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1.
Aging Cell ; 21(6): e13646, 2022 06.
Article in English | MEDLINE | ID: covidwho-1883166

ABSTRACT

Older age and underlying conditions such as diabetes/obesity or immunosuppression are leading host risk factors for developing severe complications from COVID-19 infection. The pathogenesis of COVID-19-related cytokine storm, tissue damage, and fibrosis may be interconnected with fundamental aging processes, including dysregulated immune responses and cellular senescence. Here, we examined effects of key cytokines linked to cellular senescence on expression of SARS-CoV-2 viral entry receptors. We found exposure of human umbilical vein endothelial cells (HUVECs) to the inflammatory cytokines, TNF-α + IFN-γ or a cocktail of TNF-α + IFN-γ + IL-6, increased expression of ACE2/DPP4, accentuated the pro-inflammatory senescence-associated secretory phenotype (SASP), and decreased cellular proliferative capacity, consistent with progression towards a cellular senescence-like state. IL-6 by itself failed to induce substantial effects on viral entry receptors or SASP-related genes, while synergy between TNF-α and IFN-γ initiated a positive feedback loop via hyper-activation of the JAK/STAT1 pathway, causing SASP amplification. Breaking the interactive loop between senescence and cytokine secretion with JAK inhibitor ruxolitinib or antiviral drug remdesivir prevented hyper-inflammation, normalized SARS-CoV-2 entry receptor expression, and restored HUVECs proliferative capacity. This loop appears to underlie cytokine-mediated viral entry receptor activation and links with senescence and hyper-inflammation.


Subject(s)
COVID-19 , Interferon-gamma , SARS-CoV-2 , Tumor Necrosis Factor-alpha , COVID-19/drug therapy , COVID-19/virology , Cytokines/immunology , Drug Synergism , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Inflammation/drug therapy , Inflammation/virology , Interferon-gamma/pharmacology , Interleukin-6/metabolism , Receptors, Virus/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , STAT1 Transcription Factor/biosynthesis , STAT1 Transcription Factor/immunology , Tumor Necrosis Factor-alpha/pharmacology
2.
Molecules ; 27(9)2022 May 02.
Article in English | MEDLINE | ID: covidwho-1875712

ABSTRACT

Hydroxylated polyphenols, also called flavonoids, are richly present in vegetables, fruits, cereals, nuts, herbs, seeds, stems, and flowers of numerous plants. They possess numerous medicinal properties such as antioxidant, anti-cancer, anti-microbial, neuroprotective, and anti-inflammation. Studies show that flavonoids activate antioxidant pathways that render an anti-inflammatory effect. They inhibit the secretions of enzymes such as lysozymes and ß-glucuronidase and inhibit the secretion of arachidonic acid, which reduces inflammatory reactions. Flavonoids such as quercetin, genistein, apigenin, kaempferol, and epigallocatechin 3-gallate modulate the expression and activation of a cytokine such as interleukin-1beta (IL-1ß), Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8); regulate the gene expression of many pro-inflammatory molecules such s nuclear factor kappa-light chain enhancer of activated B cells (NF-κB), activator protein-1 (AP-1), intercellular adhesion molecule-1 (ICAM), vascular cell adhesion molecule-1 (VCAM), and E-selectins; and also inhibits inducible nitric oxide (NO) synthase, cyclooxygenase-2, and lipoxygenase, which are pro-inflammatory enzymes. Understanding the anti-inflammatory action of flavonoids provides better treatment options, including coronavirus disease 2019 (COVID-19)-induced inflammation, inflammatory bowel disease, obstructive pulmonary disorder, arthritis, Alzheimer's disease, cardiovascular disease, atherosclerosis, and cancer. This review highlights the sources, biochemical activities, and role of flavonoids in enhancing human health.


Subject(s)
COVID-19 , Flavonoids , Anti-Inflammatory Agents/adverse effects , Antioxidants/adverse effects , Flavonoids/chemistry , Flavonoids/pharmacology , Flavonoids/therapeutic use , Humans , Inflammation/drug therapy , NF-kappa B/metabolism , Tumor Necrosis Factor-alpha/pharmacology
3.
Int J Mol Sci ; 22(24)2021 Dec 13.
Article in English | MEDLINE | ID: covidwho-1599176

ABSTRACT

To determine whether mitigating the harmful effects of circulating microvesicle-associated inducible nitric oxide (MV-A iNOS) in vivo increases the survival of challenged mice in three different mouse models of sepsis, the ability of anti-MV-A iNOS monoclonal antibodies (mAbs) to rescue challenged mice was assessed using three different mouse models of sepsis. The vivarium of a research laboratory Balb/c mice were challenged with an LD80 dose of either lipopolysaccharide (LPS/endotoxin), TNFα, or MV-A iNOS and then treated at various times after the challenge with saline as control or with an anti-MV-A iNOS mAb as a potential immunotherapeutic to treat sepsis. Each group of mice was checked daily for survivors, and Kaplan-Meier survival curves were constructed. Five different murine anti-MV-A iNOS mAbs from our panel of 24 murine anti-MV-A iNOS mAbs were found to rescue some of the challenged mice. All five murine mAbs were used to genetically engineer humanized anti-MV-A iNOS mAbs by inserting the murine complementarity-determining regions (CDRs) into a human IgG1,kappa scaffold and expressing the humanized mAbs in CHO cells. Three humanized anti-MV-A iNOS mAbs were effective at rescuing mice from sepsis in three different animal models of sepsis. The effectiveness of the treatment was both time- and dose-dependent. Humanized anti-MV-A iNOS rHJ mAb could rescue up to 80% of the challenged animals if administered early and at a high dose. Our conclusions are that MV-A iNOS is a novel therapeutic target to treat sepsis; anti-MV-A iNOS mAbs can mitigate the harmful effects of MV-A iNOS; the neutralizing mAb's efficacy is both time- and dose-dependent; and a specifically targeted immunotherapeutic for MV-A iNOS could potentially save tens of thousands of lives annually and could result in improved antibiotic stewardship.


Subject(s)
Cell-Derived Microparticles/metabolism , Nitric Oxide Synthase Type II/metabolism , Sepsis/therapy , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal, Humanized/pharmacology , Cell-Derived Microparticles/immunology , Disease Models, Animal , Humans , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred BALB C , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide Synthase Type II/immunology , Tumor Necrosis Factor-alpha/pharmacology
4.
Viruses ; 13(11)2021 11 03.
Article in English | MEDLINE | ID: covidwho-1502528

ABSTRACT

Men are disproportionately affected by the coronavirus disease-2019 (COVID-19), and face higher odds of severe illness and death compared to women. The vascular effects of androgen signaling and inflammatory cytokines in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated endothelial injury are not defined. We determined the effects of SARS-CoV-2 spike protein-mediated endothelial injury under conditions of exposure to androgen dihydrotestosterone (DHT) and tumor necrosis factor-a (TNF-α) and tested potentially therapeutic effects of mineralocorticoid receptor antagonism by spironolactone. Circulating endothelial injury markers VCAM-1 and E-selectin were measured in men and women diagnosed with COVID-19. Exposure of endothelial cells (ECs) in vitro to DHT exacerbated spike protein S1-mediated endothelial injury transcripts for the cell adhesion molecules E-selectin, VCAM-1 and ICAM-1 and anti-fibrinolytic PAI-1 (p < 0.05), and increased THP-1 monocyte adhesion to ECs (p = 0.032). Spironolactone dramatically reduced DHT+S1-induced endothelial activation. TNF-α exacerbated S1-induced EC activation, which was abrogated by pretreatment with spironolactone. Analysis from patients hospitalized with COVID-19 showed concordant higher circulating VCAM-1 and E-Selectin levels in men, compared to women. A beneficial effect of the FDA-approved drug spironolactone was observed on endothelial cells in vitro, supporting a rationale for further evaluation of mineralocorticoid antagonism as an adjunct treatment in COVID-19.


Subject(s)
COVID-19/pathology , Dihydrotestosterone/pharmacology , Endothelium, Vascular/pathology , Inflammation , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/physiology , Spironolactone/pharmacology , Angiotensin Receptor Antagonists/pharmacology , COVID-19/physiopathology , COVID-19/virology , Cell Adhesion Molecules/blood , Cells, Cultured , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Female , Humans , Male , Sex Characteristics , Tumor Necrosis Factor-alpha/pharmacology , Tumor Necrosis Factor-alpha/physiology , Valsartan/pharmacology
5.
SLAS Discov ; 26(9): 1079-1090, 2021 10.
Article in English | MEDLINE | ID: covidwho-1314244

ABSTRACT

The recent renascence of phenotypic drug discovery (PDD) is catalyzed by its ability to identify first-in-class drugs and deliver results when the exact molecular mechanism is partially obscure. Acute respiratory distress syndrome (ARDS) is a severe, life-threatening condition with a high mortality rate that has increased in frequency due to the COVID-19 pandemic. Despite decades of laboratory and clinical study, no efficient pharmacological therapy for ARDS has been found. An increase in endothelial permeability is the primary event in ARDS onset, causing the development of pulmonary edema that leads to respiratory failure. Currently, the detailed molecular mechanisms regulating endothelial permeability are poorly understood. Therefore, the use of the PDD approach in the search for efficient ARDS treatment can be more productive than classic target-based drug discovery (TDD), but its use requires a new cell-based assay compatible with high-throughput (HTS) and high-content (HCS) screening. Here we report the development of a new plate-based image cytometry method to measure endothelial barrier function. The incorporation of image cytometry in combination with digital image analysis substantially decreases assay variability and increases the signal window. This new method simultaneously allows for rapid measurement of cell monolayer permeability and cytological analysis. The time-course of permeability increase in human pulmonary artery endothelial cells (HPAECs) in response to the thrombin and tumor necrosis factor α treatment correlates with previously published data obtained by transendothelial resistance (TER) measurements. Furthermore, the proposed image cytometry method can be easily adapted for HTS/HCS applications.


Subject(s)
COVID-19/diagnostic imaging , High-Throughput Screening Assays/methods , Image Cytometry/methods , Respiratory Distress Syndrome/diagnostic imaging , COVID-19/diagnosis , COVID-19/virology , Cell Membrane Permeability/genetics , Drug Discovery , Endothelial Cells/ultrastructure , Endothelial Cells/virology , Humans , Image Processing, Computer-Assisted , Pandemics/prevention & control , Phenotype , Pulmonary Artery/diagnostic imaging , Pulmonary Artery/pathology , Pulmonary Artery/virology , Pulmonary Edema/diagnosis , Pulmonary Edema/diagnostic imaging , Pulmonary Edema/virology , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/virology , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/diagnostic imaging , Respiratory Insufficiency/virology , SARS-CoV-2/pathogenicity , Thrombin/pharmacology , Tumor Necrosis Factor-alpha/pharmacology
6.
Invest Ophthalmol Vis Sci ; 62(7): 25, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1280514

ABSTRACT

Purpose: The ocular surface is considered an important route for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. The expression level of the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is vital for viral infection. However, the regulation of ACE2 expression on the ocular surface is still unknown. We aimed to determine the change in ACE2 expression in inflamed corneal epithelium and explore potential drugs to reduce the expression of ACE2 on the ocular surface. Methods: The expression of the SARS-CoV-2 receptors ACE2 and TMPRSS2 in human corneal epithelial cells (HCECs) was examined by qPCR and Western blotting. The altered expression of ACE2 in inflammatory corneal epithelium was evaluated in TNFα- and IL-1ß-stimulated HCECs and inflamed mouse corneal epithelium, and the effect of resveratrol on ACE2 expression in HCECs was detected by immunofluorescence and Western blot analysis. Results: ACE2 and TMPRSS2 are expressed on the human corneal epithelial cells. ACE2 expression is upregulated in HCECs by stimulation with TNFα and IL-1ß and inflamed mouse corneas, including dry eye and alkali-burned corneas. In addition, resveratrol attenuates the increased expression of ACE2 induced by TNFα in HCECs. Conclusions: This study demonstrates that ACE2 is highly expressed in HCECs and can be upregulated by stimulation with inflammatory cytokines and inflamed mouse corneal epithelium. Resveratrol may be able to reduce the increased expression of ACE2 on the inflammatory ocular surface. Our work suggests that patients with an inflammatory ocular surface may display higher ACE2 expression, which increases the risk of SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Enzyme Inhibitors/pharmacology , Epithelium, Corneal/enzymology , Gene Expression Regulation, Enzymologic/physiology , Keratitis/enzymology , Resveratrol/pharmacology , SARS-CoV-2/physiology , Adult , Angiotensin-Converting Enzyme 2/metabolism , Animals , Blotting, Western , Cells, Cultured , Epithelium, Corneal/drug effects , Gene Expression Regulation, Enzymologic/drug effects , Humans , Inflammation/drug therapy , Inflammation/enzymology , Interleukin-1beta/pharmacology , Keratitis/drug therapy , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Microscopy, Fluorescence , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Receptors, Virus/metabolism , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Up-Regulation
7.
Am J Gastroenterol ; 115(10): 1722-1724, 2020 10.
Article in English | MEDLINE | ID: covidwho-725265

ABSTRACT

INTRODUCTION: It has been hypothesized that people suffering from inflammatory bowel disease (IBD) have an increased risk of coronavirus disease (COVID-19). However, it is not known whether immunosuppressive therapies exacerbate the COVID-19 outcome. METHODS: We reviewed data on the prevalence and clinical outcomes of COVID-19 in patients with IBD. RESULTS: COVID-19 prevalence in patients with IBD was comparable with that in the general population. Therapies using antitumor necrosis factor-α agents have been associated with better clinical outcomes. DISCUSSION: Management and treatments provided by gastroenterologists were effective in reducing COVID-19 risk. Antitumor necrosis factor-α agents seem to mitigate the course of COVID-19.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/epidemiology , Immunosuppressive Agents/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Pneumonia, Viral/epidemiology , Tumor Necrosis Factor-alpha/therapeutic use , Betacoronavirus/isolation & purification , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques/statistics & numerical data , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/therapy , Humans , Inflammatory Bowel Diseases/immunology , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/therapy , Prevalence , SARS-CoV-2 , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/pharmacology
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