Genetically predicted phosphate and cardiovascular disease: A Mendelian randomization study.

Background: Extensive epidemiological studies have highlighted the correlation between serum phosphate and cardiovascular diseases. The present study aims to determine whether genetically predicted serum phosphate is causally associated with the distinct subtypes of cardiovascular events through the use of Mendelian randomization (MR) analysis. Methods: Independent and strongly correlated single-nucleotide polymorphisms (SNPs) for serum phosphate were extracted from publicly available genome-wide association studies. Summary statistics of cardiovascular diseases were derived from large-scale consortiums, including HERMES and FinnGen biobank. MR-Egger, weighted median, inverse variance weighted, pleiotropy residual sum and outlier (MR-PRESSO) methods and MR using robust adjusted profile score (MR-RAPS) were employed to analyze causality. The sensitivity analyses comprised heterogeneity, horizontal pleiotropy, and leave-one-out approaches; these were used to ensure the stability of the results. Results: Our study demonstrated that increased genetically predicted serum phosphate is causally associated with a higher risk of valvular heart disease (VHD) [For VHD including rheumatic fever: odds ratio (OR) = 2.45; 95% confidence interval (CI), 1.52-3.94; p = 0.0002; for non-rheumatic VHD: OR = 6.58; 95% CI, 2.50-17.32; p = 0.0001]. However, no causal association was detected between serum phosphate and other common cardiovascular diseases (including coronary heart disease, heart failure, atrial fibrillation, and essential hypertension). Conclusions: The results indicate strong causality between serum phosphate and valvular heart disease. Serum phosphate-lowering therapy within the physiological range may represent a novel therapeutic method for valvular heart disease.

Causal associations between gut microbiome and cardiovascular disease: A Mendelian randomization study.

Background: Observational studies have shown gut microbiomes were associated with cardiovascular diseases (CVDs), but their roles remain controversial, and these associations have not yet been established causally. Methods: Two-sample Mendelian randomization (MR) was used to investigate whether gut microbiome had a causal effect on the risk of CVDs. To obtain comprehensive results, we performed two sets of MR analyses, one with single nucleotide polymorphisms (SNPs) that smaller than the genome-wide statistical significance threshold (5 × 10-8) as instrumental variables, and the other with SNPs that lower than the locus-wide significance level (1 × 10-5). Summary-level statistics for CVDs, including coronary artery disease (CAD), myocardial infarction, heart failure, atrial fibrillation, stroke and its subtypes were collected. The ME estimation was performed using the inverse-variance weighted and Wald ratio methods. Sensitivity analysis was performed using the weighted median, MR-Egger, leave-one-out analysis, MR pleiotropy residual sum and outlier and MR Steiger. Results: Based on the locus-wide significance level, genetically predicted genus Oxalobacter was positively associated with the risk of CAD (odds ratio (OR) = 1.06, 95% confidence interval (CI), 1.03 - 1.10, P = 1.67 × 10-4), family Clostridiaceae_1 was negatively correlated with stroke risk (OR = 0.83,95% CI, 0.75-0.93, P = 7.76 × 10-4) and ischemic stroke risk (OR = 0.823,95% CI, 0.74-0.92, P = 4.15 × 10-4). There was no causal relationship between other genetically predicted gut microbiome components and CVDs risk. Based on the genome-wide statistical significance threshold, the results showed that the gut microbiome had no causal relationship with CVDs risk. Conclusion: Our findings reveal that there are beneficial or adverse causal effects of gut microbiome components on CVDs risk and provide novel insights into strategies for the prevention and management of CVDs through the gut microbiome.

Effects of GM-CSF, IL-3, and GM-CSF/IL-3 fusion protein on apoptosis of human myeloid leukemic cell line Tf-1 induced by irradiation.

AIM: To observe the effects of three cytokines on the apoptosis of Tf-1 cells induced by gamma irradiation and investigate the relationship between apoptosis and caspase-3 activity. METHODS: Different cytokines GM-CSF, IL-3 and GM-CS/IL-3 fusion protein were added into the irradiated Tf-1 cells. MTT assay, morphology, flow cytometry, and DNA fragmentation assay were used to observe the effects of cytokines on apoptosis. The caspase-3 activity was determined with a fluorocytometer. RESULTS: Irradiated Tf-1 cells showed typical morphological characteristic of apoptosis demonstrated by transmission electron microscopy and were accumulated in G0/G1 phase. In the groups treated with growth factors after irradiation, three cytokines significantly increased the viability rate, distinctly decreased the apoptosis rate and the proportion of DNA fragmentation. When Tf-1 cells were irradiated by gamma irradiation, caspase-3 activity was increased at different time points. In comparison with the control group in which no growth factor was added after the cells were irradiated, the caspase-3 activity of irradiated Tf-1 cells was significantly inhibited by addition of the above cytokines. Thirty-six hours after irradiation, in the control group, GM-CSF, IL-3, GM-CSF and IL-3 in combination, and two GM-CSF/IL-3 fusion protein groups, the apoptosis rate was 73 %, 11 %, 15 %, 13 %, 12 %, and 13 %. The percent of fragmented DNA was 36 %, 19 %, 18 %, 14 %, 13 %, and 14 %. The fluorescence intensity was 16923, 5529, 6581, 5322, 5426, and 5485. CONCLUSION: GM-CSF, IL-3, and GM-CSF/IL-3 fusion protein could protect Tf-1 cells from apoptosis induced by gamma irradiation. After Tf-1 cells were irradiated, the caspase-3 activity was significantly increased but was dramatically decreased by the above cytokines. The remarkable inhibition of caspase-3 activity may be one of the mechanisms of these hematopoietic growth factors exerting their anti-apoptotic effects.

Effects of propofol, midazolam and thiopental sodium on outcome and amino acids accumulation in focal cerebral ischemia-reperfusion in rats.

OBJECTIVE: To investigate the effects of propofol, midazolam and thiopental sodium on outcomes and amino acid accumulation in focal cerebral ischemia-reperfusion in rats. METHODS: Male Sprague Dawley (SD) rats were scheduled to undergo 3-hour middle cerebral artery occlusion by intraluminal suture and 24-hour reperfusion. Neurologic outcomes were scored on a 0-5 grading scale. Infarct volume was shown with triphenyltetrazolium chloride staining and measured by an image analysis system. Concentrations of various amino acids (aspartate, glutamate, glycine, taurine, and gama-aminobutyric acid) were measured after 3 hours of reperfusion using high performance liquid chromatography. Propofol, midazolam and thiopental sodium were given intraperitoneally at the beginning of reperfusion. RESULTS: Both propofol and midazolam attenuated neurological deficits and reduced infarct and edema volumes. Propofol showed better neurological protection than midazolam while thiopental sodium did not exhibit any protective effect. Both propofol and midazolam decreased excitatory amino acids accumulation, while propofol increased gama-aminobutyric acid accumulation in ischemic areas in reperfusion. CONCLUSION: Propofol and midazolam, but not thiopental sodium, may provide protective effects against reperfusion induced injury in rats subjected to focal cerebral ischemia. This neurological protection may be due to the acceleration of excitatory amino acids elimination in reperfusion.