Effect of an oral astaxanthin prodrug (CDX-085) on lipoprotein levels and progression of atherosclerosis in LDLR(-/-) and ApoE(-/-) mice

Oxidative stress and inflammation are key promoters of atherosclerosis and myocardial damage. When orally administered, the novel astaxanthin prodrug CDX-085 delivers high levels of the xanthophyll antioxidant astaxanthin that protects LDL from oxidation and reduces primary thrombosis. In this study, we analyzed whether delivery of astaxanthin from administration of the CDX-085 prodrug reduces plasma lipoprotein levels and the progression of atherosclerosis in low-density lipoprotein receptor negative (LDLR^?/?) and apolipoprotein E deficient (ApoE^?/?) mice.MethodsRelative circulating levels of astaxanthin derived from CDX-085 administration compared to administration of pure astaxanthin was initially evaluated in a canine model. In mouse Study #1, 16 wild-type and 16 LDLR^?/? mice on 0.5% cholesterol diet supplemented with either 0.0%, 0.08%, 0.2% and 0.4% CDX-085 were used to assess plasma levels and lipoprotein biodistribution measured by FPLC after 4 weeks treatment. In Study #2, 36 male LDLR^?/? mice were randomized to a 0.5% cholesterol chow diet (CHOW group, n = 12) or 0.5% cholesterol chow fortified with 0.08% CDX-085 (n = 12) or 0.5% cholesterol chow with 0.4% CDX-085 (n = 12) for 12 weeks. In Study #3, 34 male ApoE^?/? mice were randomized in the same fashion as the Study #2 and fed similar diets for 9 weeks.ResultsCDX-085 administration was shown to result in significantly higher levels of circulating astaxanthin (p < 0.001 ANOVA) over a 72 h period compared to pure, non-esterified astaxanthin in a single-dose pharmacokinetic study in beagles. In Study #1, plasma astaxanthin levels were 5–9-fold higher in LDLR^?/? mice compared to wild-type mice. Astaxanthin was highly distributed among all lipoprotein fractions, generally reflecting cholesterol content of lipoproteins. In Study #2, administration of CDX-085 resulted in significantly lower total cholesterol levels (528 ± 68 mg/dL vs. 550 ± 67 mg/dL vs. 602 ± 80 mg/dL, p = 0.047) and aortic arch atherosclerosis (9.0 ± 4.2% vs. 9.8 ± 3.5% vs. 13.2 ± 3.6%, p = 0.023) in the 0.4% CDX-085 group compared to the 0.08% CDX-085 and CHOW groups, respectively. In ApoE^?/? mice, a 72% reduction in triglycerides in the 0.4% CDX-085 group and 50% reduction in the 0.08% CDX-085 groups was noted compared to CHOW group (final levels 17 ± 11 mg/dL vs. 30 ± 15 mg/dL vs. 60 ± 32 mg/dL, respectively, p = 0.001).ConclusionOral administration of the novel astaxanthin prodrug CDX-085 shows that it distributes among lipoproteins. CDX-085 lowers total cholesterol and aortic arch atherosclerosis in LDLR^?/? mice and triglyceride levels in ApoE^?/? mice and shows promise for further evaluation in human studies.     

Enhancer of polycomb1 lessens neointima formation by potentiation of myocardin-induced smooth muscle differentiation

ObjectivePreviously, we reported that enhancer of polycomb1 (Epc1) induces skeletal muscle differentiation through the serum response factor (SRF). Considering that SRF plays a critical role in vascular smooth muscle cell (VSMC) differentiation, we expected that Epc1 also works in VSMCs. Here we examined the effect of Epc1 on neointima formation after arterial balloon injury and the underlying mechanism.MethodsEpc1 expression was examined in carotid artery injury or VSMC models. Interaction with myocardin (Myocd), a master regulator of smooth muscle differentiation, was examined by immunoprecipitation or promoter analysis with smooth muscle (SM) 22α promoter. Finally, we investigated whether local delivery of Epc1 regulated neointimal formation after injury.ResultsEpc1 expression was down-regulated during proliferation induced by platelet-derived growth factor BB, whereas it was upregulated during differentiation in VSMCs. Forced expression of Epc1 induced VSMC differentiation. Epc1 physically interacted with Myocd to synergistically activate SM22α promoter activity. Transient transfection of Epc1 enhanced the physical interaction between Myocd and SRF, whereas that interaction was reduced when A10 cells were treated with siRNA for Epc1. Local delivery of Epc1 significantly reduced neointima formation induced by balloon injury.ConclusionsOur results indicate that Epc1 induces VSMC differentiation by interacting with Myocd to induce SRF-dependent smooth muscle genes. We propose that Epc1 acts as a novel negative regulator of neointima formation after carotid injury.     

Which symptoms can distinguish between subjective cognitive impairment (SCI) and mild cognitive impairment (MCI)?

The SCI, the MCI, and the Alzheimer's disease (AD) are on a spectrum of disease progression; therefore, identification of the earliest signs of cognitive deterioration is becoming a crucial issue. The goal of this study was to examine symptom characteristics and distinguish predictive symptoms in patients with MCI compared with SCI, using caregiver questionnaires. We assessed the Korean Dementia Screening Questionnaire (KDSQ) and Seoul Instrumental activities of Daily Living (S-IADL) of 344 subjects with SCI and 697 with MCI. Multivariate logistic regression analyses were conducted after adjusting for age, sex, and educational status. Common and rare symptoms were similar between the SCI and MCI groups. The most distinguishing features of KDSQ were 'Finds it hard to go somewhere on his/her own using public transportation' (odds ratio=OR=4.56, p<0.0001), 'Has difficulty in operating appliances' (OR=2.47, p=0.001), and 'Keeps repeating the same question' (OR=2.03, p<0.0001). In S-IADL, the most outstanding features were 'using household appliances' (OR=3.99, p<0.0001), 'taking medication' (OR=2.38, p=0.01), and 'using public transportation' (OR=1.94, p=0.04). The dysfunction in 'using household appliance' and 'using public transportation' reflect the possibility of MCI rather than SCI. Therefore, it is suggested that these symptoms also have a discriminative and predictive power in identifying SCI.