulator of mitochondrial functions and oxidative metabolism. Recent studies, including one from our group, have highlighted altered PGC-1α activity and transcriptional deregulation of its target genes in PD pathogenesis suggesting it as a new potential therapeutic target. Resveratrol, a natural polyphenolic compound proved to improve mitochondrial activity through the activation of several metabolic sensors resulting in PGC-1α activation. Here we have tested in vitro the effect of resveratrol treatment on primary fibroblast cultures from two patients with early-onset PD linked to different Park2 mutations. We show that resveratrol regulates energy homeostasis through activation of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) and raise of mRNA expression of a number of PGC-1α's target genes resulting in enhanced mitochondrial oxidative function, likely related to a decrease of oxidative stress and to an increase of mitochondrial biogenesis. The functional impact of resveratrol treatment encompassed an increase of complex I and citrate synthase activities, basal oxygen consumption, and mitochondrial ATP production and a decrease in lactate content, thus supporting a switch from glycolytic to oxidative metabolism. Moreover, resveratrol treatment caused an enhanced macro-autophagic flux through activation of an LC3-independent pathway. Our results, obtained in early-onset PD fibroblasts, suggest that resveratrol may have potential clinical application in selected cases of PD-affected patients