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1.
Int J Mol Sci ; 22(18)2021 Sep 16.
Article in English | MEDLINE | ID: covidwho-1409707

ABSTRACT

Global data correlate severe vitamin D deficiency with COVID-19-associated coagulopathy, further suggesting the presence of a hypercoagulable state in severe COVID-19 patients, which could promote thrombosis in the lungs and in other organs. The feedback loop between COVID-19-associated coagulopathy and vitamin D also involves platelets (PLTs), since vitamin D deficiency stimulates PLT activation and aggregation and increases fibrinolysis and thrombosis. Vitamin D and PLTs share and play specific roles not only in coagulation and thrombosis but also during inflammation, endothelial dysfunction, and immune response. Additionally, another 'fil rouge' between vitamin D and PLTs is represented by their role in mineral metabolism and bone health, since vitamin D deficiency, low PLT count, and altered PLT-related parameters are linked to abnormal bone remodeling in certain pathological conditions, such as osteoporosis (OP). Hence, it is possible to speculate that severe COVID-19 patients are characterized by the presence of several predisposing factors to bone fragility and OP that may be monitored to avoid potential complications. Here, we hypothesize different pervasive actions of vitamin D and PLT association in COVID-19, also allowing for potential preliminary information on bone health status during COVID-19 infection.


Subject(s)
Blood Platelets/immunology , COVID-19/complications , Osteoporosis/immunology , Thrombosis/immunology , Vitamin D Deficiency/immunology , Vitamin D/metabolism , Blood Platelets/metabolism , Bone Remodeling/immunology , COVID-19/blood , COVID-19/diagnosis , COVID-19/immunology , Feedback, Physiological , Humans , Osteoporosis/blood , Platelet Activation/immunology , Platelet Count , SARS-CoV-2/immunology , Severity of Illness Index , Thrombosis/blood , Vitamin D/blood , Vitamin D Deficiency/blood , Vitamin D Deficiency/complications
2.
EBioMedicine ; 58: 102887, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-684307

ABSTRACT

The pathogenesis of coronavirus disease 2019 (COVID-19) may be envisaged as the dynamic interaction between four vicious feedback loops chained or happening at once. These are the viral loop, the hyperinflammatory loop, the non-canonical renin-angiotensin system (RAS) axis loop, and the hypercoagulation loop. Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 lights the wick by infecting alveolar epithelial cells (AECs) and downregulating the angiotensin converting enzyme-2 (ACE2)/angiotensin (Ang-1-7)/Mas1R axis. The viral feedback loop includes evading the host's innate response, uncontrolled viral replication, and turning on a hyperactive adaptative immune response. The inflammatory loop is composed of the exuberant inflammatory response feeding back until exploding in an actual cytokine storm. Downregulation of the ACE2/Ang-(1-7)/Mas1R axis leaves the lung without a critical defense mechanism and turns the scale to the inflammatory side of the RAS. The coagulation loop is a hypercoagulable state caused by the interplay between inflammation and coagulation in an endless feedback loop. The result is a hyperinflammatory and hypercoagulable state producing acute immune-mediated lung injury and eventually, adult respiratory distress syndrome.


Subject(s)
Betacoronavirus/pathogenicity , Blood Coagulation , Coronavirus Infections/etiology , Cytokines/metabolism , Pneumonia, Viral/etiology , Renin-Angiotensin System , Animals , COVID-19 , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Coronavirus Infections/virology , Feedback, Physiological , Humans , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2
3.
Restor Neurol Neurosci ; 38(4): 343-354, 2020.
Article in English | MEDLINE | ID: covidwho-621099

ABSTRACT

Covid-19 is the acute illness caused by SARS-CoV-2 with initial clinical symptoms such as cough, fever, malaise, headache, and anosmia. After entry into cells, corona viruses (CoV) activate aryl hydrocarbon receptors (AhRs) by an indoleamine 2,3-dioxygenase (IDO1)-independent mechanism, bypassing the IDO1-kynurenine-AhR pathway. The IDO1-kynurenine-AhR signaling pathway is used by multiple viral, microbial and parasitic pathogens to activate AhRs and to establish infections. AhRs enhance their own activity through an IDO1-AhR-IDO1 positive feedback loop prolonging activation induced by pathogens. Direct activation of AhRs by CoV induces immediate and simultaneous up-regulation of diverse AhR-dependent downstream effectors, and this, in turn, results in a "Systemic AhR Activation Syndrome" (SAAS) consisting of inflammation, thromboembolism, and fibrosis, culminating in multiple organ injuries, and death. Activation of AhRs by CoV may lead to diverse sets of phenotypic disease pictures depending on time after infection, overall state of health, hormonal balance, age, gender, comorbidities, but also diet and environmental factors modulating AhRs. We hypothesize that elimination of factors known to up-regulate AhRs, or implementation of measures known to down-regulate AhRs, should decrease severity of infection. Although therapies selectively down-regulating both AhR and IDO1 are currently lacking, medications in clinical use such as dexamethasone may down-regulate both AhR and IDO1 genes, as calcitriol/vitamin D3 may down-regulate the AhR gene, and tocopherol/vitamin E may down-regulate the IDO1 gene. Supplementation of calcitriol should therefore be subjected to epidemiological studies and tested in prospective trials for prevention of CoV infections, as should tocopherol, whereas dexamethasone could be tried in interventional trials. Because lack of physical exercise activates AhRs via the IDO1-kynurenine-AhR signaling pathway increasing risk of infection, physical exercise should be encouraged during quarantines and stay-at-home orders during pandemic outbreaks. Understanding which factors affect gene expression of both AhR and IDO1 may help in designing therapies to prevent and treat humans suffering from Covid-19.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/physiopathology , Indoleamine-Pyrrole 2,3,-Dioxygenase/physiology , Pandemics , Pneumonia, Viral/physiopathology , Receptors, Aryl Hydrocarbon/physiology , Air Pollutants/adverse effects , COVID-19 , Calcitriol/therapeutic use , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Dexamethasone/therapeutic use , Exercise , Feedback, Physiological , Female , Fibrosis/etiology , Gene Expression Regulation/drug effects , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/biosynthesis , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Inflammation/etiology , Kynurenine/physiology , Male , Molecular Targeted Therapy , Multiple Organ Failure/etiology , Obstetric Labor, Premature/etiology , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pregnancy , Pregnancy Complications, Infectious/physiopathology , Receptors, Aryl Hydrocarbon/biosynthesis , Receptors, Aryl Hydrocarbon/genetics , SARS-CoV-2 , Sensation Disorders/etiology , Signal Transduction/drug effects , Signal Transduction/physiology , Thromboembolism/etiology , Tocopherols/therapeutic use
4.
Med Hypotheses ; 143: 109906, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-437087

ABSTRACT

Most COVID-19 infected individuals present with mild flu-like symptoms; however, 5-10% of cases suffer from life-threatening pneumonia and respiratory failure. The pathogenesis of SARS-CoV-2 and its pathology of associated acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis, coagulopathy and multiorgan failure is not known. SARS-CoV-2 is an envelope virus with S (spike), M (membrane), N (nucleocapsid) and E (envelop) proteins. In a closely related coronavirus (SARS-CoV), the transmembrane E protein exerts an important role in membrane-ionic transport through viroporins, deletion of which reduced levels of IL-1ß and a remarkably reduced lung edema compared to wild type. IL-1ß is generated by macrophages upon activation of intracellular NLRP3 (NOD-like, leucine rich repeat domains, and pyrin domain-containing protein 3), part of the functional NLRP3 inflammasome complex that detects pathogenic microorganisms and stressors, while neutrophils are enhanced by increasing levels of IL-1ß. Expiring neutrophils undergo "NETosis", producing thread-like extracellular structures termed neutrophil extracellular traps (NETs), which protect against mild infections and microbes. However, uncontrolled NET production can cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), coagulopathy, multiple organ failure, and autoimmune disease. Herein, we present arguments underlying our hypothesis that IL-1ß and NETs, mediated via NLRP3 inflammasomes, form a feed-forward loop leading to the excessive alveolar and endothelial damage observed in severe cases of COVID-19. Considering such assertions, we propose potential drug candidates that could be used to alleviate such pathologies. Considering that recent efforts to ascertain effective treatments of COVID-19 in severe patients has been less than successful, investigating novel avenues of treating this virus are essential.


Subject(s)
Acute Lung Injury/drug therapy , Acute Lung Injury/etiology , Betacoronavirus , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Extracellular Traps/drug effects , Interleukin-1beta/antagonists & inhibitors , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Acute Lung Injury/immunology , COVID-19 , Coronavirus Infections/immunology , Extracellular Traps/immunology , Feedback, Physiological , Humans , Inflammasomes/immunology , Interleukin-1beta/immunology , Models, Biological , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Pandemics , Pneumonia, Viral/immunology , SARS-CoV-2
5.
FASEB J ; 34(6): 7265-7269, 2020 06.
Article in English | MEDLINE | ID: covidwho-155381

ABSTRACT

As of April 20, 2020, over time, the COVID-19 pandemic has resulted in 157 970 deaths out of 2 319 066 confirmed cases, at a Case Fatality Rate of ~6.8%. With the pandemic rapidly spreading, and health delivery systems being overwhelmed, it is imperative that safe and effective pharmacotherapeutic strategies are rapidly explored to improve survival. In this paper, we use established and emerging evidence to propose a testable hypothesis that, a vicious positive feedback loop of des-Arg(9)-bradykinin- and bradykinin-mediated inflammation â†’ injury â†’ inflammation, likely precipitates life threatening respiratory complications in COVID-19. Through our hypothesis, we make the prediction that the FDA-approved molecule, icatibant, might be able to interrupt this feedback loop and, thereby, improve the clinical outcomes. This hypothesis could lead to basic, translational, and clinical studies aimed at reducing COVID-19 morbidity and mortality.


Subject(s)
Betacoronavirus , Bradykinin B2 Receptor Antagonists/therapeutic use , Bradykinin/analogs & derivatives , Coronavirus Infections/physiopathology , Models, Biological , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/physiopathology , Receptors, Virus/physiology , Angiotensin-Converting Enzyme 2 , Bradykinin/pharmacology , Bradykinin/physiology , Bradykinin/therapeutic use , Bradykinin B2 Receptor Antagonists/pharmacology , COVID-19 , Compassionate Use Trials , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Dyspnea/etiology , Dyspnea/physiopathology , Feedback, Physiological/drug effects , Humans , Inflammation , Off-Label Use , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Receptors, Bradykinin/drug effects , Receptors, Bradykinin/physiology , SARS-CoV-2
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