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The interacting physiology of COVID-19 and the renin-angiotensin-aldosterone system: Key agents for treatment.
Lumbers, ER, Head, R, Smith, GR, Delforce, SJ, Jarrott, B, H Martin, J, Pringle, KG
Pharmacology research & perspectives. 2022;(1):e00917
Abstract
SARS-CoV-2 interacting with its receptor, angiotensin-converting enzyme 2 (ACE2), turns the host response to viral infection into a dysregulated uncontrolled inflammatory response. This is because ACE2 limits the production of the peptide angiotensin II (Ang II) and SARS-CoV-2, through the destruction of ACE2, allows the uncontrolled production of Ang II. Recovery from trauma requires activation of both a tissue response to injury and activation of a whole-body response to maintain tissue perfusion. Tissue and circulating renin-angiotensin systems (RASs) play an essential role in the host response to infection and injury because of the actions of Ang II, mediated via its AT1 receptor. Both tissue and circulating arms of the renin angiotensin aldosterone system's (RAAS) response to injury need to be regulated. The effects of Ang II and the steroid hormone, aldosterone, on fluid and electrolyte homeostasis and on the circulation are controlled by elaborate feedback networks that respond to alterations in the composition and volume of fluids within the circulatory system. The role of Ang II in the tissue response to injury is however, controlled mainly by its metabolism and conversion to Ang-(1-7) by the enzyme ACE2. Ang-(1-7) has effects that are contrary to Ang II-AT1 R mediated effects. Thus, destruction of ACE2 by SARS-CoV-2 results in loss of control of the pro-inflammatory actions of Ang II and tissue destruction. Therefore, it is the response of the host to SARS-CoV-2 that is responsible for the pathogenesis of COVID-19.
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Resolving the equation between mucormycosis and COVID-19 disease.
Pasrija, R, Naime, M
Molecular biology reports. 2022;(4):3349-3356
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Abstract
The COVID-19 patients, both infected and recovered are rapidly contracting mucormycetes infections due to the 'Mucorales' order, under Zygomycetes class of fungi. The mucorales fungi commonly known to exist in our natural surroundings including soil, but the frequency of incidences was never rampant. This sudden spike in infections, is locally known as 'black fungus,' and is affecting various organs, including- eyes, sinuses, nose, brain, skin, intestine, lungs, etc. The severity of situation is ascertainable from the fact that, in certain cases surgical eye/jaws removal persists as the only viable option to avert mortality, as therapeutic interventions are limited. This epidemic situation intrigued experts to investigate the probable reason behind this unpredicted escalation in reported cases, including in recuperated COVID-19 patients, as person-to-person spread of infection is not common. The comparison of physiological parameters in healthy and COVID-19 afflicted patients highlights that the underlying conditions including diabetes mellitus, steroidal therapy, lymphopenia (decreased CD4+ and CD8+ lymphocytes), deregulated cytokine release storm, elevated free iron levels (hemosiderosis) in blood and insulin insensitivity are playing major roles in deteriorating conditions in rarely pathogenic fungal infections. This review is an attempt to explain the rationalities that makes people vulnerable to mucormycetes infection.
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The Effect of Plant Metabolites on Coronaviruses: A Comprehensive Review Focusing on their IC50 Values and Molecular Docking Scores.
Farshi, P, Kaya, EC, Hashempour-Baltork, F, Khosravi-Drani, K
Mini reviews in medicinal chemistry. 2022;(3):457-483
Abstract
Coronaviruses have caused worldwide outbreaks in different periods. SARS (severe acute respiratory syndrome) was the first emerged virus from this family, followed by MERS (Middle East respiratory syndrome) and SARS-CoV-2 (2019-nCoV or COVID 19), which is newly emerged. Many studies have been conducted on the application of chemical and natural drugs for treating these coronaviruses and they are mostly focused on inhibiting the proteases of viruses or blocking their protein receptors through binding to amino acid residues. Among many substances which are introduced to have an inhibitory effect against coronaviruses through the mentioned pathways, natural components are of specific interest. Secondary and primary metabolites from plants, are considered as potential drugs to have an inhibitory effect on coronaviruses. IC50 value (the concentration in which there is 50% loss in enzyme activity), molecular docking score and binding energy are parameters to understand the ability of metabolites to inhibit the specific virus. In this study we reviewed 154 papers on the effect of plant metabolites on different coronaviruses and data of their IC50 values, molecular docking scores and inhibition percentages are collected in tables. Secondary plant metabolites such as polyphenol, alkaloids, terpenoids, organosulfur compounds, saponins and saikosaponins, lectins, essential oil, and nicotianamine, and primary metabolites such as vitamins are included in this study.
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Pathogenesis of COVID-19 described through the lens of an undersulfated and degraded epithelial and endothelial glycocalyx.
du Preez, HN, Aldous, C, Hayden, MR, Kruger, HG, Lin, J
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2022;(1):e22052
Abstract
The glycocalyx surrounds every eukaryotic cell and is a complex mesh of proteins and carbohydrates. It consists of proteoglycans with glycosaminoglycan side chains, which are highly sulfated under normal physiological conditions. The degree of sulfation and the position of the sulfate groups mainly determine biological function. The intact highly sulfated glycocalyx of the epithelium may repel severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) through electrostatic forces. However, if the glycocalyx is undersulfated and 3-O-sulfotransferase 3B (3OST-3B) is overexpressed, as is the case during chronic inflammatory conditions, SARS-CoV-2 entry may be facilitated by the glycocalyx. The degree of sulfation and position of the sulfate groups will also affect functions such as immune modulation, the inflammatory response, vascular permeability and tone, coagulation, mediation of sheer stress, and protection against oxidative stress. The rate-limiting factor to sulfation is the availability of inorganic sulfate. Various genetic and epigenetic factors will affect sulfur metabolism and inorganic sulfate availability, such as various dietary factors, and exposure to drugs, environmental toxins, and biotoxins, which will deplete inorganic sulfate. The role that undersulfation plays in the various comorbid conditions that predispose to coronavirus disease 2019 (COVID-19), is also considered. The undersulfated glycocalyx may not only increase susceptibility to SARS-CoV-2 infection, but would also result in a hyperinflammatory response, vascular permeability, and shedding of the glycocalyx components, giving rise to a procoagulant and antifibrinolytic state and eventual multiple organ failure. These symptoms relate to a diagnosis of systemic septic shock seen in almost all COVID-19 deaths. The focus of prevention and treatment protocols proposed is the preservation of epithelial and endothelial glycocalyx integrity.
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Hypoxia-Inducible Factor Signaling in Inflammatory Lung Injury and Repair.
Evans, CE
Cells. 2022;(2)
Abstract
Inflammatory lung injury is characterized by lung endothelial cell (LEC) death, alveolar epithelial cell (AEC) death, LEC-LEC junction weakening, and leukocyte infiltration, which together disrupt nutrient and oxygen transport. Subsequently, lung vascular repair is characterized by LEC and AEC regeneration and LEC-LEC junction re-annealing, which restores nutrient and oxygen delivery to the injured tissue. Pulmonary hypoxia is a characteristic feature of several inflammatory lung conditions, including acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and severe coronavirus disease 2019 (COVID-19). The vascular response to hypoxia is controlled primarily by the hypoxia-inducible transcription factors (HIFs) 1 and 2. These transcription factors control the expression of a wide variety of target genes, which in turn mediate key pathophysiological processes including cell survival, differentiation, migration, and proliferation. HIF signaling in pulmonary cell types such as LECs and AECs, as well as infiltrating leukocytes, tightly regulates inflammatory lung injury and repair, in a manner that is dependent upon HIF isoform, cell type, and injury stimulus. The aim of this review is to describe the HIF-dependent regulation of inflammatory lung injury and vascular repair. The review will also discuss potential areas for future study and highlight putative targets for inflammatory lung conditions such as ALI/ARDS and severe COVID-19. In the development of HIF-targeted therapies to reduce inflammatory lung injury and/or enhance pulmonary vascular repair, it will be vital to consider HIF isoform- and cell-specificity, off-target side-effects, and the timing and delivery strategy of the therapeutic intervention.
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Platelet extracellular vesicles in COVID-19: Potential markers and makers.
Puhm, F, Flamand, L, Boilard, E
Journal of leukocyte biology. 2022;(1):63-74
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Abstract
Platelets and platelet extracellular vesicles (pEV) are at the crossroads of coagulation and immunity. Extracellular vesicles are messengers that not only transmit signals between cells, but also provide information about the status of their cell of origin. Thus, pEVs have potential as both biomarkers of platelet activation and contributors to pathology. Coronavirus Disease-19 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a complex disease affecting multiple organs and is characterized by a high degree of inflammation and risk of thrombosis in some patients. In this review, we introduce pEVs as valuable biomarkers in disease with a special focus on their potential as predictors of and contributors to COVID-19.
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Emerging Roles of Vitamin D-Induced Antimicrobial Peptides in Antiviral Innate Immunity.
White, JH
Nutrients. 2022;(2)
Abstract
Vitamin D deficiency, characterized by low circulating levels of calcifediol (25-hydroxyvitamin D, 25D) has been linked to increased risk of infections of bacterial and viral origin. Innate immune cells produce hormonal calcitriol (1,25-dihydroxyvitamin D, 1,25D) locally from circulating calcifediol in response to pathogen threat and an immune-specific cytokine network. Calcitriol regulates gene expression through its binding to the vitamin D receptor (VDR), a ligand-regulated transcription factor. The hormone-bound VDR induces the transcription of genes integral to innate immunity including pattern recognition receptors, cytokines, and most importantly antimicrobial peptides (AMPs). Transcription of the human AMP genes β-defensin 2/defensin-β4 (HBD2/DEFB4) and cathelicidin antimicrobial peptide (CAMP) is stimulated by the VDR bound to promoter-proximal vitamin D response elements. HDB2/DEFB4 and the active form of CAMP, the peptide LL-37, which form amphipathic secondary structures, were initially characterized for their antibacterial actively. Notably, calcitriol signaling induces secretion of antibacterial activity in vitro and in vivo, and low circulating levels of calcifediol are associated with diverse indications characterized by impaired antibacterial immunity such as dental caries and urinary tract infections. However, recent work has also provided evidence that the same AMPs are components of 1,25D-induced antiviral responses, including those against the etiological agent of the COVID-19 pandemic, the SARS-CoV2 coronavirus. This review surveys the evidence for 1,25D-induced antimicrobial activity in vitro and in vivo in humans and presents our current understanding of the potential mechanisms by which CAMP and HBD2/DEFB4 contribute to antiviral immunity.
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Interactions of Co, Cu, and non-metal phthalocyanines with external structures of SARS-CoV-2 using docking and molecular dynamics.
Alencar, WLM, da Silva Arouche, T, Neto, AFG, de Castro Ramalho, T, de Carvalho Júnior, RN, de Jesus Chaves Neto, AM
Scientific reports. 2022;(1):3316
Abstract
The new coronavirus, SARS-CoV-2, caused the COVID-19 pandemic, characterized by its high rate of contamination, propagation capacity, and lethality rate. In this work, we approach the use of phthalocyanines as an inhibitor of SARS-CoV-2, as they present several interactive properties of the phthalocyanines (Pc) of Cobalt (CoPc), Copper (CuPc) and without a metal group (NoPc) can interact with SARS-CoV-2, showing potential be used as filtering by adsorption on paints on walls, masks, clothes, and air conditioning filters. Molecular modeling techniques through Molecular Docking and Molecular Dynamics were used, where the target was the external structures of the virus, but specifically the envelope protein, main protease, and Spike glycoprotein proteases. Using the g_MM-GBSA module and with it, the molecular docking studies show that the ligands have interaction characteristics capable of adsorbing the structures. Molecular dynamics provided information on the root-mean-square deviation of the atomic positions provided values between 1 and 2.5. The generalized Born implicit solvation model, Gibbs free energy, and solvent accessible surface area approach were used. Among the results obtained through molecular dynamics, it was noticed that interactions occur since Pc could bind to residues of the active site of macromolecules, demonstrating good interactions; in particular with CoPc. Molecular couplings and free energy showed that S-gly active site residues interacted strongly with phthalocyanines with values of - 182.443 kJ/mol (CoPc), 158.954 kJ/mol (CuPc), and - 129.963 kJ/mol (NoPc). The interactions of Pc's with SARS-CoV-2 may predict some promising candidates for antagonists to the virus, which if confirmed through experimental approaches, may contribute to resolving the global crisis of the COVID-19 pandemic.
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The potential role of resveratrol as supportive antiviral in treating conditions such as COVID-19 - A formulator's perspective.
van Brummelen, R, van Brummelen, AC
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;:112767
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Abstract
With an increased transmissibility but milder form of disease of the omicron variant of COVID-19 and the newer antivirals often still out of reach of many populations, a refocus of the current treatment regimens is required. Safe, affordable, and available adjuvant treatments should also be considered and known drugs and substances need to be repurposed and tested. Resveratrol, a well-known antioxidant of natural origin, shown to act as an antiviral as well as playing a role in immune stimulation, down regulation of the pro-inflammatory cytokine release and reducing lung injury by reducing oxidative stress, is such an option. New initiatives and collaborations will however need to be found to unleash resveratrol's full potential in the pharmaceutical market.
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Levocetirizine and montelukast in the COVID-19 treatment paradigm.
May, BC, Gallivan, KH
International immunopharmacology. 2022;:108412
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Abstract
Levocetirizine, a third-generation antihistamine, and montelukast, a leukotriene receptor antagonist, exhibit remarkable synergistic anti-inflammatory activity across a spectrum of signaling proteins, cell adhesion molecules, and leukocytes. By targeting cellular protein activity, they are uniquely positioned to treat the symptoms of COVID-19. Clinical data to date with an associated six-month follow-up, suggests the combination therapy may prevent the progression of the disease from mild to moderate to severe, as well as prevent/treat many of the aspects of 'Long COVID,' thereby cost effectively reducing both morbidity and mortality. To investigate patient outcomes, 53 consecutive COVID-19 test (+) cases (ages 3-90) from a well-established, single-center practice in Boston, Massachusetts, between March - November 2020, were treated with levocetirizine and montelukast in addition to then existing protocols [2]. The data set was retrospectively reviewed. Thirty-four cases were considered mild (64%), 17 moderate (32%), and 2 (4%) severe. Several patients presented with significant comorbidities (obesity: n = 22, 41%; diabetes: n = 10, 19%; hypertension: n = 24, 45%). Among the cohort there were no exclusions, no intubations, and no deaths. The pilot study in Massachusetts encompassed the first COVID-19 wave which peaked on April 23, 2020 as well as the ascending portion of the second wave in the fall. During this period the average weekly COVID-19 case mortality rate (confirmed deaths/confirmed cases) varied considerably between 1 and 7.5% [37]. FDA has approved a multicenter, randomized, placebo-controlled, Phase 2 clinical trial design, replete with electronic diaries and laboratory metrics to explore scientific questions not addressed herein.