p38alpha blockade inhibits colorectal cancer growth in vivo by inducing a switch from HIF1alpha- to FoxO-dependent transcription.

Colorectal cancer cell (CRC) fate is governed by an intricate network of signaling pathways, some of which are the direct target of DNA mutations, whereas others are functionally deregulated. As a consequence, cells acquire the ability to grow under nutrients and oxygen shortage conditions. We earlier reported that p38alpha activity is necessary for proliferation and survival of CRCs in a cell type-specific manner and regardless of their phenotype and genotype. Here, we show that p38alpha sustains the expression of HIF1alpha target genes encoding for glycolytic rate-limiting enzymes, and that its inhibition causes a drastic decrease in ATP intracellular levels in CRCs. Prolonged inactivation of p38alpha triggers AMPK-dependent nuclear localization of FoxO3A and subsequent activation of its target genes, leading to autophagy, cell cycle arrest and cell death. In vivo, pharmacological blockade of p38alpha inhibits CRC growth in xenografted nude mice and azoxymethane-treated Apc(Min) mice, achieving both a cytostatic and cytotoxic effect, associated with high nuclear expression of FoxO3A and increased expression of its target genes p21 and PTEN. Hence, inhibition of p38alpha affects the aerobic glycolytic metabolism specific of cancer cells and might be taken advantage of as a therapeutic strategy targeted against CRCs.

Alcohol-free red wine prevents arterial thrombosis in dietary-induced hypercholesterolemic rats: experimental support for the 'French paradox'.

The concept of the 'French paradox' has been recently challenged. As it is difficult in a short period to produce direct clinical evidence of the protective effect of red wine on thrombosis, we evaluated such a possibility in an experimental model mimicking the conditions of the 'French paradox'. Normolipidemic rats (FNL) were fed a standard diet or a 2% cholesterol-rich-diet (Ch-rich-diet) for 5 months: the latter was given either alone (FNL + D) or in combination with 'alcohol-free' red wine (FNL + D + 5 W). Arterial thrombosis was measured as the occlusion time (OT) of an artificial prosthesis inserted into the abdominal aorta. Lipid levels, platelet adhesion to fibrillar collagen, factor VII (FVII) clotting activity and fibrinogen levels were also measured. Compared to animals fed a standard diet, Ch-rich diet induced in FNL rats a several-fold increase in lipids and FVII levels with a concomitant significant increase in both thrombotic tendency (shortening of the OT) and platelet adhesion. 'Alcohol-free' red wine supplementation almost completely reverted the prothrombotic effect of the Ch-rich-diet. Indeed, the OT was prolonged from 78 +/- 3 to 122 +/- 10 h (P < 0.01), while platelet adhesion to fibrillar collagen was reduced from 49 +/- 3.5% to 30 +/- 2.8%. Neither the increase in lipid levels induced by Ch-rich diet nor FVII or fibrinogen levels were modified by wine supplementation. In conclusion, in experimental animals, this study supports the concept of the 'French paradox' that regular consumption of wine (rather than alcohol) was able to prevent arterial thrombosis associated with dietary-induced hypercholesterolemia, an effect mediated by downregulation of platelet function.

Effect of extra virgin olive oil on experimental thrombosis and primary hemostasis in rats.

BACKGROUND AND AIM: Olive oil is a particular source of fat in the Mediterranean diet, which is associated with a lower incidence of cardiovascular disease. We investigated the possible antithrombotic role of extra virgin olive oil as a single dietary modification in experimental thrombosis and primary hemostasis models in rats. METHODS AND RESULTS: Two different groups of animals were studied: one fed a usual diet (control group) and the other a diet enriched with extra virgin olive oil (3%; weight/weight). After six weeks feeding, arterial thrombosis was initiated by inserting an artificial prosthesis (or "aortic loop") into the aorta, and venous thrombosis was induced by ligating the inferior vena cava. "Template" bleeding time (BT) was measured, as well as factor VII coagulant activity (FVII:C) and fibrinogen levels. The animals fed the olive oil enriched diet showed a significant delay in the thrombotic occlusion of the "aortic loop" (99 +/- 5 h vs 82 +/- 5 h, p < 0.04), a lower incidence of venous thrombosis (57% vs 86%; p < 0.05) and a prolonged BT (154 +/- 7 sec vs 122 +/- 4 sec; p < 0.01) in comparison with the control group. They had lower plasma fibrinogen concentrations (209 +/- 5 mg/dL vs 233 +/- 4 mg/dL; p < 0.01) but similar FVII:C levels (119 +/- 5% vs 108 +/- 5%; p = NS) despite their lower triglyceride concentrations (52 +/- 5 mg/dL vs 79 +/- 10 mg/dL; p < 0.05). CONCLUSIONS: This study provides the first in vivo experimental evidence of the thrombosis prevention properties of olive oil, which are possibly mediated by reduced fibrinogen concentrations and impaired platelet/vessel wall interactions.