Pharmacometabolomic study of drug response to antihypertensive medications for hypertension marker identification in Han Chinese individuals in Taiwan.

Various groups of antihypertensive drugs targeting different pathways have been developed; however, the pharmacometabolic responses to these drugs have rarely been compared to elucidate the common pathway of blood pressure regulation. Here, we performed a comparative multi-dimensional pharmacometabolic study on the four major lines of antihypertensive drugs, namely angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and diuretics (DIURs), through ultra-performance liquid chromatography coupled to quantum time-of-flight mass spectrometry. Two hundred fifty patients with young-onset hypertension, who were equally divided among five study groups: non-medicated, ACEi, ARB, CCB, and DIUR groups, were recruited. In a metabolome-wide association study conducted through analysis of covariance, 37 molecular features significantly associated with pharmacometabolic responses to antihypertensive drugs were identified. One-third of these features were shared by multiple medications. ACEis, ARBs, and DIURs shared more features than CCB, partially reflecting that ACEis, ARBs, and DIURs affect the renin-angiotensin-aldosterone system. Thirteen molecular features were consistently identified by all four models of the analysis of covariance. A tandem mass spectrometry (or MS/MS) experiment was performed to decipher the chemical structure of these 13 molecular features, including ARB-associated lysophosphatidylcholine (P4135), CCB-associated diacylglycerol(15:0/18:2) (P1175), and DIUR-associated oleamide (P1516). In addition, diacylglycerol(15:0/14:2) (P408) was significantly associated with the pharmacometabolic response to all four antihypertensive drugs. The identified metabolites provide insights into the mechanisms of blood pressure regulation and potential predictive markers of pharmacometabolic responses to antihypertensive drugs.

Mesenchymal Stromal Cells from Patients with Cyanotic Congenital Heart Disease are Optimal Candidate for Cardiac Tissue Engineering.

Engineered heart tissues (EHTs) are regarded as being the most promising alternative to synthetic materials, and autologous mesenchymal stem cells (MSCs) are widely used as seeding cells. However, few studies have evaluated the feasibility of using MSCs from patients with cyanotic congenital heart disease (C-CHD) as seeding cells for EHTs, in comparison with cells from patients of acyanotic congenital heart disease (A-CHD). In the present study, we cultured MSCs from A-CHD and C-CHD patients in normoxia or hypoxia conditions, and compared their pro-angiogenic, anti-apoptotic and inflammation-modulatory potentials. In vivo, we seeded the cells into collagen patches conjugated with, or without, proangiogenic cytokines, which were used to repair the right ventricular outflow tract (RVOT) of rats. The in vitro results showed that C-CHD MSCs expressed higher levels of VEGFA and VEGFR2, and secreted more pro-angiogenic and anti-inflammatory cytokines under hypoxic conditions. On the other hand, apoptosis-related genes from C-CHD MSCs were modulated adaptably, converting these cells into an anti-apoptotic phenotype. In vivo studies demonstrated that in 4 weeks after RVOT reconstruction, cytokine-immobilized patches seeded with C-CHD MSCs exhibited preserved morphology, prolonged cell survival and enhanced angiogenesis compared to A-CHD MSCs. C-CHD MSCs that undergo "naturally hypoxic precondition" present a better cell source for EHTs, which would provide a promising individualized biomaterial for C-CHD patients.

Cognitive impairment and limited dietary diversity or physical inactivity are conjoint precursors of incident diabetes more so in elderly women than men.

OBJECTIVES: To establish whether elderly people with impaired cognition are at greater risk for the de-velopment of type 2 diabetes. DESIGN: Prospective population-based cohort study. SETTING: The El-derly Nutrition and Health Survey in Taiwan (NAHSIT Elderly). PARTICIPANTS: One thousand and four hundred ninety-three diabetes-free people >=65 years were followed for incident diabetes in relation to cognitive status for up to 8 years. MEASUREMENTS: The association between cognitive impairment and diabetes incidence was analyzed with Cox proportional hazards models with exclusion of people who had diabetes within one year of cognitive function assessments. RESULTS: Cognitively-impaired women, but not men, had increased diabetes incidence density (DID). Age, gender, ethnicity and personal behavior adjusted hazard ratios (HR) and 95% confidence intervals (CI) for type 2 diabetes with normal cognition as referent were 2.43 (95% CI: 1.27-4.63) for women and 1.55 (95% CI: 0.48-5.07) for men. These gender differences and the HR significances remained with adjustments for age, ethnicity, financial status, dietary quality as a dietary diversity score, physical function, physical activity, fasting glucose, indices of body composition, body mass index, waist circumference, mid-arm muscle circumference, perceived and mental health status. There were extensive significant interactions with the covariates in women. CONCLUSION: Cognitive impairment in later life is associated with greater risk of type 2 diabetes in women and considerable potential risk enhancement.

Low and high homocysteine are associated with mortality independent of B group vitamins but interactive with cognitive status in a free-living elderly cohort.

Hyperhomocysteinemia and cognitive impairment both predict mortality and partly because of dietary associations. We have hypothesized that for, nutritional reasons, homocysteine and cognition may act jointly to determine elder survival. In a Nutrition and Health Survey in Taiwan (1999-2000), some 1412 representative elderly were followed up for mortality up to 10 years. Cognition was assessed by the Short Portable Mental Status Questionnaire. Food and B vitamin intakes with their biomarkers, and plasma homocysteine, were measured at baseline. The possible effects of cognition on homocysteine-associated mortality were ascertained with Cox proportional-hazards models. Homocysteine was higher in those who were older, male, and single, consumed less fish and tea, and with alcohol and smoking. In models adjusted for these variables, when homocysteine exceeded 14.5 µmol/L, mortality was 1.80-fold more than when <9.3 µmol/L (hazard ratio [HR], 1.80; 95% confidence interval [95% CI], 1.20-2.71). P for trend was 0.002 and interactive with sex (P < .002). However, these homocysteine-mortality associations were dependent on cognition (P = .03); adjustment for food intake or nutrient status made little difference. Homocysteine did not predict cognitive impairment (adjusted OR, 1.40; 95% CI = 0.50-3.93). Vitamins B(1), B(2), and B(6) accounted somewhat for cognitive impairment. Cognition predicted mortality, fully adjusted for available covariates and also for homocysteine (HR, 3.66; 95% CI, 1.64-8.20) but interactively with homocysteine. Thus, the B-group vitamin insufficiency and cognitive impairment associations with premature mortality are confirmed. Yet cognition is inter-related with homocysteine in its association with survival in ways not detectably altered by foods or food-derived vitamins.

Cloning, heterologous expression, and functional characterization of a chitinase gene, Lbchi32, from Limonium bicolor.

In the present study, an endochitinase gene, Lbchi32, was cloned from Limonium bicolor. The cDNA sequence of Lbchi32 was 1,443 bp in length and encoded 319 amino acid residues. The DNA sequence of Lbchi32 was 2,512 bp in length and contained three exons and two introns. The Lbchi32 gene was inserted into a pPIC9 vector and transferred into Pichia pastoris strains GS115 and KM71 for heterologous expression. SDS-PAGE analyses indicated that LbCHI32 was expressed in both GS115 and KM71 and that it was secreted extracellularly. The optimal reaction conditions for LbCHI32 activity are 45 degrees C, pH 5.0, and 5 mM Ba(2+). The LbCHI32 enzyme can efficiently degrade chitin, chitin derivatives, and the cell walls of different pathogenic fungi, including phytopathogenic Rhizoctonia solani, Fusarium oxysporum, Sclerotinia sclerotiorum, Valsa sordida, Septoria tritici, and Phytophthora sojae. These findings suggest that Lbchi32 has potential use in the degradation of chitin and chitin derivatives.