Sulforaphane prevents rat cardiomyocytes from hypoxia/reoxygenation injury in vitro via activating SIRT1 and subsequently inhibiting ER stress.

AIM: Sulforaphane (SFN), a natural dietary isothiocyanate, is found to exert beneficial effects for cardiovascular diseases. This study aimed to investigate the mechanisms underlying the protective effects of SFN in a model of myocardial hypoxia/reoxygenation (H/R) injury in vitro. METHODS: Cultured neonatal rat cardiomyocytes pretreated with SFN were subjected to 3-h hypoxia followed by 3-h reoxygenation. Cell viability and apoptosis were detected. Caspase-3 activity and mitochondrial membrane potential (ΔΨm) was measured. The expression of ER stress-related apoptotic proteins were analyzed with Western blot analyses. Silent information regulator 1 (SIRT1) activity was determined with SIRT1 deacetylase fluorometric assay kit. RESULTS: SFN (0.1-5 µmol/L) dose-dependently improved the viability of cardiomyocytes, diminished apoptotic cells and suppressed caspase-3 activity. Meanwhile, SFN significantly alleviated the damage of ΔΨm and decreased the expression of ER stress-related apoptosis proteins (GRP78, CHOP and caspase-12), elevating the expression of SIRT1 and Bcl-2/Bax ratio in the cardiomyocytes. Co-treatment of the cardiomyocytes with the SIRT1-specific inhibitor Ex-527 (1 µmol/L) blocked the SFN-induced cardioprotective effects. CONCLUSION: SFN prevents cardiomyocytes from H/R injury in vitro most likely via activating SIRT1 pathway and subsequently inhibiting the ER stress-dependent apoptosis.

Hemoglobin A1c and risk of left atrial thrombus and spontaneous echo contrast in non-valvular atrial fibrillation patients.

OBJECTIVES: To evaluate the relationship between hemoglobin A1c (HbA1c) and risk of left atrial thrombus/spontaneous echo contrast (LAT/SEC) in non-valvular atrial fibrillation (AF) patients. METHODS: In this retrospective study, 1158 consecutive non-valvular AF patients undergoing transesophageal echocardiography prior to radiofrequency catheter ablation or electric cardioversion were enrolled. Baseline characteristics were collected and analyzed. RESULTS: There were 87 (7.5%) patients with LAT/SEC. The HbA1c levels in the patients with LAT/SEC were significantly higher than that in patients without LAT/SEC (6.13 ± 0.41 vs. 5.89 ± 0.45 µmol/L, P < 0.001). The optimal cut-off point for HbA1c predicting LAT/SEC was 6.1% determined by receiver-operating characteristic curve. The area under the curve is 0.788 (95% confidence interval: 0.764-0.812). HbA1c ≥6.1% was an independent risk factor for LAT/SEC (odds ratio, 1.74; 95% confidence interval, 1.01-2.98; P = 0.045). CONCLUSIONS: Elevated HbA1c indicated a significantly increased risk for LAT/SEC in non-valvular AF patients. HbA1c might have significance in predicting the risk for prothrombotic state in non-valvular AF patients.

Study on improving the selectivity of compounds that inhibit two PI3Ks (gamma and delta).

A desirable characteristic of PI3K inhibitors is their selectivity. Up to now, there has been no report that describes the 3 D-structure differences between two PI3Ks (delta and gamma) and applies them to designing selective compounds. In the present study, we used an approach combining protein-structure modeling, GRID/PCA (Principal Component Analysis) and docking methods to investigate the detail interactions of the two PI3Ks with various chemical groups. At first, we constructed a 3 D-model of the PI3Kdelta catalytic subunit with the program Modeller7.0 based on the high resolution X-ray structure of the PI3Kgamma catalytic subunit, and then employed GRID and PCA to reveal the most relevant structural and physicochemical differences between the two PI3Ks related to their selectivity. As a result, the analysis unveiled the most important regions on the two PI3Ks that should be taken into account for the design of selective inhibitors. Finally, based on activity data of 10 PI3Kdelta-selective compounds, a docking study validated the results of the GRID/PCA method, which suggested that the approach could provide clear guidelines for selective drug design.