N-acetylcysteine negatively regulates Notch3 and its malignant signaling.

Notch3 receptor is expressed in a variety of cancers and the excised active intracellular domain (N3ICD) initiates its signaling cascade. N-acetylcysteine (NAC) as an antioxidant has been implicated in cancer prevention and therapy. In this study, we demonstrated a negative regulation of Notch3 by NAC in cancer cells. HeLa cells treated with NAC exhibited a time- and concentration-dependent decrease in Notch3 levels and its downstream effectors Hes1 and HRT1 in a manner independent of f-secretase or glutathione. In contrast, NAC did not affect protein levels of Notch1, the full length Notch3 precursor, or ectopically expressed N3ICD. Although SOD, catalase and NAC suppressed reactive oxygen species in HeLa cells, the first two antioxidants did not impact on Notch3 levels. While the mRNA expression of Notch3 was not altered by NAC, functional inhibition of lysosome, but not proteasome, blocked the NAC-dependent reduction of Notch3 levels. Furthermore, results from Notch3 silencing and N3ICD overexpression demonstrated that NAC prevented malignant phenotypes through down-regulation of Notch3 protein in multiple cancer cells. In summary, NAC reduces Notch3 levels through lysosome-dependent protein degradation, thereby negatively regulates Notch3 malignant signaling in cancer cells. These results implicate a novel NAC treatment in sensitizing Notch3-expressing tumors.

Efficacy and safety of solifenacin succinate tablets versus solifenacin succinate tablets with local estrogen for the treatment of overactive bladder in postmenopausal women--a multicenter, randomized, open-label, controlled comparison study.

OBJECTIVE: The aim of the study was to compare the effectiveness and safety of solifenacin succinate tablets alone or combined with local estrogen for overactive bladder treatment in postmenopausal women. METHODS: This multicenter, randomized, open, parallel-controlled clinical trial enrolled 104 women between January 2012 and August 2013. Participants meeting the inclusion criteria were randomized 1:1 to 12 weeks of treatment with group A (solifenacin 5 mg qd + promestriene vaginal capsules intravaginally) or group B (solifenacin 5 mg qd). Before and after 12 weeks of treatment, symptoms (urinary urgency, frequency, and urge incontinence) were analyzed. Our primary outcome was the change from baseline to the end of treatment in the mean number of voids in 24 hours. Quality of life (QoL) was assessed using International Prostate Symptom Score and Overactive Bladder Symptom Score questionnaires and safety according to the incidence of adverse events. The t test or the Mann-Whitney U test was used to compare continuous variables, and the χ(2) test or Fisher's exact test was used to compare categorical variables. RESULTS: The median decreases in the mean number of voids in 24 hours in groups A and B were 5.2. and 4.3, respectively, which were not significantly different. The median decreases in urgency episodes in groups A and B were 2.0 and 2.5, respectively. In addition, the QoL scores significantly changed in both groups (both P < 0.05). The most common adverse event was dry mouth (19.2% in both groups). CONCLUSIONS: Solifenacin with or without local estrogen was effective and safe for overactive bladder treatment in postmenopausal women. The addition of local estrogen improved subjective feelings and QoL.

The RIT2 and STX1B polymorphisms are associated with Parkinson's disease.

INTRODUCTION: GWAS meta-analysis identified RIT2 rs12456492 and STX1B rs4889603 as PD susceptible loci. While proteins encoded by the genes, in particular RIT2, may involve in PD pathogenesis, the association of these two variants with PD remains to be further clarified. METHODS: We enrolled a Chinese cohort comprising 537 PD patients and 517 controls, determined the genotypes of rs12456492 and rs4889603, and analyzed these variants in relation to PD. RESULTS: Both rs12456492 and rs4889603 were associated with PD susceptibility (P = 0.012 and 0.03, respectively). The G allele of rs12456492 and the A allele of rs4889603 served as risk alleles toward PD. Statistical differences in genotype distribution between the patients and controls were observed both in rs12456492 (marginal, P = 0.042 for GG vs. AG vs. AA) and in rs4889603 (P = 0.021 for AA + AG vs. GG) CONCLUSION: Our data suggest that the RIT2 and STX1B polymorphisms are associated with PD etiology. The role of RIT2 in PD pathogenesis warrants further mechanistical investigation.

Association analysis of PARK16-18 variants and Parkinson's disease in a Chinese population.

Genome-wide association studies identified PARK16 variants rs823128 and rs947211, PARK17/GAK rs11248051 and PARK18/HLA-DRA rs3129882 as risk factors for Parkinson's disease (PD). However the susceptibility of these loci to predisposing individuals for PD, particularly rs11248051, remains under investigation in Chinese populations. A total of 323 PD patients and 345 age and sex matched controls were recruited in eastern China. Our results show that minor allele frequencies of rs11248051 (odds ratio [OR] 1.522; p=0.016) and rs3129882 (OR 1.294; p=0.03), but not rs823128 and rs947211, were associated with risk for PD. Genetic interaction analysis revealed that subjects simultaneously carrying the T allele (TC or TT) of rs11248051 and the A allele (AG or AA) of rs3129882 had an aggravated risk (OR 1.91; p=0.016) of PD. However, rs11248051 or rs3129882 displayed no association with PD phenotypes or clinical scores. Our results suggest that rs11248051 and rs3129882 are risk factors for sporadic PD in a Chinese population, and their genetic interplay contributes to an elevated risk for PD predisposition. Our data provide a novel insight and further information regarding PARK16-18 loci in PD susceptibility.