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الملخص: أهداف البحث: على مر السنين، أثبتت أزاديراشتا إنديكا، مانجيفيرا إنديكا ومورينجا أوليفيرا أن لديهم بعض الخصائص المضادة للفيروسات. تطبق هذه الدراسة تقنيات الالتحام الجزيئي لتقييم الآثار المثبطة لبعض المركبات البيولوجية النشطة من النباتات المذكورة أعلاه ضد الإنزيم البروتيني الرئيس، وهو البروتين الرئيس المتضمن في تكاثر فيروس سارس-كوفيد-٢. وعلاوة على ذلك، تم توقع فحص المركبات للكشف عن الامتزاز والتوزيع والتمثيل الغذائي والإفراز والسمية في السيليكو. طرق البحث: تم الحصول على التركيب البلوري للإنزيم البروتيني الرئيس من قاعدة بيانات البروتين، بينما تم الحصول على المركبات البيولوجية النشطة من الكيمياء المنشورة. وتم تقييم تشابه الأدوية للمركبات المختارة ودواء التحكم (الهيدروكسيكلوروكوين). كما تمت ترسية المركبات المطابقة لقاعدة الأدوية المشابهة ضد الإنزيم البروتيني الرئيس، وتم تحليل المجمع الرأسي باستخدام خدمة التعريف ليج بلوت والبروتين المجند. تعرضت أفضل خمس مركبات ناجحة إلى فحص الامتزاز والتوزيع والتمثيل الغذائي والإفراز والسمية باستخدام معرف سار ادمت. النتائج: ١٧ من ٢٢ من المركبات التي تم فحصها اجتازت تقييم ليبينسكي. بالإضافة إلى ذلك، أظهرت أكثر المركبات نشاطا من النباتات التي تم فحصها إمكانات مثبطة نسبيا ضد الإنزيم البروتيني الرئيس عند مقارنتها بالهيدروكسيكلوروكوين، الأمر الذي يلمح إلى مشاركتهم المحتملة في تثبيط عملية التكاثر للإنزيم البروتيني الرئيس لفيروس سارس-كوفيد-٢. الاستنتاجات: في هذه الدراسة، معظم المكونات النباتية النشطة عرضت إمكانات مثبطة ضد الإنزيم البروتيني الرئيس لفيروس سارس-كوفيد-٢ والخصائص الدوائية المفضلة عند مقارنتها بالهيدروكسيكلوروكوين، مما يجعلها مضادات محتملة للفيروسات ضد مرض فيروس كورونا. Abstract: Objectives: Over the years, Azadirachta indica, Mangifera indica, and Moringa oleifera have been shown to possess some antiviral characteristics. This study applies molecular docking techniques to assess inhibitory effects of some bioactive compounds from the plants mentioned above against the main protease (Mpro), a key protein involved in SARS-CoV-2 replication. Furthermore, adsorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles for screened compounds were predicted in silico. Methods: The crystal structure of Mpro was retrieved from the Protein Data Bank, while the plant bioactive compounds were retrieved from Pubchem. Drug-likeness of the selected compounds and a control drug (hydroxychloroquine) were assessed, and the compounds that satisfied the drug-likeness rule were docked against Mpro. The docked complexes were analyzed using LigPlot and the protein-ligand profiler server. The top five compound hits were subjected to ADMET screening using the ADMETSar server. Results: A total of 17 out of 22 screened compounds passed Lipinski's assessment. Additionally, the most active compounds from the investigated plants exhibited relative inhibitory potentials against Mpro compared with hydroxychloroquine, which alludes to their possible involvement in inhibiting the SARS-CoV-2 main protease replication process. Conclusions: In our study, most of the active phytocomponents of the investigated plants exhibited relative inhibitory potentials against Mpro of SARS-CoV-2 and preferred pharmacological features when compared with hydroxychloroquine. These findings indicate these compounds are potentially antiviral candidates against SARS-CoV-2.

The novel coronavirus pandemic has spread over in 213 countries as of July 2020. Approximately 12 million people have been infected so far according to the reports from World Health Organization (WHO). Preventive measures are being taken globally to avoid the rapid spread of virus. In the current study, an in silico approach is carried out as a means of inhibiting the spike protein of the novel coronavirus by flavonoids from natural sources that possess both antiviral and anti-inflammatory properties. The methodology is focused on molecular docking of 10 flavonoid compounds that are docked with the spike protein of SARS-CoV-2, to determine the highest binding affinity at the binding site. Molecular dynamics simulation was carried out with the flavonoid-protein complex showing the highest binding affinity and highest interactions. The flavonoid naringin showed the least binding energy of −9.8 Kcal/mol with the spike protein which was compared with the standard drug, dexamethasone which is being repurposed to treat critically ill patients. MD simulation was carried out on naringin-spike protein complex for their conformational stability in the active site of the novel coronavirus spike protein. The RMSD of the complex appeared to be more stable when compared to that of the protein from 0.2 nm to 0.4 nm. With the aid of this in silico approach further in vitro studies can be carried out on these flavonoids against the novel coronavirus as a means of viral protein inhibitors.

A 34-year-old man was admitted with acute lung injury and COVID-19 pneumonia. In intensive care unit, he experienced episodes of prolonged asystole accompanied by hypotension without loss of consciousness. Once reversible causes were excluded, symptoms were related to dysfunction of the sinus node and patient underwent PM implantation., Graphical abstract

Made available in DSpace on 2022-04-28T19:44:18Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-12-01 Agencia Nacional de Investigación e Innovación Comisión Sectorial de Investigación Científica Fondo Nacional de Desarrollo Científico y Tecnológico The molecular evolution of life on earth along with changing environmental, conditions has rendered mankind susceptible to endemic and pandemic emerging infectious diseases. The effects of certain systemic viral and bacterial infections on morbidity and mortality are considered as examples of recent emerging infections. Here we will focus on three examples of infections that are important in pregnancy and early childhood: SARS-CoV-2 virus, Zika virus, and Mycoplasma species. The basic structural characteristics of these infectious agents will be examined, along with their general pathogenic mechanisms. Coronavirus infections, such as caused by the SARS-CoV-2 virus, likely evolved from zoonotic bat viruses to infect humans and cause a pandemic that has been the biggest challenge for humanity since the Spanish Flu pandemic of the early 20th century. In contrast, Zika Virus infections represent an expanding infectious threat in the context of global climate change. The relationship of these infections to pregnancy, the vertical transmission and neurological sequels make these viruses highly relevant to the topics of this special issue. Finally, mycoplasmal infections have been present before mankind evolved, but they were rarely identified as human pathogens until recently, and they are now recognized as important coinfections that are able to modify the course and prognosis of various infectious diseases and other chronic illnesses. The infectious processes caused by these intracellular microorganisms are examined as well as some general aspects of their pathogeneses, clinical presentations, and diagnoses. We will finally consider examples of treatments that have been used to reduce morbidity and mortality of these infections and discuss briefly the current status of vaccines, in particular, against the SARS-CoV-2 virus. It is important to understand some of the basic features of these emerging infectious diseases and the pathogens involved in order to better appreciate the contributions of this special issue on how infectious diseases can affect human pregnancy, fetuses and neonates. Laboratory of Ion Channels Biological Membranes and Cell Signaling Department of Biophysics Faculty of Medicine Universidad de la República Department of Infectious Diseases Faculty of Medicine Universidad de la República Cellular and Molecular Physiology Laboratory (CMPL) Department of Obstetrics Division of Obstetrics and Gynaeology School of Medicine Faculty of Medicine Pontificia Universidad Católica de Chile Department of Physiology Faculty of Pharmacy Universidad de Sevilla Medical School (Faculty of Medicine) São Paulo State University (UNESP) University of Queensland Centre for Clinical Research (UQCCR) Faculty of Medicine and Biomedical Sciences University of Queensland Department of Pathology and Medical Biology University of Groningen University Medical Center Groningen (UMCG) Department of Molecular Pathology The Institute for Molecular Medicine Medical School (Faculty of Medicine) São Paulo State University (UNESP) Fondo Nacional de Desarrollo Científico y Tecnológico: 1190316

By the end of year 2019, the new virus SARS-CoV-2 appeared, causing the Coronavirus Disease 2019 (COVID-19), and spread very fast globally. A continuing need for diagnostic tools is a must to contain its spread. Till now, the gold standard method, the reverse transcription polymerase chain reaction (RT-PCR), is the precise procedure to detect the virus. However, SARS-CoV-2 may escape RT-PCR detection for several reasons. The development of well-designed, specific and sensitive serological test like enzyme immunoassay (EIA) is needed. This EIA can stand alone or work side by side with RT-PCR. In this study, we developed several EIAs including plates that are coated with either specially designed SARS-CoV-2 nucleocapsid or surface recombinant proteins. Each protein type can separately detect anti-SARS-CoV-2 IgM or IgG antibodies. For each EIAs, the cut-off value, specificity and sensitivity were determined utilizing RT-PCR confirmed Covid-19 and pre-pandemic healthy and other viruses-infected sera. Also, the receiver operator characteristic (ROC) analysis was performed to define the specificities and sensitivities of the optimized assay. The in-house EIAs were validated by comparing against commercial EIA kits. All in-house EIAs showed high specificity (98–99%) and sensitivity (97.8–98.9%) for the detection of IgG/IgM against RBD and N proteins of SARS-CoV-2. From these results, the developed Anti-RBD and anti-N IgG and IgM antibodies EIAs can be used as a specific and sensitive tool to detect SARS-CoV-2 infection, calculate the burden of disease and case fatality rates.

Purpose Asymptomatic or minimally symptomatic infection with COVID-19 can result in silent transmission to large numbers of individuals, resulting in expansion of the pandemic with a global increase in morbidity and mortality. New ways of screening the general population for COVID-19 are urgently needed along with novel effective prevention and treatment strategies. Hypothesis A hypothetical three-part prevention, diagnostic, and treatment approach based on an up-to-date scientific literature review for COVID- 19 is proposed. Regarding diagnosis, a validated screening questionnaire and digital app for COVID-19 could help identify individuals who are at risk of transmitting the disease, as well as those at highest risk for poor clinical outcomes. Global implementation and online tracking of vital signs and scored questionnaires that are statistically validated would help health authorities properly allocate essential health care resources to test and isolate those at highest risk for transmission and poor outcomes. Second, regarding prevention, no validated protocols except for physical distancing, hand washing, and isolation exist, and recently ivermectin and the antimalarial drugs chloroquine and hydroxychloroquine has been published to have anti-viral properties against COVID-19. A randomized trial of ivermectin or hydroxychloroquine alone, and/or nutraceuticals that have been published to support immune function including Vitamin C, zinc, and immunomodulatory supplements (3,6 Beta glucan) could be beneficial in preventing transmission or lessening symptomatology but requires statistical validation. Third, concerning treatment, COVID-19 induced inflammation and “cytokine storm syndrome” with hemophagocytic lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) have resulted in extreme morbidity and mortality in those with certain comorbidities, secondary to “acute respiratory distress syndrome” (ARDS) and multiorgan dysfunction with disseminated intravascular coagulation (DIC). Deficiency in red blood cell, serum and alveolar glutathione has been published in the medical literature for ARDS, as well as viral and bacterial pneumonias, resulting from increased levels of free radical/oxidative stress. A randomized controlled trial of blocking NFKappa B and cytokine formation using glutathione precursors (N-acetyl-cysteine [NAC] and alpha lipoic acid) and PO/IV glutathione should be performed, along with an evaluation of Nrf2 activators (curcumin, sulforaphane glucosinolate) which have been scientifically proven to lower inflammation. Since high mortality rates from sepsis induced DIC due to COVID 19 infection has also been associated with thrombotic events and elevated levels of D-dimer, randomized controlled trials of using anticoagulant therapy with heparin is urgently required. This is especially important in patients on ventilators who have met certain sepsis induced coagulopathy (SIC) criteria. The use of acetazolamide with or without sildenafil also needs to be explored with or without heparin, since increased oxygen delivery to vital organs through prevention of thrombosis/pulmonary emboli along with carbonic anhydrase inhibition may help increase oxygenation and prevent adverse clinical outcomes. Conclusion and Implications a three-part prevention, diagnostic, and treatment plan is proposed for addressing the severe complications of COVID-19. Digital monitoring of symptoms to clinically diagnose early exposure and response to treatment; prevention with hydroxychloroquine and/or ivermetin as well as nutritional therapies that support a healthy immune response; treatment with anti-inflammatory therapies that block NFKappaB and activate Nrf2 pathways, as well as novel therapies that address COVID-19 pneumonia and ARDS with DIC including anticoagulation and/ or novel respiratory therapies with or without acetazolamide and sildenafil. These three broad-based interventions urgently need to be subjected to randomized, controlled trials.

Coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared by the World Health Organization (WHO) as a global pandemic on March 11, 2020. SARS-CoV-2 targets the respiratory system, resulting in symptoms such as fever, headache, dry cough, dyspnea, and dizziness. These symptoms vary from person to person, ranging from mild to hypoxia with acute respiratory distress syndrome (ARDS) and sometimes death. Although not confirmed, phylogenetic analysis suggests that SARS-CoV-2 may have originated from bats; the intermediary facilitating its transfer from bats to humans is unknown. Owing to the rapid spread of infection and high number of deaths caused by SARS-CoV-2, most countries have enacted strict curfews and the practice of social distancing while awaiting the availability of effective U.S. Food and Drug Administration (FDA)-approved medications and/or vaccines. This review offers an overview of the various types of coronaviruses (CoVs), their targeted hosts and cellular receptors, a timeline of their emergence, and the roles of key elements of the immune system in fighting pathogen attacks, while focusing on SARS-CoV-2 and its genomic structure and pathogenesis. Furthermore, we review drugs targeting COVID-19 that are under investigation and in clinical trials, in addition to progress using mesenchymal stem cells to treat COVID-19. We conclude by reviewing the latest updates on COVID-19 vaccine development. Understanding the molecular mechanisms of how SARS-CoV-2 interacts with host cells and stimulates the immune response is extremely important, especially as scientists look for new strategies to guide their development of specific COVID-19 therapies and vaccines.

Coronaviruses (CoVs), a family of enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, unusually large RNA genome, and unique replication capability. CoVs are known to cause various potentially lethal human respiratory infectious diseases, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the very recent coronavirus disease 2019 (COVID-19) outbreak. Unfortunately, neither drug nor vaccine has yet been approved to date to prevent and treat these diseases caused by CoVs. Therefore, effective prevention and treatment medications against human coronavirus are in urgent need. In the past decades, many natural compounds have been reported to possess multiple biological activities, including antiviral properties. In this article, we provided a comprehensive review on the natural compounds that interfere with the life cycles of SARS and MERS, and discussed their potential use for the treatment of COVID-19., Graphical abstract Chinese herbal medicines and natural compounds possess promising antiviral effects against Human coronaviruses (HCoVs) and provide a rich resource for novel antiviral drug development. This review provides an update on natural compounds against HCoVs and summarizes the active natural compounds and their possible action mechanisms.Image 1

Currently, antiviral drugs and/or vaccines are not yet available to treat or prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, we narrated the available data, from credible publishers, regarding the possible role of polyphenols and natural extracts-containing polyphenols in the prevention of coronavirus disease 2019 (COVID-19), and their immune-boosting properties. It was revealed that polyphenols could be considered as promising biologically active substances for the prevention of COVID-19. The underlying potential mechanism behind this action is mostly due to the antiviral activities and the immune-regulation functions of polyphenols against COVID-19-infections. Antivirus polyphenolic-based medications can mitigate SARS-CoV-2-enzymes, which are vital for virus duplication and infection. It was also found that triterpenoid, anthraquinone, flavonoids, and tannins are possible keys to scheming antiviral therapies for inhibiting SARS-CoV-2-proteases. The identified pharmacophore structures of polyphenols could be utilized in the explanation of novel anti-COVID-19 designs. The advantage of using mixtures containing polyphenols is related to the high-safety profile without having major side-effects, but further randomized controlled trials are required in the upcoming studies., Highlights • Polyphenols possess many potential health benefits, including antiviral effects. • Polyphenols consider promising bioactive substances for COVID-19 prevention. • Polyphenol-rich foods will be helpful during the COVID-19's treatment. • Polyphenols assist as blocking agent for protease's enzymatic activity of COVID-19.

The outbreak of mysterious pneumonia at the end of 2019 is associated with widespread research interest worldwide. The coronavirus disease-19 (COVID-19) targets multiple organs through inflammatory, immune, and redox mechanisms, and no effective drug for its prophylaxis or treatment has been identified until now. The use of dietary bioactive compounds, such as phenolic compounds (PC), has emerged as a putative nutritional or therapeutic adjunct approach for COVID-19. In the present study, scientific data on the mechanisms underlying the bioactivity of PC and their usefulness in COVID-19 mitigation are reviewed. In addition, antioxidant, antiviral, anti-inflammatory, and immunomodulatory effects of dietary PC are studied. Moreover, the implications of digestion on the putative benefits of dietary PC against COVID-19 are presented by addressing the bioavailability and biotransformation of PC by the gut microbiota. Lastly, safety issues and possible drug interactions of PC and their implications in COVID-19 therapeutics are discussed.

Made available in DSpace on 2022-04-28T19:45:52Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 Agencia Nacional de Investigación e Innovación Comisión Sectorial de Investigación Científica Rijksuniversiteit Groningen Universidad de la República Uruguay Fondo Nacional de Desarrollo Científico y Tecnológico During pregnancy, a series of physiological changes are determined at the molecular, cellular and macroscopic level that make the mother and fetus more susceptible to certain viral and bacterial infections, especially the infections in this and the companion review. Particular situations increase susceptibility to infection in neonates. The enhanced susceptibility to certain infections increases the risk of developing particular diseases that can progress to become morbidly severe. For example, during the current pandemic caused by the SARS-CoV-2 virus, epidemiological studies have established that pregnant women with COVID-19 disease are more likely to be hospitalized. However, the risk for intensive care unit admission and mechanical ventilation is not increased compared with nonpregnant women. Although much remains unknown with this particular infection, the elevated risk of progression during pregnancy towards more severe manifestations of COVID-19 disease is not associated with an increased risk of death. In addition, the epidemiological data available in neonates suggest that their risk of acquiring COVID-19 is low compared with infants (

The COVID-19 (coronavirus disease) pandemic caused by SARS-CoV-2 with its rapid expansion has led to extraordinary implications in our understanding of viral infections and their management globally. In this current scenario of unusual circumstances and public health emergency, the cancer care per se is facing unprecedented challenges. The peculiarity of the SARS-CoV-2 infections is still being uncovered as the pandemic spreads across the populations than showing signs of its curtailment. The review highlights the significance of idiosyncrasy of the SARS-Cov-2 infection especially putting forth the importance of immunosenescence, both in the COVID-19 specific immune response in the infected lungs of the elderly and in the cancer patients infected with SARS-CoV-2.The focus of the article is directed towards demystifying the unparalleled essence of a proprotein convertase, Furin in the biology of the SARS-Cov-2 infection and its role in facilitating viral transmission through expedited cellular entry into alveolar epithelial cells in COVID-19 infected cancer patients. The risk stratification of the cancer treatment and guidelines shaped up by national and international oncology societies in providing uncompromised patient care during the COVID-19 crisis have also been addressed. The global efforts towards vaccination in developing SARS CoV-2 immunity are also discussed in this article.

Graphical abstract, ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules controlling major biological processes as diverse as DNA damage repair, transcriptional regulation, intracellular transport, immune and stress responses, cell survival and proliferation. Furthermore, enzymatic reactions of ADPr are central in the pathogenesis of many human diseases, including infectious conditions. By providing a review of ADPr signalling in bacterial systems, we highlight the relevance of this chemical modification in the pathogenesis of human diseases depending on host-pathogen interactions. The post-antibiotic era has raised the need to find alternative approaches to antibiotic administration, as major pathogens becoming resistant to antibiotics. An in-depth understanding of ADPr reactions provides the rationale for designing novel antimicrobial strategies for treatment of infectious diseases. In addition, the understanding of mechanisms of ADPr by bacterial virulence factors offers important hints to improve our knowledge on cellular processes regulated by eukaryotic homologous enzymes, which are often involved in the pathogenesis of human diseases.

The lethal Coronaviruses (CoVs), Severe Acute Respiratory Syndrome-associated Coronavirus (SARS-CoV) and most recently Middle East Respiratory Syndrome Coronavirus, (MERS-CoV) are serious human health hazard. A successful viral infection requires fusion between virus and host cells carried out by the surface spike glycoprotein or S protein of CoV. Current models propose that the S2 subunit of S protein assembled into a hexameric helical bundle exposing hydrophobic fusogenic peptides or fusion peptides (FPs) for membrane insertion. The N-terminus of S2 subunit of SARS-CoV reported to be active in cell fusion whereby FPs have been identified. Atomic-resolution structure of FPs derived either in model membranes or in membrane mimic environment would glean insights toward viral cell fusion mechanism. Here, we have solved 3D structure, dynamics and micelle localization of a 64-residue long fusion peptide or LFP in DPC detergent micelles by NMR methods. Micelle bound structure of LFP is elucidated by the presence of discretely folded helical and intervening loops. The C-terminus region, residues F42-Y62, displays a long hydrophobic helix, whereas the N-terminus is defined by a short amphipathic helix, residues R4-Q12. The intervening residues of LFP assume stretches of loops and helical turns. The N-terminal helix is sustained by close aromatic and aliphatic sidechain packing interactions at the non-polar face. 15N{1H}NOE studies indicated dynamical motion, at ps-ns timescale, of the helices of LFP in DPC micelles. PRE NMR showed that insertion of several regions of LFP into DPC micelle core. Together, the current study provides insights toward fusion mechanism of SARS-CoV., Graphical abstract Image 2, Highlights • 3-D structure of long fusion peptide (LFP) of SRAS-CoV in DPC micelles • LFP adopts helix-loop-helix structure and inserts into micelle. • The structure provides mechanism of membrane fusion process.

Highlights • Optimal protocol for freeze-drying that allows safe and effective preservation of HCoV-NL63 infectious material was developed. • Lyophilized virus preparations can be stored either at ambient temperature or at +4 °C. In the latter case samples may be stored for at least two months. • HCoV-NL63 virions are exquisitely stable in liquid media and can be stored also without preservatives at ambient temperature for up to 14 days., The human coronavirus NL63 was identified in 2004 and subsequent studies showed its worldwide distribution. Infection with this pathogen is associated with upper and lower respiratory tract diseases of mild to moderate severity. Furthermore, HCoV-NL63 is the main cause of croup in children. Within this study an optimal protocol for freeze-drying that allows safe and effective preservation of HCoV-NL63 infectious material was developed. Lyophilized virus preparations can be stored either at ambient temperature or at +4 °C. In the latter case samples may be stored for at least two months. Surprisingly, conducted analysis showed that HCoV-NL63 virions are exquisitely stable in liquid media and can be stored also without preservatives at ambient temperature for up to 14 days.