Folic Acid and Leucovorin Have Potential to Prevent SARS-CoV-2-Virus Internalization by Interacting with S-Glycoprotein/Neuropilin-1 Receptor Complex

The interaction of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain with the host-cell ACE2 receptor is a well-known step in virus infection. Neuropilin-1 (NRP-1) is another host factor involved in virus internalization. The interaction between S-glycoprotein and NRP-1 has been identified as a potential COVID-19 treatment target. Herein, the effectiveness of folic acid and leucovorin in preventing contact between S-glycoprotein and NRP-1 receptors was investigated using in silico studies and then confirmed in vitro. The results of a molecular docking study showed that leucovorin and folic acid had lower binding energies than EG01377, a well-known NRP-1 inhibitor, and lopinavir. Two hydrogen bonds with Asp 320 and Asn 300 residues stabilized the leucovorin, while interactions with Gly 318, Thr 349, and Tyr 353 residues stabilized the folic acid. The molecular dynamic simulation revealed that the folic acid and leucovorin created very stable complexes with the NRP-1. The in vitro studies showed that the leucovorin was the most active inhibitor of the S1-glycoprotein/NRP-1 complex formation, with an IC75 value of 185.95 µg/mL. The results of this study suggest that folic acid and leucovorin could be considered as potential inhibitors of the S-glycoprotein/NRP-1 complex and, thus, could prevent the SARS-CoV-2 virus' entry into host cells.

Folic Acid and Leucovorin Have Potential to Prevent SARS-CoV-2-Virus Internalization by Interacting with S-Glycoprotein/Neuropilin-1 Receptor Complex.

The interaction of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain with the host-cell ACE2 receptor is a well-known step in virus infection. Neuropilin-1 (NRP-1) is another host factor involved in virus internalization. The interaction between S-glycoprotein and NRP-1 has been identified as a potential COVID-19 treatment target. Herein, the effectiveness of folic acid and leucovorin in preventing contact between S-glycoprotein and NRP-1 receptors was investigated using in silico studies and then confirmed in vitro. The results of a molecular docking study showed that leucovorin and folic acid had lower binding energies than EG01377, a well-known NRP-1 inhibitor, and lopinavir. Two hydrogen bonds with Asp 320 and Asn 300 residues stabilized the leucovorin, while interactions with Gly 318, Thr 349, and Tyr 353 residues stabilized the folic acid. The molecular dynamic simulation revealed that the folic acid and leucovorin created very stable complexes with the NRP-1. The in vitro studies showed that the leucovorin was the most active inhibitor of the S1-glycoprotein/NRP-1 complex formation, with an IC75 value of 185.95 µg/mL. The results of this study suggest that folic acid and leucovorin could be considered as potential inhibitors of the S-glycoprotein/NRP-1 complex and, thus, could prevent the SARS-CoV-2 virus' entry into host cells.

Dynamic changes in coagulation, hematological and biochemical parameters as predictors of mortality in critically ill COVID–19 patients:a prospective observational study (preprint)

Background This study was created to analyze dynamic alterations in coagulation, hematological and biochemical parameters and their association with mortality of COVID-19 patients.Methods The present study was a prospective, one-year-long observational study conducted during the period September 2020/September 2021 on all critically ill, COVID–19 patients with respiratory failure, admitted to the Medical Intensive Care Unit (MICU) of the University Clinical Centre of the Republic of Srpska. The following data were collected: demographic and clinical characteristics of the study population, pre-existing comorbidities (cardiovascular diseases, pulmonary diseases, diabetes mellitus), coagulation, biochemical and hematological parameters. The primary outcome was the proportion of patients who died (non-survivors).Results As much as 91 patients with median age 60 (50–67), 76.9% male, met the acute respiratory distress syndrome (ARDS) criteria. It was tested whether dynamic change (delta-Δ) of parameters (C-reactive protein-CRP, interleukin 6-IL-6, absolute lymphocyte count-Ly, fibrinogen, coagulation cascade factors: F II, factor II; F V, factor V, F X, factor X; F XI, factor XI; F XIII, factor XIII) that were found to be predictors of mortality is independently associated with poor outcome in patients. Adjusted (multivariate) analysis was used, where tested parameters were corrected for basic and clinical patients’ characteristics. The only inflammatory (biochemical and hematological) parameter which dynamic change had statistically significant odds ratio (OR) was ΔCRP (p < 0.005), while among coagulation parameters statistically significant OR was found for Δ fibrinogen (p < 0.005) in predicting mortality.Conclusion Coagulation, hematological and biochemical parameters' abnormalities are common in critically ill COVID–19 patients. Monitoring of these parameters and their dynamical changes can potentially improve management and predict mortality in critically ill COVID – 19 patients.

Exhaustion while teleworking during COVID-19: a moderated-mediation model of role clarity, self-efficacy, and task interdependence

Research background: The global COVID-19 pandemic created an unprecedented challenge not only for employees' well-being, but also for the nature of their work, as teleworking became the norm for many of them almost overnight. Thus, there is a need to a more fine-grained understanding of the specific job demands experienced while teleworking during COVID-19, and the specific resources that mitigate the detrimental effects of demands and help employees to adopt resilient responses during and beyond COVID-19. Purpose of the article: Drawing upon the job demands-resources model, the present study aims at investigating the link between work overload (a job demand) and employee well-being (i.e., burnout). considering role clarity (a job resource) as a mediator, and task interdependence and self-efficacy as two potential boundary conditions. Methods: In order to examine the link between work overload, role clarity and emotional exhaustion moderated by task interdependence and self-efficacy, we used survey data from 701 Romanian employees at a large information technology company, who worked from home during COVID-19. We employed regression-based path analysis to examine the hypothesized relations. Findings & value added: The results reveal that role clarity partially mediates the relation between work overload and emotional exhaustion while teleworking during COVID-19. Moreover, the results from the moderated mediation analysis show that role clarity. self-efficacy, and task interdependence interact in their effects on emotional exhaustion. This study has important theoretical and managerial implications for employee well-being that go beyond the pandemic. As this study shows, when high levels of workload and task interdependence cannot be avoided, employees' personal (self-efficacy) and job (role clarity) resources might be particularly useful to reduce their exhaustion while teleworking. Based on these results, managers can design better jobs for remote workers and more flexible work arrangements in the future.

Computational study of pomegranate peel extract polyphenols as potential inhibitors of SARS-CoV-2 virus internalization.

The search for effective coronavirus disease (COVID-19) therapy has attracted a great deal of scientific interest due to its unprecedented health care system overload worldwide. We have carried out a study to investigate the in silico effects of the most abundant pomegranate peel extract constituents on the multi-step process of serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) internalization in the host cells. Binding affinities and interactions of ellagic acid, gallic acid, punicalagin and punicalin were studied on four selected protein targets with a significant and confirmed role in the process of the entry of virus into a host cell. The protein targets used in this study were: SARS-CoV-2 spike glycoprotein, angiotensin-converting enzyme 2, furin and transmembrane serine protease 2. The results showed that the constituents of pomegranate peel extracts, namely punicalagin and punicalin had very promising potential for significant interactions with the selected protein targets and were therefore deemed good candidates for further in vitro and in vivo evaluation.