By using a cell-based high throughput screening campaign, a novel angelicin derivative 6a was identified to inhibit influenza A (H1N1) virus induced cytopathic effect in Madin-Darby canine kidney cell culture in low micromolar range. Detailed structure-activity relationship studies of 6a revealed that the angelicin scaffold is essential for activity in pharmacophore B, while meta-substituted phenyl/2-thiophene rings are optimal in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h]chromen-2-one (8g, IC(50) = 70 nM) showed 64-fold enhanced activity compared to the high throughput screening (HTS) hit 6a. Also, 8g was found effective in case of influenza A (H3N2) and influenza B virus strains similar to approved anti-influenza drug zanamivir (4). Preliminary mechanistic studies suggest that these compounds act as anti-influenza agents by inhibiting ribonucleoprotein (RNP) complex associated activity and have the potential to be developed further, which could form the basis for developing additional defense against influenza pandemics.

BACKGROUND-Heart failure increases autonomic nerve activities and changes intracellular calcium (Ca i ) dynamics.

Background. LCZ696 (valsartan/sacubitril) therapy significantly reduced mortality in patients with heart failure (HF). Although a clinical trial (PARADISE-MI Trial) has been ongoing to examine the effects of LCZ696 in myocardial infarction (MI) patients, the effects of LCZ696 on remodeling of cardiac electrophysiology in animal models remain largely unclear. Methods. We performed coronary artery ligation to create MI in Sprague-Dawley rats. Echocardiography was performed one week after MI to confirm the development of HF with left ventricular ejection fraction ≤ 40%. MI rats were randomly assigned to receive medical therapy for 4 weeks: LCZ696, enalapril, or vehicle. The sham-operation rats received sham operation without MI creation. In vivo electrophysiological exams were performed under general anesthesia. Western blot analyses were conducted to quantify ion channel proteins. Results. The HF-vehicle group did not show significant changes in LVEF. Both enalapril and LCZ696 therapy significantly improved LVEF. The HF-vehicle group had higher ventricular arrhythmia (VA) inducibility than the sham group. As compared with the HF-vehicle group, LCZ696 therapy significantly reduced VA inducibility, but enalapril therapy did not. Western blot analyses showed significant downregulation of NaV1.5, ERG, KCNE1, and KCNE2 channel proteins in the HF vehicle group compared with the sham group. LCZ696 therapy upregulated protein expression of ERG, KCNE1, and KCNE2. Conclusion. As compared with enalapril therapy, LCZ696 therapy led to improvement of LVEF, reduced VA inducibility, and upregulated expression of K+ channel proteins.

This study investigates whether indoor environmental quality (IEQ) influences allostatic load (AL) and whether AL can be a predictor for sick building syndrome (SBS). We also assessed and compared the associations between AL and SBS versus 8-hydroxydeoxyguanosine (8-OHdG) and SBS. A total of 115 office workers from 21 offices completed self-reported SBS questionnaires, and provided 11 biomarkers for their AL. Multiple linear regressions and logistic regression analysis were applied to examine the correlations between IEQ and AL or 8-OHdG and between AL or 8-OHdG and SBS, respectively. Our data revealed that the neuroendocrine system was correlated with CO2, the difference between indoor and outdoor CO2 levels (dCO2), and the indoor-outdoor ratio of CO2 (CO2 I/O). Metabolic system effects were associated with illumination. The relationships between illumination, CO2, dCO2, CO2 I/O and 8-OHdG were consistent with those and AL in specific systems. Furthermore, we found that risks for SBS syndromes were related with neuroendocrine and metabolic system of the AL. 8-OHdG was associated with eye dryness or irritation, eye tiredness and vomiting. We conclude that IEQ significantly influences AL and that AL can be a predictor for reporting SBS with information on system-specific effects.