A GCase Chaperone Improves Motor Function in a Mouse Model of Synucleinopathy

Mutation of the lysosomal hydrolase acid-β-glucosidase (GCase), which leads to reduced GCase activity, is one of the most frequent genetic risk factors for Parkinson’s disease (PD) and promotes α-synuclein accumulation in the brain, a hallmark of PD and other synucleinopathies. Whether targeting GCase pharmacologically is a valid therapeutic strategy for sporadic PD in the absence of GCase mutation is unknown. We have investigated whether increasing the stability, trafficking, and activity of wild-type GCase could be beneficial in synucleinopathies by administering the pharmacological chaperone AT2101 (afegostat-tartrate, isofagomine) to mice that overexpress human wild-type α-synuclein (Thy1-aSyn mice). AT2101 administered orally for 4 months to Thy1-aSyn mice improved motor and nonmotor function, abolished microglial inflammatory response in the substantia nigra, reduced α-synuclein immunoreactivity in nigral dopaminergic neurons, and reduced the number of small α-synuclein aggregates, while increasing the number of large α-synuclein aggregates. These data support the further investigation of pharmacological chaperones that target GCase as a therapeutic approach for sporadic PD and other synucleinopathies, even in the absence of glucocerebrosidase mutations.     

Whey protein preloads are more beneficial than soy protein preloads in regulating appetite,calorie intake,anthropometry, and body composition of overweight and obese men

High-protein diets exert beneficial effects on appetite, anthropometry, and body composition; however, the effects of protein preloads depend on the amount, type, and time of consumption. Therefore, we hypothesized that long-term supplemental preloads of whey protein concentrate (WPC) and soy protein isolate (SPI) consumed 30 minutes before the largest meal would decrease appetite, calorie intake (CI), and anthropometry and improve body composition in overweight and obese men in free-living conditions. The subjects included 45 men with a body mass index between 25 and 40 kg/m² and who were randomly allocated to either the WPC (n = 26) or SPI (n = 19) groups. For 12 weeks, the subjects consumed 65 g WPC or 60 g SPI that was dissolved in 500 mL water 30 minutes before their ad libitum lunch. Appetite, CI, anthropometry, and body composition were assessed before and after the study and biweekly throughout. After 12 weeks, mean changes between the groups were significant for appetite (P = .032), CI (P = .045), anthropometry (body weight [P = .008], body mass index [P = .006], and waist circumference), and body composition (body fat mass and lean muscle [P < .001]). Relative to baseline, within-group mean changes from WPC were significant for appetite, CI, anthropometry, and body composition (P < .001). In the SPI group, mean changes were significant, relative to baseline, for all variables except lean muscle (P = .37). According to this 12-week study, WPC preloads conducted 30 minutes prior to the ad libitum main meal exerted stronger beneficial effects than did SPI preloads on appetite, CI, anthropometry, and body composition of free-living overweight and obese men.     

Effects of N-Acetylcysteine on the Cardiac Remodeling Biomarkers and Major Adverse Events Following Acute Myocardial Infarction: A Randomized Clinical Trial

Aims

The aims of this study were to evaluate the effects of N-acetylcysteine (NAC) on cardiac remodeling and major adverse events following acute myocardial infarction (AMI).

Methods

In a prospective, double-blind, randomized clinical trial, the effect of NAC on the serum levels of cardiac biomarkers was compared with that of placebo in 98 patients with AMI. Also, the patients were followed up for a 1-year period for major adverse cardiac events (MACE), including the occurrence of recurrent myocardial infarction, death, and need for target vessel revascularization.

Results

In patients who received NAC, the serum levels of matrix metalloproteinase (MMP)-9 and MMP-2 after 72 h were significantly lower than those in the placebo group (p = 0.014 and p = 0.045, respectively). The length of hospitalization in patients who received NAC was significantly shorter than that in the placebo group (p = 0.024). With respect to MACE, there was a significant difference between those who received NAC (14 %) and those patients on placebo (25 %) (p = 0.024). Re-infarction took place in 4 % of patients in the NAC group as compared with 16.7 % in patients who received placebo (p = 0.007).

Conclusion

NAC can be beneficial in preventing early remodeling by reducing the level of MMP-2 and MMP-9. Moreover, NAC decreased the length of hospital stays in patients after AMI. By decreasing MACE, NAC could possibly be introduced as a ‘magic bullet’ in the pharmacotherapy of patients with AMI. Further studies are needed to elucidate NAC’s role in this population.     

Effects of rutin on acrylamide-induced neurotoxicity

Background

Rutin is an important flavonoid that is consumed in the daily diet. The cytoprotective effects of rutin, including antioxidative, and neuroprotective have been shown in several studies. Neurotoxic effects of acrylamide (ACR) have been established in humans and animals. In this study, the protective effects of rutin in prevention and treatment of neural toxicity of ACR were studied.

Results

Rutin significantly reduced cell death induced by ACR (5.46 mM) in time- and dose-dependent manners. Rutin treatment decreased the ACR-induced cytotoxicity significantly in comparison to control (P <0.01, P < 0.001). Rutin (100 and 200 mg/kg) could prevent decrease of body weight in rats. In combination treatments with rutin (50, 100 and 200 mg/kg), vitamin E (200 mg/kg) and ACR, gait abnormalities significantly decreased in a dose-dependent manner (P < 0.01 and P < 0.001). The level of malondialdehyde significantly decreased in the brain tissue of rats in both preventive and therapeutic groups that received rutin (100 and 200 mg/kg).

Conclusion

It seems that rutin could be effective in reducing neurotoxicity and the neuroprotective effect of it might be mediated via antioxidant activity.     

Sulfaphenazole treatment restores endothelium-dependent vasodilation in diabetic mice

Vascular dysfunction is linked with increased free radical generation and is a major contributor to the high mortality rates observed in diabetes. Several probable sources of free radical generation have been suggested in diabetes, including cytochrome P450 (CYP) monooxygenase-dependent pathways. CYP-mediated superoxide production reduces nitric oxide (NO) bioavailability. In this study, we focus on the contribution of monooxygenase enzyme-generated reactive oxygen species in vascular dysfunction in an experimental model of diabetes mellitus type II. Diabetic male mice (db/db strain) and their age-matched controls received daily intraperitoneal injections of either the CYP 2C inhibitor sulfaphenazole (5.13 mg/kg) or saline (vehicle control) for 8 weeks. Although sulfaphenazole did not change endothelium-dependent vasodilation in control mice, it restored endothelium-mediated relaxation in db/db mice. We report for the first time that CYP 2C inhibition reduces oxidative stress (measured as plasma levels of 8-isoprostane), increases NO bioavailability (measured as NO(2)(-)) and restores endothelial function in db/db mice without affecting plasma glucose levels. Based on our findings, we speculate that inhibition of free radical generating CYP 450 monooxygenase enzymes restores endothelium-dependent vasodilation to acetylcholine. In addition, it reduces oxidative stress and increases NO bioavailability.     

Profiling of benzophenone derivatives using fish and human estrogen receptor-specific in vitro bioassays

Benzophenone (BP) derivatives, BP1 (2,4-dihydroxybenzophenone), BP2 (2,2′,4,4′-tetrahydroxybenzophenone), BP3 (2-hydroxy-4-methoxybenzophenone), and THB (2,4,4′-trihydroxybenzophenone) are UV-absorbing chemicals widely used in pharmaceutical, cosmetics, and industrial applications, such as topical sunscreens in lotions and hair sprays to protect skin and hair from UV irradiation. Studies on their endocrine disrupting properties have mostly focused on their interaction with human estrogen receptor alpha (hERα), and there has been no comprehensive analysis of their potency in a system allowing comparison between hERα and hERβ activities. The objective of this study was to provide a comprehensive ER activation profile of BP derivatives using ER from human and fish origin in a battery of in vitro tests, i.e., competitive binding, reporter gene based assays, vitellogenin (Vtg) induction in isolated rainbow trout hepatocytes, and proliferation based assays. The ability to induce human androgen receptor (hAR)-mediated reporter gene expression was also examined. All BP derivatives tested except BP3 were full hERα and hERβ agonists (BP2 > THB > BP1) and displayed a stronger activation of hERβ compared with hERα, the opposite effect to that of estradiol (E₂). Unlike E₂, BPs were more active in rainbow trout ERα (rtERα) than in hERα assay. All four BP derivatives showed anti-androgenic activity (THB > BP2 > BP1 > BP3). Overall, the observed anti-androgenic potencies of BP derivatives, together with their proposed greater effect on ERβ versus ERα activation, support further investigation of their role as endocrine disrupters in humans and wildlife.     

Endogenous cannabinoids contribute to remote ischemic preconditioning via cannabinoid CB2 receptors in the rat heart

In addition to well-known neurobehavioral effects, endogenous cannabinoids exert diverse cardiovascular actions. Recently, they have been suggested to protect the myocardium against ischemia/reperfusion injury. The aim of this study is to examine the contribution of endogenous cannabinoids to cardioprotection afforded by remote ischemic preconditioning. Three groups of remote preconditioned (15 min of mesenteric artery occlusion followed by 15 min of reperfusion) and three groups of sham-operated rats were included in the study. Animals were pretreated intravenously by vehicle, cannabinoid CB(1) (AM251, 1 mg/kg) or CB(2) (AM630, 1 mg/kg) receptor antagonist 15 min prior to remote preconditioning or sham operation. Myocardial injury was induced by 30 min of coronary artery occlusion followed by 2 h of reperfusion. The resultant arterial hypotension, ventricular arrhythmias, and infarct size were compared among the groups. Remote preconditioning exerted potent cardioprotection manifested as significant reductions in infarct size (P<0.001) as well as number and duration of arrhythmias (P<0.01, 0.01 and 0.05 for premature ventricular contractions, ventricular tachycardias and fibrillations; respectively). The cannabinoid CB(1) receptor antagonist pretreatment had no significant effect on ischemia-induced hypotension, arrhythmias or infarct size. On the other hand, the cannabinoid CB(2) receptor antagonist pretreatment abolished the protective effects of remote preconditioning on infarct size (P<0.01) and arrhythmias (P<0.01), without any significant effect on ischemia-induced hypotension. The results of this study suggest that endogenous cannabinoids, through acting on cannabinoid CB(2) receptors, are involved in the cardioprotective phenomenon of remote ischemic preconditioning, induced by mesenteric artery occlusion and reperfusion.