Standardized extract from the leaves of the Ginkgo biloba tree, labeled EGb761, has been used in clinical trials for its beneficial effects on brain functions, particularly in connection with agerelated dementias and Alzheimer's disease (AD). Substantial experimental evidence indicates that EGb761 protects against neuronal damage from a variety of insults, but its cellular and molecular mechanisms remain unknown. Using a neuroblastoma cell line stably expressing an AD-associated double mutation, we report that EGb761 inhibits formation of amyloid- (A) fibrils, which are the diagnostic, and possibly causative, feature of AD. The decreased A fibrillogenesis in the presence of EGb761 was observed both in the conditioned medium of this A-secreting cell line and in solution in vitro. In the cells, EGb761 significantly attenuated mitochondrion-initiated apoptosis and decreased the activity of caspase 3, a key enzyme in the apoptosis cell-signaling cascade. These results suggest that (i) neuronal damage in AD might be due to two factors: a direct A toxicity and the apoptosis initiated by the mitochondria; and (ii) multiple cellular and molecular neuroprotective mechanisms, including attenuation of apoptosis and direct inhibition of A aggregation, underlie the neuroprotective effects of EGb761.
Calorie restriction (CR) delays the development of age-associated disease and increases lifespan in rodents, but the effects in humans remain uncertain.Purpose-Determine the effect of 6 months of CR with or without exercise on cardiovascular disease (CVD) risk factors and estimated 10-year CVD risk in healthy non-obese men and women.Methods-Thirty-six individuals were randomized to one of three groups for 6 months: Control, 100% of energy requirements; CR, 25% calorie restriction; CR+EX, 12.5% CR + 12.5% increase in energy expenditure via aerobic exercise. CVD risk factors were assessed at baseline, 3 and 6 months.Results-After 6 months, CR and CR+EX lost approximately 10% of body weight. CR significantly reduced triacylglycerol (-31 ± 15 mg/dL) and factor VIIc (-10.7 ± 2.3%). Similarly CR+EX reduced triacylglycerol (-22 ± 8 mg/dL) and additionally reduced LDL-C (-16.0 ± 5.1 mg/dL) and DBP (-4.0 ± 2.1 mmHg). In contrast, both triacylglycerol (24 ± 14 mg/dL) and factor VIIc (7.9 ± 2.3%) were increased in the control group. HDL-cholesterol was increased in all groups while hsCRP was lower in the Controls vs. CR+EX. Estimated 10-year CVD risk significantly declined from baseline by 29% in CR (P< 0.001) and 38% in the CR+EX (P<0.001) while remaining unchanged in the Control group.Conclusions-Based on combined favorable changes in lipid and blood pressure, caloric restriction with or without exercise that induces weight loss favorably reduces risk for CVD even in already healthy non-obese individuals.
The role of amyloid β-peptide (Aβ) in the free-radical oxidative-stress model of neurotoxicity in Alzheimer's disease (AD) has received much attention recently. In this study, we have employed both in vitro and in vivo models displaying endogenous Aβ production to study the effects of Aβ on intracellular free radical levels. We employed a neuroblastoma cell line stably expressing an AD-associated double mutation, which exhibits both increased secretion and intracellular accumulation of Aβ when stimulated, as well as transgenic Caenorhabditis elegans constitutively expressing human Aβ. A rise in levels of hydrogen peroxide (H2O2) was observed in both in vitro and in vivo AD-associated transgenic models expressing the Aβ peptide compared with the wild type controls. Treatment of the cells or C. elegans with Ginkgo biloba extract EGb 761 significantly attenuated the basal as well as the induced levels of H2O2-related reactive oxygen species (ROS). Among individual EGb 761 components tested, kaempferol and quercetin provided maximum attenuation in both models. Furthermore, an age-dependent increase in H2O2-related ROS was observed in wild type C. elegans, which is accelerated in the AD-associated C. elegans mutant. These results support the hypothesis of the involvement of Aβ and ROS in association with AD.
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