Statin-conferred enhanced cellular resistance against bacterial pore-forming toxins in airway epithelial cells.

Statins are widely used to prevent cardiovascular disease. In addition to their inhibitory effects on cholesterol synthesis, statins have beneficial effects in patients with sepsis and pneumonia, although molecular mechanisms have mostly remained unclear. Using human airway epithelial cells as a proper in vitro model, we show that prior exposure to physiological nanomolar serum concentrations of simvastatin (ranging from 10-1,000 nM) confers significant cellular resistance to the cytotoxicity of pneumolysin, a pore-forming toxin and the main virulence factor of Streptococcus pneumoniae. This protection could be demonstrated with a different statin, pravastatin, or on a different toxin, α-hemolysin. Furthermore, through the use of gene silencing, pharmacological inhibitors, immunofluorescence microscopy, and biochemical and metabolic rescue approaches, we demonstrate that the mechanism of protection conferred by simvastatin at physiological nanomolar concentrations could be different from the canonical mevalonate pathways seen in most other mechanistic studies conducted with statins at micromolar levels. All of these data are integrated into a protein synthesis-dependent, calcium-dependent model showing the interconnected pathways used by statins in airway epithelial cells to elicit an increased resistance to pore-forming toxins. This research fills large gaps in our understanding of how statins may confer host cellular protection against bacterial infections in the context of airway epithelial cells without the confounding effect from the presence of immune cells. In addition, our discovery could be potentially developed into a host-centric strategy for the adjuvant treatment of pore-forming toxin associated bacterial infections.

[Inhibitory effect of resveratrol against enterovirus type 71 in vitro].

OBJECTIVE: To observe the inhibitory effect of resveratrol against the cytopathogenicity of enterovirus type 71. METHODS: The cytotoxicity of resveratrol on Vero cells was detected using cell counting kit-8 (CCK-8). The antiviral activity of resveratrol in different stages of infection, with ribavirin as the control, was evaluated by determining the virus inhibition rate, medium effective concentration (IC(50)), and selection index (SI). RESULTS: Resveratrol was nonpoisonous to Vero cells with an median toxic concentration (TC50) of 307.6 mmol/L. Resveratrol produced an obvious inhibitory effect against enterovirus type 71 only before the cell infection by the virus (IC(50)=20.2 mmol/L , SI=15.2), and once the cells were infected, resveratrol no longer had such antiviral effect. CONCLUSIONS: Resveratrol may offer some protection against enterovirus type 71 in vitro.

[Effect of high dose glucose-insulin-potassium infusion in patients with acute ST-segment elevation myocardial infarction: analysis of 7510 patients in China as part of CREATE-ECLA study].

OBJECTIVE: To investigate the effect of high-dose glucose-insulin-potassium (GIK) infusion on the outcomes of ST-elevation myocardial infarction (STEMI) in China. METHODS: As part of the international multicentre CREATE-ECLA study, 7510 patients with STEMI, aged (62 +/- 12), presenting their symptoms within 12 hours of onset who were hospitalized in 274 centers throughout China from July 2001 through July 2004 were randomized to receive GIK intravenous infusion for 24 hours plus routine treatment (3739) or control group (n=3771) receiving routine treatment alone. The patients were flowed up in the out-patient department 30 days after the randomization to assess the rates of mortality, cardiac arrest, cardiogenic shock and re-infarction. RESULTS: The median time from symptom onset to randomization was 5.8 hours. The mortality of the control group was 10.4%, not significantly different from that of the GIK group (11.2%, hazard ratio = 1.05, 95% CI: 0.916-1.207, P = 0.476). There rates of cardiac arrest, cardiogenic shock, and re-infarction of the GIK group were 0.8%, 6.8%, and 2.0% respectively, all not significantly different from those of the control group (1.0%, 6.4%, and 1.9% respectively, all P > 0.05). At the Day 7 the heart failure rate of the GIK group was 19.7%, not significantly different from that of the control group (18.3%, P = 0.102). The symptomatic hypotension rate of the GIK group was 3.7%, significantly higher than that of the control group (1.2%, P < 0.01). The phlebitis rate of the GIK group was 2.2%, significantly higher than that f the control group (0.1%, P < 0.01). The net increased fluid volume of the control group wasl3 584 ml. more than that of the GIK group (1036 ml). CONCLUSIONS: High dose GIK infusion has neutral effect on mortality, cardiac arrest or cardiogenic shock in patients with acute STEMI in China.

[Efficacy of intravenous Acehytisine Hydrochloride versus propafenone on terminating paroxysmal supraventricular tachycardia: a double-blinded, randomized multi-center study].

OBJECTIVE: In this double-blinded, randomized, parallel study, we investigated the clinical efficacy of intravenous Acehytisine Hydrochloride (AHH) and propafenone on terminating paroxysmal supraventricular tachycardia (PSVT). METHODS: Patients (18 - 70 years old) with either spontaneous or induced sustained supraventricular tachycardia lasted at least 15 min were recruited in this study. Exclusion criteria included sick sinus syndrome, atrial ventricular block or intraventricular block, etc. Eligible patients were randomly assigned to receive intravenously AHH (n=101) or propafenone (n=100) according to a proportion of 1:1 in a double-blinded manner. AHH (4 mg/kg, iv.) or propafenone (PRO, 1 mg/kg, iv.) was administered in 5 min followed by the same dose if no response was observed. Conversion times, vital signs, electrocardiograms were documented before and after drug administration. RESULTS: Except for age, the demographic characteristics and clinical features were comparable between the two groups. Efficacy on PSVT termination was comparable between AHH (72/101, 71.3%) and PRO group (73/100, 73.0%, P=0.6368). The average time from drug administration to conversion was also similar [AHH: (9.62 +/- 8.39) min vs. PRO: (10.61 +/- 9.47) min, P=0.5035]. In the AHH group, 59/72 episodes of PSVT were terminated by the first dose, and 66/72 were terminated prematurely. The average AHH dose in the 72 converted patients was (273.7 +/- 111.2) mg. In the PRO group, 54/73 episodes of PSVT were terminated by the first dose. The electrocardiographic parameters, such as sinus recovery time, longest PP and RR interval, PR interval, QRS interval, QT interval after conversion were similar between the two groups. Transient adverse events were reported in 11/101 (10.9%) patients in the AHH group and in 18/100 (18.0%,) in the PRO group (P=0.1653). CONCLUSION: With the dosage used in the present study, the efficacy on terminating PSVT was comparable between AHH and PRO.

[Electrophysiological effects of acehytisine hydrochloride in a porcine model of acute coronary occlusion].

OBJECTIVE: To observe the electrophysiological effect of Acehytisine Hydrochloride (AHH) in Wu Zhi Shan (WZS) micropigs with experimental acute coronary occlusion. METHODS: Adult WZS micropigs were randomized into group A: coronary ligation with AHH infusion (n = 9); group B: AHH infusion without coronary ligation (n = 9) and group C: coronary ligation with saline (NS) infusion (n = 9). Surface ECGs and cardiac electrophysiological data including atrium, atrium-ventricle junction and ventricle electrograms were collected by programmed electrical stimulation at ischemic baseline and after AHH (or NS) infusion. RESULTS: Compared to animals treated with AHH without ischemia, VARC-ERP was significantly increased while QT, QTc intervals, VRRP and VFRP were significantly reduced in ischemic animals treated with AHH. Compared to ischemic animals treated with saline, AHH prolongs the P-wave duration and PR interval, shortens QTc interval, prolongs ARP and AEP, also prolongs V-A reverse conduction time and VARC-ERP but shortens VFRP. No proarrhythmia effect was found in both AHH treated groups. CONCLUSION: AHH resulted in significant electrophysiological effects on this porcine acute coronary ischemic model.

[Effects of Panax notoginseng saponins on rat cardiomyocytes apoptosis induced by angiotengin II in vitro].

OBJECTIVE: To study the protective effects of Panax notoginseng saponins (PNS) on angiotensin II (Ang II)-induced rat cardiomyocyte apoptosis in vitro and the probable mechanism. METHOD: Cultured cardiomyocytes from neonatal rats were stimulated with Ang II. Cell viability was measured by MTT. Apoptosis was evaluated using Acridine Orange (AO) fluorescent dye staining and flow cytometry; Fluo-3 AM was used to test the change of intracellular free calcium. RESULT: It was found that incubating with Ang II (10(-7) mol x L(-1)) for 48 h increased cardiomyocyte apoptosis, PNS (25, 100 mg x mL(-1)) increased myocyte viability. PNS (50 mg x mL(-1)) significantly decreased this Ang II-induced rat cardiomyocyte apoptosis (P < 0.05) and decreased fluorescent intensity of intracellular calcium. CONCLUSION: PNS has a significant effect on Ang II-induced rat cardiomyocytes apoptosis in vitro by alleviating intracellular calcium overload.