The neutralization effect of montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies

Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the enzyme (main protease) inhibition-based assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T/hACE2+TMPRSS2, and virus neutralization assay using xCELLigence MP real-time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of montelukast both on the main protease enzyme inhibition and virus entry into the host cell (spike/ACE2). The virus neutralization assay results showed that SARS-CoV-2 virus activity was delayed with montelukast for 20 h on the infected cells. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and, if its effect is proved in clinical phase studies, it should be used against coronavirus disease 2019 (COVID-19).     

The role of baseline and post‐procedural frontal plane QRS‐T angles for cardiac risk assessment in patients with acute STEMI

Background

To our knowledge, no study so far investigated the importance of post‐procedural frontal QRS‐T angle f(QRS‐T) in ST segment elevation myocardial infarction (STEMI). The aim of our study was to investigate the role of baseline and post‐procedural f(QRS‐T) angles for determining high risk STEMI patients, and the success of reperfusion.

Methods

A total of 248 patients with first acute STEMI that underwent primary percutaneous coronary intervention (pPCI) or thrombolytic therapy (TT) between 2013 and 2014 were included in this study. Baseline f(QRS‐T) angle was defined as the angle which measured from the first ECG at the time of hospital admission. Post‐procedural (QRS‐T) angle was defined according to the treatment strategy as follows: the angle which measured from the post‐PCI ECG in patients treated with pPCI; the angle which measured from the ECG taken 90 min after onset of therapy in patients treated with TT.

Results

The baseline (101.9° ± 48.0 vs. 72.1° ± 49.1, p = 0.014) and post‐procedural f(QRS‐T) angles (95.7° ± 48.1 vs. 58.1° ± 47.1, p = 0.002) were significantly higher in patients who developed in‐hospital mortality than the patients who did not develop in‐hospital mortality. Also, f(QRS‐T) angle measured at 90 min was significantly lower in patients with successful thrombolysis group compared to failed thrombolysis group (53.2° ± 42.8 vs. 77.3° ± 52.9, p = 0.033), whereas baseline f(QRS‐T) angle was similar between two groups (78.6° ± 53.4 vs. 78.9° ± 54.0, p = 0.976). Multivariate analysis showed that post‐procedural f(QRS‐T) angle ≥89.6° (odds ratio: 3.541, 95% confidence interval: 1.235–10.154, p = 0.019), but not baseline f(QRS‐T) angle, was independent predictor of in‐hospital mortality.

Conclusion

f(QRS‐T) angle may be used as a beneficial tool for determining high risk patients in acute STEMI. Unlike previous studies, we showed for the first time that that post‐procedural f(QRS‐T) can predict in‐hospital mortality and TT failure.

     

Evaluation of staining susceptibility of resin artificial teeth and stain removal efficacy of denture cleansers

Objective. To assess the staining susceptibility of four acrylic resin (Ivostar, SR Vivodent PE, Major Dent, Integral) and a nanocomposite resin (Veracia) artificial teeth and to evaluate the stain removal efficacy of denture cleansers. Materials and methods. Sixty maxillary incisors of each brand (total = 300) were divided into three groups according to staining solution as coffee, red wine and tea. Baseline color measurements were performed with a spectrophotometer. Specimens were immersed in staining solutions for 14 h (2 h × 7 days) and then second color measurements were performed. Each group was further divided into four sub-groups according to denture cleanser as Corega tabs, Fittydent, NaOCl (0.5%) and distilled water (control) (n = 5). Specimens were immersed in denture cleansers for 8 h and third color measurements were made. Thus, the weekly simulation period was completed. This cycle was repeated 12 times to simulate a 3-month time period and measurements were performed at the end of the 4th, 8th and 12th cycles. ΔE values were calculated and data were analyzed with 3-way repeated measures ANOVA and Bonferroni tests. Results. Significant color differences were found among the teeth and staining solutions, but all of the color differences were in the clinically acceptable range (ΔE < 5.5). Integral showed the highest ΔE values for all solutions, while Ivostar and Vivodent demonstrated the lowest ΔE values for red wine and tea solutions. There was no significant difference among the denture cleansers in terms of stain removal efficacy. Conclusions. Cross-linked acrylic (Integral) and nanocomposite (Veracia) resin teeth were more susceptible to staining. Denture cleansers were efficient on stain removal from artificial teeth.     

Leukoaraiosis in stroke patients

Pathogenesis of leukoaraiosis (LA) is not clearly understood and its significance in patients with stroke remains undetermined. In the Neurology Department of Ankara Hospital, computed tomography (CT) examination of brain was performed for various reasons in 288 patients. LA was detected in 178 patients by the use of brain CT. Patients with LA had a higher incidence of hypertension history (70.8%) when compared with the non-LA group (57.3%; p <.05). There was no statistically significant difference in terms of sex, mean age, smoking, diabetes mellitus, history of cerebrovascular disease, cardiac failure, ischemic cardiac disease between patients with and without LA. We showed that LA is related to hypertension but not related to age, diabetes mellitus, or cardiac disease in our patient population.     

Nitric oxide levels in rat cortex,hippocampus, cerebellum,and brainstem after impact acceleration head injury

Nitric oxide (NO) is a potential mediator of secondary brain injury in the settings of cerebral ischemia and inflammation. Traumatic brain injury (TBI) alters the levels of stable end products of NO metabolism. We investigated these changes and attempted to identify brain regions that were unique with regard to NO production in the period immediately after TBI. The experiment involved assaying nitrite-nitrate concentrations in the rat cortex, cerebellum, hippocampus, and brainstem after impact-acceleration head injury. Five rats comprised the sham-operated (control) group, five sustained mild head injury (MHI), and five sustained severe head injury (SHI). There was a uniform decline in the tissue concentrations of NO metabolites in all four brain regions in both injured groups. There were no significant differences in the concentrations of NO metabolites among the various sites tested in the MHI group; however, there appeared to be a relationship between degree of decline in NO levels and amount of trauma sustained by a given region in the SHI group. In these rats, NO dropped to the lowest levels in the brain region where the direct trauma was most severe. The results suggest that nitrite-nitrate levels in these four brain regions fall below normal in the first 5 min after impact trauma. This decrease may, in part, be related to reduced activity of all nitric oxide synthase isoforms, which would cause a drop in the levels of NO metabolites. We believe that this decline may be linked to, and may even cause, the global decrease in cerebral blood flow that occurs in the initial stages of TBI.     

Sex difference in perceptual-verbal ability in relation to body size

Sex difference in verbal ability was reconsidered in relation to body size. The perceptual-verbal ability (PVA) was assessed using the A's Test. For the raw data, women excelled men, as expected. PVA positively correlated with height and weight of the subjects, but only for women. As a covariate of height, sex difference increased by increasing the women's score; men's score did not change. Tall women had much higher scores than short men. It was concluded that sex difference in PVA is stable despite the smaller body size of females than males, and body height may be predictive for this ability, but only in women.