The scorpion toxin BeKm-1 blocks hERG cardiac potassium channels using an indispensable arginine residue.

BeKm-1 is a peptide toxin from scorpion venom that blocks the pore of the potassium channel hERG (Kv11.1) in the human heart. Although individual protein structures have been resolved, the structure of the complex between hERG and BeKm-1 is unknown. Here, we used molecular dynamics and ensemble docking, guided by previous double-mutant cycle analysis data, to obtain an in silico model of the hERG-BeKm-1 complex. Adding to the previous mutagenesis study of BeKm-1, our model uncovers the key role of residue Arg20, which forms three interactions (a salt bridge and hydrogen bonds) with the channel vestibule simultaneously. Replacement of this residue even by lysine weakens the interactions significantly. In accordance, the recombinantly produced BeKm-1R20K mutant exhibited dramatically decreased activity on hERG. Our model may be useful for future drug design attempts.

Loading of the Model Amino Acid Leucine in UiO-66 and UiO-66-NH2: Optimization of Metal-Organic Framework Carriers and Evaluation of Host-Guest Interactions.

Two metal-organic frameworks (MOFs), UiO-66 and UiO-66-NH2, were considered as containers for bioactive chemicals. We provide a synthesis technique, which allowed the production of these materials suitable for biomedical applications. Both MOFs were characterized as single-phase porous materials composed of nanoparticles (30-65 nm) with a ζ-potential of more than 40 mV in water suspension. D,L-Leucine was applied as a model molecule, which allowed us to trace the mechanism of the loading process. We showed that after synthesis, amino groups of UiO-66-NH2 are coordinated with solvent residuals. It results in a similar route of leucine loading in UiO-66 and UiO-66-NH2 samples. Using joint data of thermogravimetric analysis and calorimetry, infrared spectroscopy, and nitrogen adsorption, we revealed that methyl groups of leucine molecules are responsible for bonding of an MOF matrix. We proposed the formation of bonds between CH3 groups and benzene rings of linkers via CH-π interaction. We also assessed the toxicity of the synthesized MOFs toward HeLa cells at 50 µg/mL after 24 h incubation and revealed no negative effects on the viability of the cells, prompting further biomedical research in the areas of small-molecule delivery and cell signaling and metabolism modulation.

Timing of invasive strategy in diabetic and non-diabetic patients with non-ST-segment elevation acute coronary syndrome.

INTRODUCTION: Patients with acute coronary syndrome without ST segment elevation are a heterogeneous group with respect to the risk of having a major adverse cardiac event (MACE). A history of diabetes mellitus (DM) is no doubt one of the factors that define a patient as being at a higher risk of having the syndrome. AIM: To compare early invasive strategy with selective invasive strategy indicated for patients with and without DM. PATIENTS AND METHODS: The study enrolled 178 patients with unstable angina or non-ST elevation myocardial infarction (UA/NSTEMI), and of these 52 (29.2%) had DM. Patients were randomly assigned to an early invasive strategy (these were scheduled to undergo coronary arteriography and percutaneous coronary intervention within 24 hours after admission) or to a selective invasive strategy (at first these were medically stabilized, with coronary arteriography required only in case of angina recurrence and/or evidence of inducible myocardial ischemia). The patients were followed up for a mean period of 22.8 +/- 14 months. RESULTS: In the follow up the diabetics allocated to an early invasive strategy were found to have a significantly lower angina recurrence incidence (p = 0.005), rehospitalization rate (p = 0.001), fewer arteriographies (p = 0.001) and coronary interventions (p = 0.001) and low cumulative incidence of MACE (p = 0.008) in comparison with the diabetics assigned to selective invasive strategy. We also found, using the Kaplan-Meier curves survival analysis, that the time to MACE in patients assigned to an early invasive strategy was significantly longer than that in the group of selective invasive strategy. In the follow-up of non-diabetics we found no significant difference in MACE rate between the patients allocated to early invasive strategy and those assigned to selective invasive strategy. In the selective invasive strategy group, however, the cardiovascular adverse events tended to occur earlier than in the early invasive strategy group. CONCLUSIONS: Early invasive strategy in diabetic patients with non-ST-segment elevation acute coronary syndrome is associated with a reduced MACE rate compared with the selective invasive strategy used in these patients. Early invasive strategy applied in diabetic patients is also associated with a significantly longer time to MACE. In non-diabetics the advantages of early over selective invasive strategy are not so clearly differentiated.

Effects of statins on endothelial function in patients with coronary artery disease.

BACKGROUND: Flow-mediated dilatation (FMD) of the brachial artery is a method capable of detecting endothelium dysfunction. Statins are generally consent drugs for reducing cardiovascular morbidity and mortality and are shown to improve the systemic endothelial function. HYPOTHESIS: The aim of our study was to assess the endothelial function using FMD of the brachial artery in patients with different degrees of coronary artery stenosis with respect to their treatment with statins. METHODS: We evaluated the FMD of 221 patients with coronary arteriography performed, of whom 99 (44.8%) were receiving statins and 122 (55.2%) were not receiving statins. RESULTS: We did not find a statistically significant difference in the FMD values between the patients with and without a statin treatment: 5.57 +/- 5.68 and 4.69 +/- 4.48, respectively, P = .581. In the subgroup of patients without angiographically visible coronary artery stenoses or with stenoses <20% (86 patients), patients undergoing statin treatment had a significantly better endothelial function compared to patients without such a treatment: FMD 9.24 +/- 6.87 and 6.50 +/- 4.51, respectively, P = .047. CONCLUSIONS: FMD could not distinguish between the patients who were treated with statin and those not treated with statins with the same demographic, clinical, and angiographic characteristics. The only exception was in the group of patients with a minor coronary disease. Statin treatment had a more pronounced effect in the earlier stages of coronary atherosclerosis.

Endothelial function in patients with and without diabetes mellitus with different degrees of coronary artery stenosis.

PURPOSE: To evaluate endothelial function using flow-mediated dilatation (FMD) of the brachial artery in patients with and without diabetes mellitus (DM) with different degrees of coronary artery stenosis. METHOD: We investigated 293 patients, 69 (23.6%) of whom had DM. FMD and coronary arteriography were performed. RESULTS: Patients with DM had a significantly lower FMD (mean +/- SD, 3.7 +/- 3.8%) compared with patients without DM (mean +/- SD, 5.2 +/- 5.3%) (p < 0.05). When the results were broken down by the severity of coronary artery disease (CAD) (no significant coronary artery stenosis, 1-vessel disease, 2-vessel disease, and 3-vessel disease) the only statistically significant difference between diabetics and nondiabetics was found in patients without significant coronary stenosis (mean FMD +/- SD: 5.2 +/- 4.4% in diabetics, 7.6 +/- 5.4% in nondiabetics [p < 0.05]). CONCLUSION: In CAD patients, the presence of DM was associated with endothelial dysfunction. The difference in the FMD was clearly expressed between patients with and without DM in the subgroup without significant coronary stenosis, and was no longer present with advanced coronary atherosclerosis.

Evaluation of the SCHILLER BR-102 plus noninvasive ambulatory blood pressure monitor according to the International Protocol introduced by the Working Group on Blood Pressure Monitoring of the European Society of Hypertension.

OBJECTIVE: To evaluate the SCHILLER BR-102 plus (Schiller AG, Baar, Switzerland) noninvasive ambulatory blood pressure recorder according to the International Protocol for validation of blood pressure measuring devices in adults introduced by the Working Group on Blood Pressure Monitoring of the European Society of Hypertension. METHOD: One SCHILLER BR-102 plus blood pressure recorder was tested by a validation team, consisting of three persons: two observers (nurses) and a doctor, acting as supervisor and 'expert'. The European Society of Hypertension International Protocol comprises two phases. Fifteen participants were recruited for the first phase and, following a successful test, a further 18 persons (giving a total of 33) were recruited additionally. For phase 1, five of the 15 participants had systolic blood pressure and diastolic blood pressure in each of the ranges: low, medium and high. For phase 2, 11 of the 33 participants (including the first 15 participants) had systolic blood pressure and diastolic blood pressure in each of the ranges. The mercury standard for validation was preferred over the optional Sphygmocorder. Because the SCHILLER BR-102 plus has the oscillometric method as backup to the basic auscultatory measurement, both systems of measurement were subjected to individual validations. RESULTS: Results obtained show that the SCHILLER BR-102 plus noninvasive ambulatory blood pressure recorder meets all the requirements specified in the International Protocol for both oscillometric and auscultatory methods. CONCLUSION: On the basis of these results, the SCHILLER BR-102 plus can be recommended for ambulatory blood pressure measurement in clinical practice using both auscultatory and oscillometric modes.