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1.
Curr Drug Targets ; 23(13): 1277-1287, 2022.
Article in English | MEDLINE | ID: covidwho-2098966

ABSTRACT

Covid-19 may be associated with various neurological disorders, including dysautonomia, a dysfunction of the autonomic nervous system (ANS). In Covid-19, hypoxia, immunoinflammatory abnormality, and deregulation of the renin-angiotensin system (RAS) may increase sympathetic discharge with dysautonomia development. Direct SARS-CoV-2 cytopathic effects and associated inflammatory reaction may lead to neuroinflammation, affecting different parts of the central nervous system (CNS), including the autonomic center in the hypothalamus, causing dysautonomia. High circulating AngII, hypoxia, oxidative stress, high pro-inflammatory cytokines, and emotional stress can also provoke autonomic deregulation and high sympathetic outflow with the development of the sympathetic storm. During SARS-CoV-2 infection with neuro-invasion, GABA-ergic neurons and nicotinic acetylcholine receptor (nAChR) are inhibited in the hypothalamic pre-sympathetic neurons leading to sympathetic storm and dysautonomia. Different therapeutic modalities are applied to treat SARS-CoV-2 infection, like antiviral and anti-inflammatory drugs. Ivermectin (IVM) is a robust repurposed drug widely used to prevent and manage mild-moderate Covid-19. IVM activates both GABA-ergic neurons and nAChRs to mitigate SARS-CoV-2 infection- induced dysautonomia. Therefore, in this brief report, we try to identify the potential role of IVM in managing Covid-19-induced dysautonomia.


Subject(s)
COVID-19 , Primary Dysautonomias , Humans , Animals , Bees , SARS-CoV-2 , Ivermectin , Hypoxia , gamma-Aminobutyric Acid
2.
Clin Exp Med ; 2022 Oct 17.
Article in English | MEDLINE | ID: covidwho-2075449

ABSTRACT

Coronavirus disease 19 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome 2 (SARS-CoV-2). Throughout the pandemic, evidence on the effects of COVID-19 during pregnancy has been inadequate due to the limited number of studies published. Therefore, the objective of this systematic review was to evaluate current literature regarding the effects of COVID-19 during pregnancy and establish pregnancy outcomes and vertical and perinatal transmission during pregnancy. Multiple databases were searched, including Embase, Medline, Web of Science, Scopus, and Cochrane Central Register of Control Clinical Trials, using the following keywords: [Pregnancy] AND [COVID-19 OR SARS-CoV-2 OR nCoV-19] OR [Perinatal transmission, Vertical transmission (VT), Pregnancy complications], [Pregnancy] AND [Hyperinflammation OR Cytokine storm]. We excluded in vitro and experimental studies, but also ex-vivo and animal study methods. To exclude the risk of bias during data collection and interpretation, all included studies were peer-reviewed publications. This review is estimated to tabulate the study intervention characteristics and compare them against the planned groups for each synthesis. Our findings showed that pregnant women are commonly susceptible to respiratory viral infections and severe pneumonia due to physiological immune suppression and pregnancy-induced changes. VT of SARS-CoV-2 infection during pregnancy is associated with a great deal of controversy and conflict. However, there is still no robust clinical evidence of VT. Furthermore, the clinical presentation and management of COVID-19 during pregnancy are nearly identical to those of non-pregnant women. Finally, chloroquine and remdesivir are the only two drugs evaluated as adequate for the management of COVID-19 during pregnancy.

4.
Biotechnol Genet Eng Rev ; : 1-21, 2022 Sep 13.
Article in English | MEDLINE | ID: covidwho-2028787

ABSTRACT

In response to different viral infections, including SARS-CoV-2 infection, pro-inflammatory, anti-inflammatory cytokines, and bioactive lipids are released from infected and immune cells. One of the most critical bioactive lipids is prostaglandins (PGs) which favor perseverance of inflammation leading to chronic inflammation as PGs act as cytokine amplifiers. PGs trigger the release of pro-inflammatory cytokines, activate Th cells, recruit immune cells, and increase the expression of pro-inflammatory genes. Therefore, PGs may induce acute and chronic inflammations in various inflammatory disorders and viral infections like SARS-CoV-2. PGs are mainly inhibited by non-steroidal anti-inflammatory drugs (NSAIDs) by blocking cyclooxygenase enzymes (COXs), which involve PG synthesis. NSAIDs reduce inflammation by selective or non-selective blocking activity of COX2 or COX1/2, respectively. In the Covid-19 era, there is a tremendous controversy regarding the use of NSAIDs in the management of SARS-CoV-2 infection. As well, the possible role of PGs in the pathogenesis of SARS-CoV-2 infection is not well-defined. Thus, the objective of the present study is to review the potential role of PGs and NSAIDs in Covid-19 in a narrative review regarding the preponderance of assorted views.

5.
Curr Alzheimer Res ; 2022 Sep 08.
Article in English | MEDLINE | ID: covidwho-2022271

ABSTRACT

The COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), a respiratory pathogen with neuroinvasive potential. Neurological COVID-19 manifestations include loss of smell and taste, headache, dizziness, stroke, and potentially fatal encephalitis. Several studies found elevated proinflammatory cytokines such as TNF-α, IFN-γ, IL-6 IL-8, IL-10 IL-16, IL-17A, and IL-18 in severely and critically ill COVID-19 patients, which may persist even after apparent recovery from infection. Biomarker studies on CSF and plasma and serum from COVID-19 patients have also shown a high level of IL-6, intrathecal IgG, neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and tau protein. Emerging evidence on the matter has established the concept of COVID-19 associated neuroinflammation, in the context of COVID-19 associated cytokine storm. While the short-term implications of this condition are extensively documented, its long-term implications are yet to be understood. The association of the aforementioned cytokines with the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington disease, and amyotrophic lateral sclerosis, may increase COVID-19 patients' risk to develop neurodegenerative diseases. Analysis of proinflammatory cytokines and CSF biomarkers in patients with COVID-19 can contribute to the early detection of the disease's exacerbation, monitoring the neurological implications of the disease and devising risk scales, and identifying treatment targets.

6.
Curr Med Chem ; 2022 Aug 29.
Article in English | MEDLINE | ID: covidwho-2022257

ABSTRACT

COVID-19 is caused by SARS-CoV-2 and leads to acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and extrapulmonary manifestations in severely affected cases. However, most of the affected cases are mild or asymptomatic. Cannabinoids (CBs) such as tetrahydrocannabinol (THC) and cannabidiol (CBD), which act on G-protein-coupled receptors called CB1 and CB2, have anti-inflammatory effects. Many published studies show that CBs are effective in various inflammatory disorders, viral infections, and attenuation of ALI and ARDS. Therefore, the aim of the present narrative review was to summarize the possible immunological role of CBs in COVID-19. The effects of CBs are controversial, although they have beneficial effects via CB2 receptors and adverse effects via CB1 receptors against ALI, ARDS, and hyperinflammation, which are hallmarks of COVID-19. The present narrative review has shown that CBs effectively manage ALI and ARDS by suppressing pro-inflammatory cytokines, which are common in COVID-19. Therefore, CBs may be used to manage COVID-19 because of their potent anti-inflammatory effects with suppression of pro-inflammatory cytokines and inhibition of inflammatory signaling pathways.

7.
Biotechnol Genet Eng Rev ; : 1-20, 2022 Sep 12.
Article in English | MEDLINE | ID: covidwho-2017140

ABSTRACT

Coronavirus disease 2019 (Covid-19) is a recent and current infectious pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Covid-19 may lead to the development of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and extrapulmonary manifestations in severe cases. Down-regulation of angiotensin-converting enzyme (ACE2) by the SARS-CoV-2 increases the production of angiotensin II (AngII), which increases the release of pro-inflammatory cytokines and placental growth factor (PlGF). PlGF is a critical molecule involved in vasculogenesis and angiogenesis. PlGF is stimulated by AngII in different inflammatory diseases through a variety of signaling pathways. PlGF and AngII are interacted in SARS-CoV-2 infection resulting in the production of pro-inflammatory cytokines and the development of Covid-19 complications. Both AngII and PlGF are interacted and are involved in the progression of inflammatory disorders; therefore, we aimed in this review to highlight the potential role of the PlGF/AngII axis in Covid-19.

8.
J Cell Physiol ; 2022 Sep 05.
Article in English | MEDLINE | ID: covidwho-2013564

ABSTRACT

Extracellular vehicles (EVs) are nanoscale lipid bilayer vesicles that carry biologically active biomolecule cargos like proteins, lipids, and nucleic acids (DNA, RNA) outside of the cell. Blood (serum/plasma), urine, and bronchoalveolar lavage fluid are all examples of biofluids from which they may be collected. EVs play a vital role in intracellular communication. The molecular signature of EVs largely depends on the parental cell's status. EVs are classified into two groups, (1) exosomes (originated by endogenous route) and (2) microvesicles (originated from the plasma membrane, also known as ectosomes). The quantity and types of EV cargo vary during normal conditions compared to pathological conditions (chronic inflammatory lung diseases or lung cancer). Consequently, EVs contain novel biomarkers that differ based on the cell type of origin and during lung diseases. Small RNAs (e.g., microRNAs) are transported by EVs, which is one of the most rapidly evolving research areas in the field of EVs biology. EV-mediated cargos transport small RNAs that can result in reprograming the target/recipient cells. Multiple chronic inflammatory lung illnesses, such as chronic obstructive pulmonary disease, asthma, pulmonary hypertension, pulmonary fibrosis, cystic fibrosis, acute lung injury, and lung cancer, have been demonstrated to be regulated by EV. In this review, we will consolidate the current knowledge and literature on the novel role of EVs and their small RNAs concerning chronic lung diseases (CLDs). Additionally, we will also provide better insight into the clinical and translational impact of mesenchymal stem cells-derived EVs as novel therapeutic agents in treating CLDs.

9.
Biotechnol Genet Eng Rev ; : 1-26, 2022 Aug 30.
Article in English | MEDLINE | ID: covidwho-2004861

ABSTRACT

Coronavirus disease 2019 (Covid-19) is a pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In Covid-19, there is uncontrolled activation of immune cells with a massive release of pro-inflammatory cytokines and the development of cytokine storm. These inflammatory changes induce impairment of different organ functions, including the central nervous system (CNS), leading to acute brain injury and substantial changes in the neurotransmitters, including serotonin (5-HT) and calcitonin gene-related peptide (CGRP), which have immunomodulatory properties through modulation of central and peripheral immune responses. In Covid-19, 5-HT neurotransmitters and CGRP could contribute to abnormal and atypical vascular reactivity. Sumatriptan is a pre-synaptic 5-HT (5-HT1D and 5-HT1B) agonist and inhibits the release of CGRP. Both 5-HT and CGRP seem to be augmented in Covid-19 due to underlying activation of inflammatory signaling pathways and hyperinflammation. In virtue of its anti-inflammatory and antioxidant properties with inhibition release of 5-HT and CGRP, Sumatriptan may reduce Covid-19 hyperinflammation. Therefore, Sumatriptan might be a novel potential therapeutic strategy in managing Covid-19. In conclusion, Sumatriptan could be an effective therapeutic strategy in managing Covid-19 through modulation of 5-HT neurotransmitters and inhibiting CGRP.

10.
Front Aging Neurosci ; 14: 878276, 2022.
Article in English | MEDLINE | ID: covidwho-2002497

ABSTRACT

Alzheimer's disease (AD) is a severe neurodegenerative disorder of the brain that manifests as dementia, disorientation, difficulty in speech, and progressive cognitive and behavioral impairment. The emerging therapeutic approach to AD management is the inhibition of ß-site APP cleaving enzyme-1 (BACE1), known to be one of the two aspartyl proteases that cleave ß-amyloid precursor protein (APP). Studies confirmed the association of high BACE1 activity with the proficiency in the formation of ß-amyloid-containing neurotic plaques, the characteristics of AD. Only a few FDA-approved BACE1 inhibitors are available in the market, but their adverse off-target effects limit their usage. In this paper, we have used both ligand-based and target-based approaches for drug design. The QSAR study entails creating a multivariate GA-MLR (Genetic Algorithm-Multilinear Regression) model using 552 molecules with acceptable statistical performance (R 2 = 0.82, Q 2 loo = 0.81). According to the QSAR study, the activity has a strong link with various atoms such as aromatic carbons and ring Sulfur, acceptor atoms, sp2-hybridized oxygen, etc. Following that, a database of 26,467 food compounds was primarily used for QSAR-based virtual screening accompanied by the application of the Lipinski rule of five; the elimination of duplicates, salts, and metal derivatives resulted in a truncated dataset of 8,453 molecules. The molecular descriptor was calculated and a well-validated 6-parametric version of the QSAR model was used to predict the bioactivity of the 8,453 food compounds. Following this, the food compounds whose predicted activity (pKi) was observed above 7.0 M were further docked into the BACE1 receptor which gave rise to the Identification of 4-(3,4-Dihydroxyphenyl)-2-hydroxy-1H-phenalen-1-one (PubChem I.D: 4468; Food I.D: FDB017657) as a hit molecule (Binding Affinity = -8.9 kcal/mol, pKi = 7.97 nM, Ki = 10.715 M). Furthermore, molecular dynamics simulation for 150 ns and molecular mechanics generalized born and surface area (MMGBSA) study aided in identifying structural motifs involved in interactions with the BACE1 enzyme. Molecular docking and QSAR yielded complementary and congruent results. The validated analyses can be used to improve a drug/lead candidate's inhibitory efficacy against the BACE1. Thus, our approach is expected to widen the field of study of repurposing nutraceuticals into neuroprotective as well as anti-cancer and anti-viral therapeutic interventions.

11.
Curr Protein Pept Sci ; 23(7): 465-474, 2022.
Article in English | MEDLINE | ID: covidwho-1993661

ABSTRACT

In Covid-19, the pathological effect of SARS-CoV-2 infection is arbitrated through direct viral toxicity, unusual immune response, endothelial dysfunction, deregulated renin-angiotensin system [RAS], and thrombo-inflammation, leading to acute lung injury (ALI), with a succession of acute respiratory distress syndrome (ARDS) in critical conditions. C1 esterase inhibitor (C1INH) is a protease inhibitor that inhibits the spontaneous activation of complement and contact systems and kinin pathway, clotting, and fibrinolytic systems. Therefore, targeting the complement system through activation of C1INH might be a novel therapeutic modality in the treatment of Covid-19. Therefore, this study aims to illustrate the potential nexus between C1INH and the pathophysiology of SARS-CoV-2 infection. C1INH is highly dysregulated in Covid-19 due to inflammatory and coagulation disorders. C1INH is up-regulated in Covid-19 and sepsis as an acute phase response, but this increase is insufficient to block the activated complement system. In addition, the C1INH serum level predicts the development of ARDS in Covid-19 patients, as its up-regulation is associated with the development of cytokine storm. In Covid-19, C1INH might be inhibited or dysregulated by SARS-CoV-2, leading to propagation of complement system activation with subsequent uncontrolled immunological stimulation due to activation of bradykinin and FXII with sequential activation of coagulation cascades and polymerization of fibrin. Thus, suppression of C1INH by SARS-CoV-2 infection leads to thrombosis and excessive inflammation due to uncontrolled activation of complements and contact systems.


Subject(s)
COVID-19 , Complement C1 Inhibitor Protein , Respiratory Distress Syndrome , Humans , Complement C1 Inhibitor Protein/metabolism , Esterases , Inflammation , SARS-CoV-2
12.
Inflammopharmacology ; 30(5): 1493-1501, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-1971761

ABSTRACT

SARS-CoV-2 (severe acute respiratory syndrome coronavirus type 2) has been identified as the source of a world coronavirus pandemic in 2019. Covid-19 is considered a main respiratory disease-causing viral pneumonia and, in severe cases, leads to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Although, extrapulmonary manifestations of Covid-19 like neurological, cardiovascular, and gastrointestinal have been confirmed. Exaggerated immune response and release of a high amount of pro-inflammatory cytokines may progress, causing a cytokine storm. Consequently, direct and indirect effects of SARS-CoV-2 infection can evolve into systemic complications due to the progression of hyper inflammation, oxidative stress and dysregulation of the renin-angiotensin system (RAS). Therefore, anti-inflammatory and antioxidant agents could be efficient in alleviating these disorders. Ursolic acid has anti-inflammatory, antioxidant, and antiviral effects; it reduces the release of pro-inflammatory cytokines, improves anti-inflammatory cytokines, and inhibits the production of reactive oxygen species (ROS). In virtue of its anti-inflammatory and antioxidant effects, ursolic acid may minimize SARS-CoV-2 infection-induced complications. Also, by regulating RAS and inflammatory signaling pathways, ursolic acid might effectively reduce the development of ALI in ARDS in Covid-19. In this state, this perspective discusses how ursolic acid can mitigate hyper inflammation and oxidative stress in Covid-19.


Subject(s)
Acute Lung Injury , COVID-19 , Respiratory Distress Syndrome , Acute Lung Injury/drug therapy , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antioxidants/pharmacology , Antioxidants/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytokines , Humans , Inflammation/drug therapy , Oleanolic Acid/analogs & derivatives , Reactive Oxygen Species , SARS-CoV-2
13.
Curr Protein Pept Sci ; 23(5): 321-334, 2022.
Article in English | MEDLINE | ID: covidwho-1910825

ABSTRACT

Natriuretic peptide system (NPS) is a group of peptide hormones or paracrine factors, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and natriuretic peptide precursor C (NPC), that are structurally related. The physiological effects of NPS include natriuresis, increased glomerular filtration rate, inhibition release of renin, vasopressin, and aldosterone, sympathetic inhibition, vasodilatations, and prevents cardiac hypertrophy and remodeling. ANP has immunological effects, as it is produced locally from immune cells; it regulates innate and adaptive immune responses. Metabolism and degradation of ANP are achieved by neutral endopeptidase (NEP), also known as neprilysin. Coronavirus disease 2019 (Covid-19) pandemic may lead to acute lung injury (ALI) and/or respiratory distress syndrome (ARDS). The underlying causes of inflammatory and immunological disorders in patients with severe Covid-19 are connected to the immune over-stimulation with the subsequent release of pro-inflammatory cytokines. Covid-19 severity is linked with high ANP serum levels regardless of acute cardiac injury. Inflammatory stimuli appear to be linked with the release of NPs, which anti-inflammatory effects prevent the development of ALI/ARDS in Covid-19. Therefore, neprilysin inhibitors like sacubitril increase endogenous NPs and may reduce the risk of ALI in Covid-19 due to the potentiation of endogenous anti-inflammatory effects of NPs. However, sacubitril increases gastrin-releasing peptide, cathepsin G and release of pro-inflammatory cytokines that are inactivated by neprilysin. In conclusion, NPs and neprilysin have cardio-pulmonary protective effects against Covid-19-induced ALI/ARDS. Neprilysin inhibitor sacubitril has dual protective and harmful effects regarding metabolizing vasoactive peptides by neprilysin. These findings require potential reevaluation of the effect of neprilysin inhibitors in managing Covid-19.


Subject(s)
COVID-19 , Heart Failure , Respiratory Distress Syndrome , Aldosterone , Aminobutyrates , Anti-Inflammatory Agents , Atrial Natriuretic Factor/metabolism , Atrial Natriuretic Factor/therapeutic use , Biphenyl Compounds , COVID-19/drug therapy , Cathepsin G , Cytokines , Gastrin-Releasing Peptide/therapeutic use , Heart Failure/drug therapy , Humans , Natriuretic Peptide, Brain/metabolism , Natriuretic Peptide, Brain/therapeutic use , Natriuretic Peptides , Neprilysin/metabolism , Neprilysin/therapeutic use , Renin/therapeutic use , Tetrazoles/pharmacology , Tetrazoles/therapeutic use , Valsartan/therapeutic use
14.
Curr Protein Pept Sci ; 23(5): 310-320, 2022.
Article in English | MEDLINE | ID: covidwho-1892473

ABSTRACT

The pathogenesis of SARS-CoV-2 infection is related to the direct cytopathic effect and associated hyper-inflammation due to exaggerated immune response. Different experimental and clinical studies revealed that many biomarkers could be used to determine the Covid-19 severity, such as Ddimer, procalcitonin, C-reaction protein (CRP), IL-6, and ferritin. Calprotectin (CP) is associated with intestinal inflammation, intestinal injury, and different respiratory diseases such as cystic fibrosis. Thus, CP might be a possible biomarker linking intestinal injury and acute lung injury (ALI) in Covid-19. Therefore, this study aimed to find a potential role of CP regarding GITI and ALI in Covid-19. CP is a complex protein consisting of S100A8 and S100A9, belonging to the Ca+2-binding proteins S100 family abundant in the cytosol of neutrophils and expressed on the monocyte membranes, macrophages, and intestinal epithelial cells. CP is a proinflammatory protein that acts through activation of the receptor for the advanced glycation end product (RAGE) and toll-like receptor 4 (TLR4). CP is a biomarker of neutrophil activation and is released following the turnover of neutrophils. CP could be controversial; it increases airway inflammation or protects lung and airway epithelium from an exaggerated immune response. Therefore, a high level of CP in different respiratory disorders might be protective and compensate against abnormal immune responses. CP level is high in Covid-19 and correlated with Covid-19 severity and oxygen demand due to activation of proinflammatory cytokines and inflammatory signaling pathways. Therefore, CP level is elevated in both ALI and intestinal inflammation so that it could be a potential biomarker that links the respiratory and intestinal injury in Covid-19.


Subject(s)
Acute Lung Injury , COVID-19 , Gastrointestinal Diseases , Leukocyte L1 Antigen Complex , Acute Lung Injury/virology , Biomarkers , COVID-19/complications , Cytokines/metabolism , Ferritins , Gastrointestinal Diseases/virology , Glycation End Products, Advanced/metabolism , Humans , Inflammation/metabolism , Interleukin-6/metabolism , Leukocyte L1 Antigen Complex/metabolism , Oxygen/metabolism , Procalcitonin/metabolism , SARS-CoV-2 , Toll-Like Receptor 4/metabolism
15.
Environ Sci Pollut Res Int ; 29(34): 51384-51397, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1864443

ABSTRACT

COVID-19 has become one of the few leading causes of death and has evolved into a pandemic that disrupts everyone's routine, and balanced way of life worldwide, and will continue to do so. To bring an end to this pandemic, scientists had put their all effort into discovering the vaccine for SARS-CoV-2 infection. For their dedication, now, we have a handful of COVID-19 vaccines. Worldwide, millions of people are at risk due to the current pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). Despite the lack of clinically authorized antiviral medications and vaccines for COVID-19, clinical trials of many recognized antiviral agents, their combination, and vaccine development in patients with confirmed COVID-19 are still ongoing. This discovery gave us a chance to get immune to this disease worldwide and end the pandemic. However, the unexpected capacity of mutation of the SARS-CoV-2 virus makes it difficult, like the recent SAS-CoV-2 Omicron variant. Therefore, there is a great necessity to spread the vaccination programs and prevent the spread of this dreadful epidemic by identifying and isolating afflicted patients. Furthermore, several COVID-19 tests are thought to be expensive, time-consuming, and require the use of adequately qualified persons to be carried out efficiently. In addition, we also conversed about how the various COVID-19 testing methods can be implemented for the first time in a developing country and their cost-effectiveness, accuracy, human resources requirements, and laboratory facilities.


Subject(s)
COVID-19 , Antiviral Agents , COVID-19 Testing , COVID-19 Vaccines , Developing Countries , Humans , SARS-CoV-2
16.
Curr Protein Pept Sci ; 23(3): 166-169, 2022.
Article in English | MEDLINE | ID: covidwho-1847031

ABSTRACT

Current coronavirus disease (COVID-19) is regarded as a primary respiratory and vascular disease leading to acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and endothelial dysfunction (ED) in severe cases. The causative virus of COVID-19 is SARS-CoV-2, which binds angiotensin-converting enzyme 2 (ACE2) for its entry. It has been shown that ED is linked to various COVID-19 complications since endothelial cells are regarded as the chief barrier against SARS-CoV- 2 invasion. SARS-CoV-2-indued ED leads to endotheliitis and thrombosis due to endothelial nitric oxide (NO) inhibition with subsequent vasoconstriction and tissue hypoxia. Loss of vasodilator NO and anti-thrombin factor from endothelial SARS-CoV-2 infection contribute to the progression of vascular dysfunction and coagulopathy. Therefore, NO restoration improves pulmonary function and hinders viral replication during respiratory viral infections, including COVID-19. L-arginine is a semiessential amino acid that has antiviral and immunomodulatory effects as well as improves the biosynthesis of NO in endothelial cells. L-arginine may reduce the risk of ALI through inhibition of generation of peroxynitrite and suppression of the release of proinflammatory cytokines from alveolar macrophages. Of interest, restoration of NO by L-arginine may attenuate SARS-CoV-2 infection through different mechanisms, including reduction binding of SARS-CoV-2 to ACE2, inhibition of transmembrane protease serine-type 2 (TMPRSS2), critical for the activation of SARS-CoV-2 spike protein and cellular entry, inhibition proliferation and replication of SARS-CoV-2, and prevention of SARS-CoV-2-induced coagulopathy. In conclusion, through antiviral and immunomodulatory effects, L-arginine and released NO have mutual and interrelated actions against SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Arginine , COVID-19/drug therapy , Dietary Supplements , Endothelial Cells/metabolism , Humans , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
17.
Comb Chem High Throughput Screen ; 25(14): 2387-2390, 2022.
Article in English | MEDLINE | ID: covidwho-1834105

ABSTRACT

Neglected Tropical Diseases (NTDs) are a group of twenty (20) chronic, communicable, infectious diseases endemic to the tropics and sub-tropics climate countries, which are intimately associated with poverty, poor sanitation, limited clean water, and healthcare delivery; and dwellers live in proximity to pathogens and diseases vectors. The pathogens are protozoans, bacteria, helminths, fungi, and viruses. NTDs currently affect about one billion people globally, out of which 500 million are Africans living in rural settlements with low political voice and support. In recent years, NTDs have received little research recognition, development, and funding because more research efforts by global health stakeholders are focused on recognized diseases like cancers, hepatitis, tuberculosis, Acquired Immune-Deficiency Syndrome (AIDS), and malaria that affects most developed countries. The emergence of the viral novel COVID-19 will exacerbate the burden of NTDs on disadvantaged communities as global health efforts are again focused on COVID-19 clearance in terms of research and development to find a drug/vaccine amidst other investigations on recognized infections. This development can result in high death tolls due to NTDs if control measures are not prioritized now. This perspective addresses the need for NTDs control amidst COVID-19 clearance efforts to mitigate another viral health crisis in Africa.


Subject(s)
COVID-19 , Tuberculosis , Humans , COVID-19/epidemiology , COVID-19/prevention & control , Pandemics/prevention & control , Neglected Diseases/epidemiology , Neglected Diseases/prevention & control , Global Health
18.
Comb Chem High Throughput Screen ; 25(14): 2413-2428, 2022.
Article in English | MEDLINE | ID: covidwho-1793195

ABSTRACT

Favipiravir is a potential antiviral drug undergoing clinical trials to manage various viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Favipiravir possesses antiviral properties against RNA viruses, including SARS-CoV-2. Unfortunately, these viruses do not have authorized antiviral drugs for the management of diseases resulting from their infection, hence the dire need to accentuate the discovery of antiviral drugs that are efficacious and have a broad spectrum. Favipiravir acts primarily by blocking inward and outward movements of the virus from cells. Favipiravir is a prodrug undergoing intracellular phosphorylation and ribosylation to form an active form, favipiravir-RTP, which binds viral RNA-dependent RNA polymerase (RdRp). Considering the novel mechanism of favipiravir action, especially in managing viral infections, it is vital to pay more attention to the promised favipiravir hold in the management of SARS-CoV-2, its efficacy, and dosage regimen, and interactions with other drugs. In conclusion, favipiravir possesses antiviral properties against RNA viruses, including COVID- 19. Favipiravir is effective against SARS-CoV-2 infection through inhibition of RdRp. Pre-clinical and large-scalp prospective studies are recommended for efficacy and long-term safety of favipiravir in COVID-19.


Subject(s)
COVID-19 , Viruses , Humans , COVID-19/drug therapy , SARS-CoV-2 , Prospective Studies , Amides/pharmacology , Amides/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , RNA-Dependent RNA Polymerase
19.
Inflammation ; 45(4): 1651-1667, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1709501

ABSTRACT

SARS-CoV-2 by the direct cytopathic effect or indirectly through the propagation of pro-inflammatory cytokines could cause endothelial dysfunction (ED) and oxidative stress (OS). It has been reported that OS is triggered by various types of viral infections, including SARS-CoV-2. Into the bargain, allopurinol is regarded as a potent antioxidant that acts through inhibition of xanthine oxidase (XO), which is an essential enzyme of purine metabolism. Herein, the present study aimed to find the potential protective effects of allopurinol on the biomarkers of OS and ED in patients with severe Covid-19. This single-center cohort study recruited 39 patients with mild-moderate Covid-19 compared with 41 patients with severe Covid-19. Nineteen patients with severe Covid-19 were on the allopurinol treatment because of underlying chronic gout 3 years ago compared with 22 Covid-19 patients not on this treatment. The recruited patients were allocated into three groups: group I, mild-moderate Covid-19 on the standard therapy (n = 39); group II, severe Covid-19 patients on the standard therapy only (n = 22); and group III, severe Covid-19 patients on the standard therapy plus allopurinol (n = 19). The duration of the study was 3 weeks from the time of hospitalization till the time of recovery. In addition, inflammatory biomarkers (D-dimer, LDH, ferritin, CRP, procalcitonin), neutrophil-lymphocyte ratio (NLR), endothelin-1 (ET-1), uric acid and oxidative stress index (OSI), CT scan score, and clinical score were evaluated at the time of admission and discharge regarding the effect of allopurinol treatment adds to the standard treatment of Covid-19. Allopurinol plus standard treatment reduced LDH, ferritin, CRP, procalcitonin, and ET-1 serum level significantly (P < 0.05) compared with Covid-19 patients on standard treatment. Besides, neutrophil (%), lymphocyte (%), and neutrophil-lymphocyte ratio (NLR) were reduced in patients with severe Covid-19 on standard treatment plus allopurinol compared with Covid-19 patients on standard treatment alone (P < 0.01). OSI was higher in patients with severe Covid-19 than mild-moderate Covid-19 patients (P = 0.00001) at admission. At the time of discharge, the oxidative status of Covid-19 patients was significantly improved compared with that at admission (P = 0.01). In conclusion, Covid-19 severity is linked with high OS and inflammatory reaction with ED development. High uric acid in patients with severe Covid-19 is correlated with high OS and inflammatory biomarkers. Allopurinol with standard treatment in patients with severe Covid-19 reduced oxidative and inflammatory disorders with significant amelioration of ED and clinical outcomes.


Subject(s)
Allopurinol , COVID-19 , Endothelium, Vascular , Oxidative Stress , Allopurinol/therapeutic use , Biomarkers , COVID-19/drug therapy , Cohort Studies , Endothelium, Vascular/physiopathology , Ferritins , Humans , Procalcitonin , Prospective Studies , SARS-CoV-2 , Uric Acid
20.
Int Immunopharmacol ; 104: 108516, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1611782

ABSTRACT

Coronavirus disease 2019 (Covid-19) is a worldwide infectious disease caused by severe acute respiratory coronavirus 2 (SARS-CoV-2). In severe SARS-CoV-2 infection, there is severe inflammatory reactions due to neutrophil recruitments and infiltration in the different organs with the formation of neutrophil extracellular traps (NETs), which involved various complications of SARS-CoV-2 infection. Therefore, the objective of the present review was to explore the potential role of NETs in the pathogenesis of SARS-CoV-2 infection and to identify the targeting drugs against NETs in Covid-19 patients. Different enzyme types are involved in the formation of NETs, such as neutrophil elastase (NE), which degrades nuclear protein and release histones, peptidyl arginine deiminase type 4 (PADA4), which releases chromosomal DNA and gasdermin D, which creates pores in the NTs cell membrane that facilitating expulsion of NT contents. Despite of the beneficial effects of NETs in controlling of invading pathogens, sustained formations of NETs during respiratory viral infections are associated with collateral tissue injury. Excessive development of NETs in SARS-CoV-2 infection is linked with the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) due to creation of the NETs-IL-1ß loop. Also, aberrant NTs activation alone or through NETs formation may augment SARS-CoV-2-induced cytokine storm (CS) and macrophage activation syndrome (MAS) in patients with severe Covid-19. Furthermore, NETs formation in SARS-CoV-2 infection is associated with immuno-thrombosis and the development of ALI/ARDS. Therefore, anti-NETs therapy of natural or synthetic sources may mitigate SARS-CoV-2 infection-induced exaggerated immune response, hyperinflammation, immuno-thrombosis, and other complications.


Subject(s)
Acute Lung Injury/immunology , Anti-Inflammatory Agents/pharmacology , COVID-19/immunology , Cytokine Release Syndrome/immunology , Extracellular Traps/immunology , Acute Lung Injury/prevention & control , Acute Lung Injury/virology , Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Cytokine Release Syndrome/prevention & control , Cytokine Release Syndrome/virology , Extracellular Traps/drug effects , Extracellular Traps/metabolism , Humans , Immunity, Innate/drug effects , Leukocyte Elastase/antagonists & inhibitors , Leukocyte Elastase/metabolism , Neutrophil Infiltration/drug effects , Phosphate-Binding Proteins/antagonists & inhibitors , Phosphate-Binding Proteins/metabolism , Pore Forming Cytotoxic Proteins/antagonists & inhibitors , Pore Forming Cytotoxic Proteins/metabolism , Protein-Arginine Deiminase Type 4/antagonists & inhibitors , Protein-Arginine Deiminase Type 4/metabolism , SARS-CoV-2/immunology
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