Identification of DAPK1 Promoter Hypermethylation as a Biomarker for Intra-Epithelial Lesion and Cervical Cancer: A Meta-Analysis of Published Studies, TCGA, and GEO Datasets.

Background: Promoter hypermethylation in death-associated protein kinase 1 (DAPK1) gene has been long linked to cervical neoplasia, but the established results remained controversial. Here, we performed a meta-analysis to assess the associations of DAPK1 promoter hypermethylation with low-grade intra-epithelial lesion (HSIL), high-grade intra-epithelial lesion (HSIL), cervical cancer (CC), and clinicopathological features of CC. Methods: Published studies with qualitative methylation data were initially searched from PubMed, Web of Science, EMBASE, and China National Knowledge Infrastructure databases (up to March 2018). Then, quantitative methylation datasets, retrieved from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, were pooled to validate the results of published studies. Results: In a meta-analysis of 37 published studies, DAPK1 promoter hypermethylation progressively increased the risk of LSIL by 2.41-fold (P = 0.012), HSIL by 7.62-fold (P < 0.001), and CC by 23.17-fold (P < 0.001). Summary receiver operating characteristic curves suggested a potential diagnostic value of DAPK1 promoter hypermethylation in CC, with a large area-under-the-curve of 0.83, a high specificity of 97%, and a moderate sensitivity of 59%. There were significant impacts of DAPK1 promoter hypermethylation on histological type (odds ratio (OR) = 3.53, P < 0.001) and FIGO stage of CC (OR = 2.15, P = 0.003). Then, a pooled analysis of nine TCGA and GEO datasets, covering 13 CPG sites within DAPK1 promoter, identified eight CC-associated sites, six sites with diagnostic values for CC (pooled specificities: 74-90%; pooled sensitivities: 70-81%), nine loci associated with the histological type of CC, and all 13 loci with down-regulated effects on DAPK1 mRNA expression. Conclusion: The meta-analysis suggests that DAPK1 promoter hypermethylation is significantly associated with the disease severity of cervical neoplasia. DAPK1 methylation detection exhibits a promising ability to discriminate CC from cancer-free controls.

PARP-1 Variant Rs1136410 Confers Protection against Coronary Artery Disease in a Chinese Han Population: A Two-Stage Case-Control Study Involving 5643 Subjects.

Inhibition of poly(ADP-ribose) polymerase (PARP) may protect against coronary artery disease (CAD) in animal models, and rs1136410, a non-synonymous single nucleotide polymorphism (SNP) in PARP-1, has a potential impact on PARP activities in vitro. This two-stage case-control study, involving 2803 CAD patients and 2840 controls, aimed to investigate the associations of PARP-1 rs1136410 with CAD development, lipid levels, PARP activities, 8-hydroxy-2'-dexyguanosine (8-OHdG), and interleukin (IL)-6 levels in a Chinese Han population. Assuming a recessive model, the variant genotype GG of SNP rs1136410 showed a significantly inverse association with CAD risk (adjusted odds ratio (OR) = 0.73, P < 0.001), left main coronary artery (LMCA) lesions (P = 0.003), vessel scores (P = 0.003), and modified Gensini scores (P < 0.001). There were significant correlations of SNP rs1136410 with higher levels of total cholesterol (TC) and lower levels of high-density lipoprotein cholesterol (HDL-c). In gene-environment interaction analyses, participants with the variant genotype GG, but without smoking habit, type 2 diabetes mellitus, and hyperlipidemia, conferred an 84% (P < 0.001) decreased risk of CAD. The genotype-phenotype correlation analyses further supported the functional roles of SNP rs1136410 in decreasing PARP activities and 8-OHdG levels. Taken together, our data suggest that SNP rs1136410 may confer protection against CAD through modulation of PARP activities and gene-environment interactions in a Chinese Han population.

Pharmacokinetic mechanism of enhancement by Radix Pueraria flavonoids on the hyperglycemic effects of Cortex Mori extract in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes mellitus, characterized by abnormal blood glucose evaluation, is a serious chronic disease. In the treatment of the disease, α-glycosidase inhibitors play an important role for controlling the postprandial blood glucose level. Cortex Mori, a traditional Chinese herbal medicine, has a long history of use for the treatment of headaches, cough, edema and diabetes. Modern pharmacological studies have shown that the herb has beneficial effects on the suppression of postprandial blood glucose levels by inhibiting α-glycosidase activity in the small intestine. 1-Deoxynojirimycin (DNJ), the main active ingredient of this herb, is recognized as a potent α-glycosidase inhibitor. Our previous studies have shown that the hypoglycemic effect of Cortex Mori extract (CME) was significantly improved when giving CME in combination with Radix Pueraria flavonoids (RPF). In the present study, the pharmacokinetics and intestinal permeability of DNJ were comparatively investigated in rats after being given orally or by intestinal perfusion with CME alone or in CME-RPF pairs, to explore the mechanism of this synergistic effect. MATERIALS AND METHODS: The role of RPF on the plasma and urine concentrations of DNJ from CME orally administered was investigated. Four groups of rats received a single oral dose of either CME or CME-RPF, at DNJ equivalent doses of 20 and 40mg/kg, respectively. After dosing, plasma and urine were collected and assayed by LC/MS/MS. In addition, another two groups of rats were used for small intestinal perfusion with CME or CME-RPF at DNJ concentration of 10µM. RESULTS: Compared to the data when dosing with CME alone, the Cmax of DNJ were decreased from 5.78 to 2.94µg/ml (p<0.05) and 10.66 to 5.35µg/ml (p<0.01); Tmax were delayed from 0.40 to 0.55h and 0.35 to 0.50h (p<0.05); and MRT were significantly prolonged from 1.14 to 1.72h (p<0.05) and 0.95 to 1.62h (p<0.01), after dosing with CME-RPF at DNJ doses of 20 and 40mg/kg, respectively. In addition, the urinary recovery of DNJ over the first 4h after dosing significantly decreased from 48.76% to 33.86%. Effective permeability (Peff) of DNJ was decreased from 7.53×10(-3) to 3.09×10(-3)cm/s (p<0.05) when RPF was added to CME, when it was evaluated using the rat intestinal perfusion model. CONCLUSIONS: All the above results demonstrate that RPF was able to suspend and delay the absorption of DNJ, but did not affect the total amount of DNJ in the body. The resulting higher concentration of DNJ in the small intestine produced a relatively stronger effect of depressing the elevation of the postprandial blood glucose level. These findings support the important role of RPF in the application of CME on blood glucose control.

[Latent structure model evaluation of syndrome elements and features in 826 hypertriglyceridemia patients].

OBJECTIVE: To evaluate main Chinese medical syndrome elements and features of hypertriglyceridemia patients. METHODS: Using latent structure model (LSM) method, the latent structure diagram of 826 hypertriglyceridemia patients were established. Hypertriglyceridemia syndrome elements and features were interpreted by using latent probability, conditional probability, mutual information, and cumulative information coverage to quantify symptoms/syndromes data,as well as using manual interpretation methods. RESULTS: The accumulative information coverage rate reaching 95% was taken as the judgment standard for major syndrome elements. In the 826 hypertriglyceridemia patients, moderate and severe symptoms/syndromes (with the latent probability being 35% and 60% respectively) were dominant. The syndrome elements mainly included qi deficiency, qi stagnation,fire heat, stasis blood, yin deficiency, and yang deficiency. The main targets were dominated in Xin, Gan, and Shen. CONCLUSION: LSM based syndrome element evaluation method could quantify the association degree of each variable (syndrome element; Chinese medical symptoms) and the occurrence probability.

A new monacolin analogue from Xuezhikang capsule.

Xuezhikang capsule (ethanol extract of red yeast rice) which produced by Beijing WBL Peking University Biotech Co., Ltd., is a traditional Chinese medication with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibiting activity. Clinical trials indicated that Xuezhikang with lipid-lowering action could reduce the risk of cardiac events and total mortality of Chinese coronary heart disease patients. To exactly explain the clinical features of Xuezhikang, we undertook a complete study of the chemical constituents of Xuezhikang. This study resulted in the isolation of a new monacolin analogue, named alpha, beta-dehydromonacolin L (1), along with two known compounds: monacolin L (2) and 3-(2, 6-dimethyl-1, 2, 4a, 5, 6, 7, 8, 8a-octahydronaphthalen-1-yl)propanoic acid (3). The chemical structures were determined by extensive 1D and 2D NMR and MS spectroscopic analysis.

[A new isoflavone from Huoxue Yiqi Tang].

OBJECTIVE: To study the chemical constituents in the active parts of Huoxue Yiqi Tang. METHOD: The silica gel, Sephadex LH-20 were used to isolate the compounds, El, FAB-MS and 1D, 2D-NMR were used to identify the obtained compounds. RESULT: 14 compounds were obtained from the prescription. CONCLUSION: They were all first time obtained from the prescription. Among them, 7, 3'-dihydroxyl-5'-methoxyisoflavone is new.