New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kα Complexed with a Potent Lead Compound

Abstract Phosphatidylinositol 3-kinase α is an attractive target to potentially treat a range of cancers. Herein, we described the evolution of a reported PI3K inhibitor into a moderate PI3Kα inhibitor with a low molecular weight. We used X-ray crystallography to describe the accurate binding mode of the compound YXY-4F. A comparison of the p110α–YXY-4F and apo p110α complexes showed that YXY-4F induced additional space by promoting a flexible conformational change in residues Ser773 and Ser774 in the PI3Kα ATP catalytic site. Specifically, residue 773(S) in PI3Kα is quite different from that of PI3Kβ (D), γ (A), and δ (D), which might guide further optimization of substituents around the NH group and phenyl group to improve the selectivity and potency of PI3Kα

The prognostic significance of LncRNA BLACAT1 overexpression in various tumors: a meta-analysis

Objective:Recent studies have revealed increasing evidence that the long non-coding RNA bladder cancer associated transcript 1 (LncRNA BLACAT1) plays an essential role in the emergence of different malignancies. This meta-analysis aimed to evaluate the prognostic significance of LncRNA BLACAT1 in various cancers.Methods:Six electronic databases (PubMed, Embase, Medline, Web of Science, China National Knowledge Infrastructure (CNKI), and the Chinese WanFang database) were comprehensively searched for relevant studies. The analysis of overall survival (OS) and clinicopathological characteristics was conducted.Results:Nineteen studies with 1,559 patients were eventually eligible to be included in this meta-analysis. High expression level of LncRNA BLACAT1 was identified to be linked with shorter OS (HR: 2.02, 95% CI: 1.66–2.46, p < 0.001) and PFS (HR: 2.424, 95% CI: 1.827–3.020, p < 0.001) in cancer patients as opposed to low expression levels. Subgroup analysis showed that analysis model (multivariate or univariate), cut-off value (mean or median), sample size (more or fewer than 100), and cancer type had little effect on OS in multiple tumors. Moreover, high LncRNA BLACAT1 expression was associated with positive lymph node metastasis (HR: 2.29, 95% CI: 1.66–3.16, p < 0.00001), advanced clinical stage (HR: 2.29, 95% CI: 1.65–3.19, p < 0.00001) and worse differentiation status (HR: 0.58, 95% CI: 0.37–0.92, p = 0.02), compared to low LncRNA BLACAT1 expression.Conclusion:The findings highlight that high LncRNA BLACAT1 expression might be detrimental and induce a worse prognosis for cancer patients

Considering Genetic Heterogeneity in the Association Analysis Finds Genes Associated With Nicotine Dependence

While substantial progress has been made in finding genetic variants associated with nicotine dependence (ND), a large proportion of the genetic variants remain undiscovered. The current research focuses have shifted toward uncovering rare variants, gene-gene/gene-environment interactions, and structural variations predisposing to ND, the impact of genetic heterogeneity in ND has been nevertheless paid less attention. The study of genetic heterogeneity in ND not only could enhance the power of detecting genetic variants with heterogeneous effects in the population but also improve our understanding of genetic etiology of ND. As an initial step to understand genetic heterogeneity in ND, we applied a newly developed heterogeneity weighted U (HWU) method to 26 ND-related genes, investigating heterogeneous effects of these 26 genes in ND. We found no strong evidence of genetic heterogeneity in genes such as CHRNA5. However, results from our analysis suggest heterogeneous effects of CHRNA6 and CHRNB3 on nicotine dependence in males and females. Following the gene-based analysis, we further conduct a joint association analysis of two gene clusters, CHRNA5-CHRNA3-CHRNB4 and CHRNB3-CHRNA6. While both CHRNA5-CHRNA3-CHRNB4 and CHRNB3-CHRNA6 clusters are significantly associated with ND, there is a much stronger association of CHRNB3-CHRNA6 with ND when considering heterogeneous effects in gender (p-value = 2.11E-07)

Chinese Medicinal Herbs in Relieving Perimenopausal Depression: A Randomized, Controlled Trial

Abstract Objective: To explore the effects of GengNianLe (GNL, also called perimenopausal depression relieving formula), a defined formula of Chinese medicinal herbs in relieving perimenopausal depression in Chinese women. Methods : Between September 2004 and April 2008, 47 Chinese women were randomized into a GNL group (n ϭ 21) and a control group which received tibolone (n ϭ 26) using a randomization chart. Depression was rated with the 24-item Hamilton Depression Scale (HAMD). The serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E 2 ) were detected before and after the treatment. Results: After 12 weeks of treatment, HAMD scores in both groups decreased significantly (p Ͻ 0.05) with no significant difference between the groups (p Ͼ 0.05). The levels of FSH decreased significantly and the level of E 2 increased significantly in both groups, and they changed more in the control group. No side-effect of treatment was reported in either group during treatment. Conclusions: The Chinese medicinal formula GNL showed promise in relieving perimenopausal depression and merits further study. 9

Protective Effect of Tetrahydroxystilbene Glucoside on 6-OHDA-Induced Apoptosis in PC12 Cells through the ROS-NO Pathway

Oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease. The molecule, 2,3,5,4′-tetrahydr- oxystilbene-2-O-β-D-glucoside (TSG), is a potent antioxidant derived from the Chinese herb, Polygonum multiflorum Thunb. In this study, we investigated the protective effect of TSG against 6-hydroxydopamine-induced apoptosis in rat adrenal pheochromocytoma PC12 cells and the possible mechanisms. Our data demonstrated that TSG significantly reversed the 6-hydroxydopamine-induced decrease in cell viability, prevented 6-hydroxydopamine-induced changes in condensed nuclei and decreased the percentage of apoptotic cells in a dose-dependent manner. In addition, TSG slowed the accumulation of intracellular reactive oxygen species and nitric oxide, counteracted the overexpression of inducible nitric oxide syntheses as well as neuronal nitric oxide syntheses, and also reduced the level of protein-bound 3-nitrotyrosine. These results demonstrate that the protective effects of TSG on rat adrenal pheochromocytoma PC12 cells are mediated, at least in part, by the ROS-NO pathway. Our results indicate that TSG may be effective in providing protection against neurodegenerative diseases associated with oxidative stress

The raw data of the paper named "Ventral subiculum promotes wakefulness through several pathways in male mice".

The raw data of the paper named "Ventral subiculum promotes wakefulness through several pathways in male mice".</p