Simvastatin inhibits protein isoprenylation in the brain.

Evidence suggests that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, may reduce the risk of Alzheimer's disease (AD). Statin action in patients with AD, as in those with heart disease, is likely to be at least partly independent of the effects of statins on cholesterol. Statins can alter cellular signaling and protein trafficking through inhibition of isoprenylation of Rho, Cdc42, and Rab family GTPases. The effects of statins on protein isoprenylation in vivo, particularly in the central nervous system, are poorly studied. We utilized two-dimensional gel electrophoresis approaches to directly monitor the levels of isoprenylated and non-isoprenylated forms of Rho and Rab family GTPases. We report that simvastatin significantly inhibits RhoA and Rab4, and Rab6 isoprenylation at doses as low as 50nM in vitro. We also provide the first in vivo evidence that statins inhibit the isoprenylation of RhoA in the brains of rats and RhoA, Cdc42, and H-Ras in the brains of mice treated with clinically relevant doses of simvastatin.

Protective effects of Brassica oleracea sprouts extract toward renal damage in high-salt-fed SHRSP: role of AMPK/PPARα/UCP2 axis.

OBJECTIVES: Renal damage precedes occurrence of stroke in high-sodium/low-potassium-fed stroke-prone spontaneously hypertensive rat (SHRSP). We previously reported a marked suppression of uncoupling protein-2 (UCP2) upon high-salt Japanese-style diet in SHRSP kidneys. Vegetable compounds are known to exert protective effects in cardiovascular diseases. We aimed at evaluating the impact of Brassica oleracea sprouts juice toward renal damage in Japanese diet-fed SHRSP and exploring the role of 5'-adenosine monophosphate-activated protein kinase (AMPK)/NAD-dependent deacetylase sirtuin-1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α)/peroxisome proliferator-activated receptor-α (PPARα)/UCP2 axis. METHODS: SHRSP received Japanese diet for 4 weeks. A group of SHRSP received Japanese diet and B. oleracea. A third group received Japanese diet, B. oleracea, and PPARα inhibitor (GW6471). A group of SHRSP fed with regular diet served as control. RESULTS: Japanese diet induced marked increases of oxidative stress, inflammation, and proteinuria, along with glomerular and tubular damage, as compared with regular diet. A significant suppression of AMPK/UCP2 pathway was observed. Despite Japanese diet feeding, concomitant administration of B. oleracea prevented oxidative stress accumulation, inflammation, renal damage, and proteinuria. All components of the UCP2 regulatory pathway were significantly increased by B. oleracea. Superoxide dismutase 2 and phosphoendothelial nitric oxide synthase were also stimulated. Addition of PPARα inhibitor to B. oleracea and Japanese diet significantly reduced the B. oleracea beneficial effects. SBP levels were comparable among the different groups of rats.In vitro, UCP2 inhibition by genipin offset the antioxidant effect of B. oleracea in renal mesangial and proximal tubular cells. CONCLUSION: B. oleracea administration prevented renal damage in salt-loaded SHRSP, independently from SBP, with parallel stimulation of AMPK/SIRT1/PGC1α/PPARα/UCP2 axis. Stimulation of the latter mechanism may provide relevant renal protective effect and play a therapeutic role in target organ damage progression in hypertension.

Lactones from Ligusticum chuanxiong Hort. reduces atherosclerotic lesions in apoE-deficient mice via inhibiting over expression of NF-kB-dependent adhesion molecules.

The present study aims to investigate the anti-atherosclerotic effects of lactones extracted from Ligusticum chuanxiong Hort (LLC) in apoE-deficient mice (ApoE(-/-) mice) and proclaim its underlying mechanisms. Expression of endothelial adhesion molecules and NF-κB around the atherosclerotic lesions was detected by immunohistochemistry (IHC). To further validate the mechanism, effect of LLC on the secretion of ICAM-1 and VCAM-1 of human umbilical vein endothelial cells (HUVECs) induced by tumor necrosis factor α (TNF-α) was measured by ELISA. And the activation of NF-κB was detected by western blot. Mice treated with LLC showed significant reduction in lesion sizes of thoracic segments of the aorta (p<0.01). Meanwhile, LLC treatments lead to decreases of serum TG, TC and LDL-C contents, respectively. LLC also decreased the expression of CD31, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1) and nuclear factor-kappa B (NF-κB) in the atherosclerotic plaque. Moreover, LLC at 3.125-25 µg/mL can dose-dependently attenuate the expression of ICAM-1 and VCAM-1 in TNF-α stimulated HUVECs. Western blot result indicated LLC inhibited activation of NF-κB. These results suggested that LLC could ameliorate atherosclerosis in ApoE(-/-) mice. The mechanism of action of LLC on anti-atherosclerotic effect may be attributed to the suppression of the production of NF-κB-dependent adhesion molecules.