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).     

Melatonin protects myocardium from ischemia-reperfusion injury in hypertensive rats: role of myeloperoxidase activity

Increased levels of reactive oxygen species, alterations in nitric oxide synthesis, and increased migration of neutrophils to the ischemic tissue play an important role in the pathophysiology of myocardial ischemia-reperfusion (IR) injury. In this study, we have evaluated the effects of melatonin on myeloperoxidase (MPO) activity, tissue glutathione (GSH), lipid peroxidation levels, and blood pressure in L-NAME-induced hypertensive rats with or without IR. NOS inhibitor L-NAME was administrated before inducing cardiac ischemia for 15 days intraperitoneally. For the cardiac ischemia, the left coronary artery was ligated for 30 min, and reperfusion was performed for 120 min after the ischemia. L-NAME treatment in non-ischemic animals increased blood pressure and lipid peroxidation, and decreased glutathione level in myocardial tissue significantly as compared with non-L-NAME-treated animals. Melatonin reversed L-NAME-induced blood pressure elevation and oxidative changes. Cardiac IR increased MDA levels and MPO activity and decreased GSH levels as compared with non-ischemic animals. L-NAME treatment did not change in IR-induced MDA and GSH levels as compared with ischemic control animals. However, MPO activity was significantly higher than control ischemic animals. MDA levels and MPO activity resulting from ischemic injury in melatonin-treated animals were significantly less than L-NAME-treated animals. Taken together-the ischemic and non-ischemic control and melatonin-treated animals-this study shows that neutrophil migration plays an important role on the development of ischemic injury in hypertensive rats.     

The role of extracellular matrix and activin-A in in vitro growth and survival of murine preantral follicles

Extracellular matrix plays a key role in cell growth, survival, and differentiation in a wide array of tissue types through integrin-mediated signaling pathways and its interaction with growth factors. This study investigates the role of extracellular matrix and its interaction with activin-A on in vitro growth and survival of mouse preantral follicles. Preantral follicles isolated from 14-day-old immature mouse ovaries were cultured either 3 dimensionally using basement membrane matrix (growth factor - reduced matrigel) or 2 dimensionally on cover slips coated with a single component of extracellular matrix (fibronectin, collagen, or laminin), on polylysine (negative control), or in standard culture plates in a serum-free culture medium with or without activin-A for 7 days. Follicles cultured in matrigel maintained well their 3-dimensional structure compared to those cultured conventionally. This observation was confirmed by analyzing 3-dimensional images of follicles cultured in matrigel and standard culture plate using confocal microscopy. Furthermore, follicles displayed higher growth and survival rates and exhibited antral space formation as early as day 5 of culture when activin-A was added to matrigel; in contrast, the addition of activin-A had no effect on the growth and survival of follicles cultured on individual extracellular matrix components after 7 days of culture. These data may suggest that 3-dimensional culture with extracellular matrix and activin-A provides a better milieu for in vitro growth and survival of preantral follicles in immature mice.     

Falling FSH levels predict poor IVF pregnancy rates in patients whom the gonadotropins are withheld

Aim  

To determine whether monitoring follicle stimulating hormone (FSH) levels in over-responding patients whom the gonadotropins were withheld would predict pregnancy outcome.     

Myeloperoxydase Expression in The Pathogenesis of Nasal Polyps

Nasal polyps are benign mucosal protrusions that expand into the nasal cavity. There are no any etiological factors that may explain the pathogenesis of nasal polyps but currently inflammation continues to be the major factor. As a result of inflammation, neutrophils become activated and migrate to the inflammatory area and form their bactericidal effects by producing free oxygen radicals. The objective of our study is to investigate the expression of myeloperoxydase enzyme, which is usually an indicator of leukocyte infiltration and is responsible in the formation of free oxygen radicals in polyp tissues and to determine its role in the pathogenesis of nasal polyps.     

Exercise-induced ventricular tachycardia in children

Two children with exercise-induced tachycardia, one with idiopathic long-QT syndrome, are presented. The patients were evaluated by exercise testing and electrophysiologic study. From the onset of treatment with the beta-blocking agent, pindolol, the patients have been symptom-free. These findings emphasize that children with syncope must be evaluated by ECG, exercise testing, 24-h Holter-monitoring, and finally, electrophysiological study.     

Diagnostic Value of Magnetic Resonance Imaging in Gynaecology

In this study 23 patients with various gynaecological pathologies were evaluated. Ultrasonography and magnetic resonance imaging were performed in all cases, but only 14 were evaluated with computed tomography. On the basis of ultrasonography, 4 patients were labelled as having malignant ovarian tumours, however, this diagnosis was confirmed by magnetic resonance imaging in only 1 of the 4. Magnetic resonance imaging also determined the correct diagnosis in a patient with endometrioma whereas computed tomography showed only a simple cyst, and ultrasonography diagnosed a subserous myoma. Tumour was demonstrated by magnetic resonance imaging in 2 patients with cervical carcinoma although computed tomography and ultrasonography had previously shown no tumour mass in these patients. It was concluded that magnetic resonance imaging is much superior to computed tomography and ultrasonography in gynaecological diagnosis. This advantage results from the correct detection of the contents of ovarian cysts, the number and localization of uterine leiomyomas in T2 scans, invasion of uterine malignancies and differential diagnosis of subserous uterine leiomyomas from ovarian tumours.