Protective effects of melatonin on changes occurring in the experimental autoimmune encephalomyelitis model of multiple sclerosis.

BACKGROUND: Melatonin has been related to the pathophysiology of multiple sclerosis (MS), and its anti-inflammatory and immunomodulatory properties have been proved in numerous neurodegenerative diseases. This study aimed to find out whether a melatonin supplement in MS is able to act as a benefit to its clinical status, i.e. oxidative stress, inflammation and indirect biomarkers of bacterial dysbiosis, lipopolysaccharide (LPS) and LPS-binding protein (LBP), verifying its therapeutic potential and its possible clinical use in patients with MS. METHODS: The animal MS model, experimental autoimmune encephalomyelitis (EAE), was employed whereby 25 male Dark Agouti rats (5 animals per group) were divided into: a control group (not manipulated); a control+vehicle group; a control+melatonin group; an EAE group; an EAE+melatonin group. Melatonin was administered daily for 51 days, at a dose of 1 mg/kg body weight/i.p., once a day, five days a week. RESULTS: The results from the administration of melatonin demonstrated an improvement in clinical status, a diminution in oxidative stress and inflammation, as well as in bacterial dysbiosis. CONCLUSION: Melatonin could play an effective role against MS, either alone or as a therapy combined with traditional agents.

Cerivastatin improves insulin sensitivity and insulin secretion in early-state obese type 2 diabetes.

In a double-blind, placebo-controlled, randomized crossover study, 15 stable mild hyperglycemic patients without treatment and with features of metabolic syndrome were treated with cerivastatin (0.4 mg/day) or placebo for 3 months. The insulin sensitivity index during the euglycemic-hyperinsulinemic clamp (EHC; 5.4 mmol/l; 80 mU x m(-2) x min(-1)) was increased by cerivastatin treatment (66.39 +/- 3.9 nmol x lean body mass [LBM](-1) x min(-1) x pmol(-1) x l(-1)) as compared with placebo (58.37 +/- 3.69 nmol x LBM(-1) x min(-1) x pmol(-1) x l(- 1); P < 0.01) by 13.7%. Glucose oxidation during EHC was significantly higher with statin treatment (16.1 +/- 1.37 micromol x LBM(-1) x min(-1)) as compared with placebo (14.58 +/- 1.48 micromol x LBM(-1) x min(-1); P < 0.05). During hyperinsulinemia (approximately 800 pmol/l) in EHC steady-state, lipid oxidation was significantly decreased and respiratory quotient was significantly increased with statin treatment (0.33 +/- 0.05 mg x LBM(-1) x min(- 1), 0.94 +/- 0.01) as compared with placebo (0.48 +/- 0.06 mg x LBM(-1) x min(-1), 0.91 +/- 0.01; P < 0.01 and P < 0.05, respectively). During statin treatment, the first-phase insulin response increased from 2.07 +/- 0.28 to 2.82 +/- 0.38 pmol x l(-1) x pmol(-1) (P < 0.05). The second phase of insulin responses examined by C-peptide and insulin levels averaged during the hyperglycemic clamp (20 mmol/l) was unchanged. In conclusion, this study demonstrates that 0.4 mg cerivastatin therapy improves first-phase insulin secretion and increases insulin-mediated glucose uptake and respiratory quotient in the early state of obese type 2 diabetes.

A Mediterranean and a high-carbohydrate diet improve glucose metabolism in healthy young persons.

AIMS/HYPOTHESIS: Insulin resistance usually precedes the diagnosis of Type II (non-insulin-dependent) diabetes mellitus. However, in most patients, the clinical expression of the disease could be prevented by dietary and lifestyle changes. We investigated the effects of a diet enriched in monounsaturated fatty acids (Mediterranean diet) and a low fat, high-carbohydrate diet on in vivo and in vitro glucose metabolism in 59 young subjects (30 men and 29 women). METHODS: We carried out an intervention dietary study with a saturated fat phase and two randomized-crossover dietary periods: a high-carbohydrate diet and a Mediterranean diet for 28 days each. We analysed the plasma lipoproteins fractions, free fatty acids, insulin sensitivity and glucose uptake in isolated monocytes at the end of the three dietary periods. RESULTS: In comparison to the saturated fat diet, the CHO and Mediterranean diets induced a decrease of LDL-cholesterol (p < 0.001) and HDL-cholesterol (p < 0.001). Steady-state plasma glucose decreased (p = 0.023) and basal and insulin-stimulated 2-deoxiglucose uptake in peripheral monocytes increased in both diets (CHO and Mediterranean), (p = 0.007) indicating an improvement in insulin sensitivity. Fasting free fatty acids plasma values were correlated positively with steady state plasma glucose (r = 0.45; p < 0.0001). In addition, there was an inverse correlation between the mean glucose of the steady state plasma glucose period and logarithmic values of basal (r = -0.34; p = 0.003) and insulin stimulated glucose uptake in monocytes (r = -0.32; p = 0.006). CONCLUSION/INTERPRETATION: Isocaloric substitution of carbohydrates and monounsaturated fatty acids for saturated fatty acids improved insulin sensitivity in vivo and in vitro, with an increase in glucose disposal. Both diets are an adequate alternatives for improving glucose metabolism in healthy young men and women.

Mediterranean and low-fat diets improve endothelial function in hypercholesterolemic men.

BACKGROUND: The regulatory function of the endothelium is altered in hypercholesterolemia, and the subsequent endothelial dysfunction plays a central role in the development of atherosclerosis. OBJECTIVE: To determine whether endothelial function in hypercholesterolemic patients is affected by replacing a saturated fat-enriched diet with a low-fat, low-saturated fat diet (the U.S. National Cholesterol Education Program stage 1 [NCEP-1] diet) or a diet rich in monounsaturated fat (such as that common in Mediterranean countries). DESIGN: Intervention dietary study with a baseline phase and two randomized crossover dietary periods. SETTING: Hospital Universitario Reina Sofía, Córdoba, Spain. PATIENTS: 22 hypercholesterolemic men. INTERVENTION: Patients followed a diet high in saturated fat, then were assigned in a crossover design to the NCEP-1 diet or a Mediterranean diet. Each dietary period lasted 28 days. MEASUREMENTS: Plasma P-selectin levels, lipid concentrations, and endothelial function. RESULTS: Compared with the saturated fat diet, flow-mediated dilatation increased during the Mediterranean diet but not during the NCEP-1 diet. In addition, levels of plasma cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and P-selectin decreased during the NCEP-1 and Mediterranean diets. CONCLUSION: In hypercholesterolemic men, diets low in fat (especially saturated fat) and diets rich in monounsaturated fats improve endothelial function.

Circulating levels of endothelial function are modulated by dietary monounsaturated fat.

BACKGROUND: For the most part, the benefits of monounsaturated-rich diets (MUFA-diet) have been related to their action on plasma lipid levels. However other non-lipidic effects could also be involved in their protective effects. One of these involves the decrease in plasma levels of plasminogen activator inhibitor type 1 (PAI-1), the main inhibitor of fibrinolysis. Given that the PAI-1 is of endothelial origin, one hypothesis is that the MUFA-diet could protect against CHD by modulating some endothelial components. METHODS AND RESULTS: Healthy male subjects (n = 25) received three different consecutive diets, each lasting 28 days: a low fat NCEP-I-diet, with 28% calories as fat, 10% saturated fat (SAT), 12% monounsaturated (MUFA) and 6% polyunsaturated (PUFA); a MUFA-diet, with 38% calories as fat, 10% SAT, 22% MUFA and 6% PUFA; and a SAT rich-diet (SAT-diet), with 38% calories as fat, 20% SAT, 12% MUFA and 6% PUFA. After each dietary period, the plasma lipid profile was determined, including total cholesterol, HDL cholesterol, LDL cholesterol, total triglyceride, apo A1, apo B plasma levels and conjugated diene formation, after incubation of LDL particles with Cu 5 microM/l. Endothelial products measured in plasma were von Willebrand factor (vWF), E-selectin, Thrombomodulin and Tissue Factor Pathway Inhibitor (TFPI) levels. We observed a decrease in vWF, PAI-1 and TFPI plasma levels and an increase in lag time of conjugated diene formation after the MUFA-diet. There was a positive correlation between the decreases in TFPI and vWF and the changes in total cholesterol, LDL-C, apo B plasma levels. The decrease in TFPI was negatively correlated with the increase in lag time of conjugated diene formation. PAI-1 plasma levels were positively correlated with total cholesterol, LDL-C and triglycerides and negatively correlated with HDL-C. CONCLUSIONS: Consumption of a Mediterranean-type MUFA-diet produces a decrease in plasma levels of vWF, TFPI and PAI-1 plasma levels in young healthy males. Given that these substances are of endothelial origin, one could suggest that the MUFA of the diet has a beneficial effect on endothelial function resulting in protective changes against thrombogenesis.