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1.
Molecules ; 27(12)2022 Jun 12.
Article in English | MEDLINE | ID: covidwho-1917634

ABSTRACT

Inflammation is a severe topic in the immune system and play a role as pro-inflammatory mediators. In response to such inflammatory substances, immune cells release cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). Lipopolysaccharide (LPS) is known as an endotoxin in the outer membrane of Gram-negative bacteria, and it catalyzes inflammation by stimulating the secretion of inflammatory-mediated cytokines such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) by stimulated immune cells. Among the pathways involved in inflammation, nuclear factor kappa (NF-кB) and mitogen-activated protein kinases (MAPKs) are important. NF-kB is a diploid composed of p65 and IkBα and stimulates the pro- gene. MAPKs is a family consisting of the extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38, JNK and p38 play a role as proinflammatory mediators. Thus, we aim to determine the scutellarein (SCU) effect on LPS stimulated RAW264.7 cells. Furthermore, since scutellarein has been shown to inhibit the SARS coronavirus helicase and has been used in Chinese medicine to treat inflammatory disorders like COVID-19, it would be required to examine scutellarein's anti-inflammatory mechanism. We identified inflammation-inducing substances using western blot with RAW264.7 cells and SCU. And we discovered that was reduced by treatment with SCU in p-p65 and p-IκBα. Also, we found that p-JNK and p-ERK were also decreased but there was no effect in p-p38. In addition, we have confirmed that the iNOS was also decreased after treatment but there is no change in the expression of COX-2. Therefore, this study shows that SCU can be used as a compound to treat inflammation.


Subject(s)
COVID-19 , NF-kappa B , Animals , Apigenin , Cyclooxygenase 2/metabolism , Cytokines/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/metabolism , Lipopolysaccharides/adverse effects , Mice , NF-kappa B/metabolism , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , RAW 264.7 Cells , Signal Transduction
2.
Molecules ; 27(7)2022 Apr 05.
Article in English | MEDLINE | ID: covidwho-1776292

ABSTRACT

Nitric oxide is a ubiquitous signaling radical that influences critical body functions. Its importance in the cardiovascular system and the innate immune response to bacterial and viral infections has been extensively investigated. The overproduction of NO is an early component of viral infections, including those affecting the respiratory tract. The production of high levels of NO is due to the overexpression of NO biosynthesis by inducible NO synthase (iNOS), which is involved in viral clearance. The development of NO-based antiviral therapies, particularly gaseous NO inhalation and NO-donors, has proven to be an excellent antiviral therapeutic strategy. The aim of this review is to systematically examine the multiple research studies that have been carried out to elucidate the role of NO in viral infections and to comprehensively describe the NO-based antiviral strategies that have been developed thus far. Particular attention has been paid to the potential mechanisms of NO and its clinical use in the prevention and therapy of COVID-19.


Subject(s)
COVID-19 , Virus Diseases , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Immunity, Innate , Nitric Oxide , Nitric Oxide Synthase Type II/metabolism , Virus Diseases/drug therapy
3.
Immunity ; 55(3): 423-441.e9, 2022 03 08.
Article in English | MEDLINE | ID: covidwho-1693372

ABSTRACT

Cell death plays an important role during pathogen infections. Here, we report that interferon-γ (IFNγ) sensitizes macrophages to Toll-like receptor (TLR)-induced death that requires macrophage-intrinsic death ligands and caspase-8 enzymatic activity, which trigger the mitochondrial apoptotic effectors, BAX and BAK. The pro-apoptotic caspase-8 substrate BID was dispensable for BAX and BAK activation. Instead, caspase-8 reduced pro-survival BCL-2 transcription and increased inducible nitric oxide synthase (iNOS), thus facilitating BAX and BAK signaling. IFNγ-primed, TLR-induced macrophage killing required iNOS, which licensed apoptotic caspase-8 activity and reduced the BAX and BAK inhibitors, A1 and MCL-1. The deletion of iNOS or caspase-8 limited SARS-CoV-2-induced disease in mice, while caspase-8 caused lethality independent of iNOS in a model of hemophagocytic lymphohistiocytosis. These findings reveal that iNOS selectively licenses programmed cell death, which may explain how nitric oxide impacts disease severity in SARS-CoV-2 infection and other iNOS-associated inflammatory conditions.


Subject(s)
COVID-19/immunology , Caspase 8/metabolism , Interferon-gamma/metabolism , Lymphohistiocytosis, Hemophagocytic/immunology , Macrophages/immunology , Mitochondria/metabolism , SARS-CoV-2/physiology , Animals , Caspase 8/genetics , Cells, Cultured , Cytotoxicity, Immunologic , Humans , Interferon-gamma/genetics , Macrophage Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , Nitric Oxide Synthase Type II/metabolism , Pathogen-Associated Molecular Pattern Molecules/immunology , Signal Transduction , bcl-2 Homologous Antagonist-Killer Protein/genetics , bcl-2 Homologous Antagonist-Killer Protein/metabolism , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism
4.
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
5.
Nutrients ; 13(11)2021 Nov 12.
Article in English | MEDLINE | ID: covidwho-1512522

ABSTRACT

BACKGROUND: We aimed to establish an acute treatment protocol to increase serum vitamin D, evaluate the effectiveness of vitamin D3 supplementation, and reveal the potential mechanisms in COVID-19. METHODS: We retrospectively analyzed the data of 867 COVID-19 cases. Then, a prospective study was conducted, including 23 healthy individuals and 210 cases. A total of 163 cases had vitamin D supplementation, and 95 were followed for 14 days. Clinical outcomes, routine blood biomarkers, serum levels of vitamin D metabolism, and action mechanism-related parameters were evaluated. RESULTS: Our treatment protocol increased the serum 25OHD levels significantly to above 30 ng/mL within two weeks. COVID-19 cases (no comorbidities, no vitamin D treatment, 25OHD <30 ng/mL) had 1.9-fold increased risk of having hospitalization longer than 8 days compared with the cases with comorbidities and vitamin D treatment. Having vitamin D treatment decreased the mortality rate by 2.14 times. The correlation analysis of specific serum biomarkers with 25OHD indicated that the vitamin D action in COVID-19 might involve regulation of INOS1, IL1B, IFNg, cathelicidin-LL37, and ICAM1. CONCLUSIONS: Vitamin D treatment shortened hospital stay and decreased mortality in COVID-19 cases, even in the existence of comorbidities. Vitamin D supplementation is effective on various target parameters; therefore, it is essential for COVID-19 treatment.


Subject(s)
COVID-19/drug therapy , SARS-CoV-2 , Vitamin D/administration & dosage , Antimicrobial Cationic Peptides/blood , Antimicrobial Cationic Peptides/genetics , Antimicrobial Cationic Peptides/metabolism , COVID-19/complications , COVID-19/mortality , Dietary Supplements , Gene Expression Regulation/drug effects , Humans , Intercellular Adhesion Molecule-1/blood , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/metabolism , Interferon-gamma/blood , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-1beta/blood , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Nitric Oxide Synthase Type II/blood , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Prospective Studies , Retrospective Studies , Vitamin D/blood , Vitamin D/pharmacology , Vitamins/administration & dosage , Vitamins/pharmacology
6.
Mol Neurobiol ; 59(1): 445-458, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1491383

ABSTRACT

In addition to respiratory complications produced by SARS-CoV-2, accumulating evidence suggests that some neurological symptoms are associated with the disease caused by this coronavirus. In this study, we investigated the effects of the SARS-CoV-2 spike protein S1 stimulation on neuroinflammation in BV-2 microglia. Analyses of culture supernatants revealed an increase in the production of TNF-α, IL-6, IL-1ß and iNOS/NO. S1 also increased protein levels of phospho-p65 and phospho-IκBα, as well as enhanced DNA binding and transcriptional activity of NF-κB. These effects of the protein were blocked in the presence of BAY11-7082 (1 µM). Exposure of S1 to BV-2 microglia also increased the protein levels of NLRP3 inflammasome and enhanced caspase-1 activity. Increased protein levels of p38 MAPK was observed in BV-2 microglia stimulated with the spike protein S1 (100 ng/ml), an action that was reduced in the presence of SKF 86,002 (1 µM). Results of immunofluorescence microscopy showed an increase in TLR4 protein expression in S1-stimulated BV-2 microglia. Furthermore, pharmacological inhibition with TAK 242 (1 µM) and transfection with TLR4 small interfering RNA resulted in significant reduction in TNF-α and IL-6 production in S1-stimulated BV-2 microglia. These results have provided the first evidence demonstrating S1-induced neuroinflammation in BV-2 microglia. We propose that induction of neuroinflammation by this protein in the microglia is mediated through activation of NF-κB and p38 MAPK, possibly as a result of TLR4 activation. These results contribute to our understanding of some of the mechanisms involved in CNS pathologies of SARS-CoV-2.


Subject(s)
Microglia/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Animals , Caspase 1/metabolism , Cell Line , Furans/pharmacology , Indenes/pharmacology , Inflammasomes/metabolism , Interleukin-1beta/genetics , Interleukin-6/metabolism , Mice , Microglia/pathology , NF-kappa B/metabolism , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , Nitriles/pharmacology , RNA, Small Interfering , Recombinant Proteins/metabolism , Sulfonamides/pharmacology , Sulfones/pharmacology , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
7.
Molecules ; 26(16)2021 Aug 22.
Article in English | MEDLINE | ID: covidwho-1376916

ABSTRACT

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a "two-bottle" as well as a "drinking in the dark" paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.


Subject(s)
Alcohol Drinking/pathology , Cannabinoid Receptor Antagonists/pharmacology , Endotoxemia/pathology , Ethanol/adverse effects , Nitric Oxide Synthase Type II/antagonists & inhibitors , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Alcohol Drinking/blood , Animals , Anxiety/blood , Anxiety/complications , Behavior, Animal/drug effects , Catalepsy/chemically induced , Catalepsy/complications , Cyclohexanols/administration & dosage , Elevated Plus Maze Test , Endotoxemia/blood , Endotoxemia/complications , Endotoxins/blood , Gastrointestinal Tract/drug effects , Gastrointestinal Tract/metabolism , Hypothermia, Induced , Mice, Inbred C57BL , Nitric Oxide Synthase Type II/metabolism , Pyrazoles/administration & dosage , Receptor, Cannabinoid, CB1/metabolism , Rimonabant/administration & dosage , Rimonabant/pharmacology , Stereoisomerism , Sulfonamides/administration & dosage
8.
Nutr Diabetes ; 11(1): 20, 2021 06 23.
Article in English | MEDLINE | ID: covidwho-1281688

ABSTRACT

Defences to pathogens such as SarCoV2 in mammals involves interactions between immune functions and metabolic pathways to eradicate infection while preventing hyperinflammation. Amino acid metabolic pathways represent with other antimicrobial agent potential targets for therapeutic strategies. iNOS-mediated production of NO from Arg is involved in the innate inflammatory response to pathogens and NO overproduction can induce hyperinflammation. The two Arg-catabolising enzymes Arg1 and IDO1 reduce the hyperinflammation by an immunosuppressive effect via either Arg starvation (for Arg1) or via the immunoregulatory activity of the Arg-derived metabolites Kyn (for IDO1). In response to amino acid abundance mTOR activates the host protein translation and Coronaviruses use this machinery for their own protein synthesis and replication. In contrast GCN2, the sensor of amino acid starvation, activates pathways that restrict inflammation and viral replication. Gln depletion alters the immune response that become more suppressive, by favouring a regulatory T phenotype rather than a Th1 phenotype. Proliferating activated immune cells are highly dependent on Ser, activation and differentiation of T cells need enough Ser and dietary Ser restriction can inhibit their proliferation. Cys is strictly required for T-cell proliferation because they cannot convert Met to Cys. Restricting Met inhibits both viral RNA cap methylation and replication, and the proliferation of infected cells with an increased requirement for Met. Phe catabolism produces antimicrobial metabolites resulting in the inhibition of microbial growth and an immunosuppressive activity towards T lymphocytes.


Subject(s)
Amino Acids/metabolism , Immunity, Innate , Infections/therapy , Animals , Anti-Infective Agents/therapeutic use , Arginine/metabolism , Humans , Infections/metabolism , Inflammation/metabolism , Nitric Oxide Synthase Type II/metabolism , Signal Transduction , T-Lymphocytes/metabolism , TOR Serine-Threonine Kinases/metabolism , Virus Replication
9.
Nitric Oxide ; 111-112: 64-71, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1164254

ABSTRACT

Symptoms of COVID-19 range from asymptomatic/mild symptoms to severe illness and death, consequence of an excessive inflammatory process triggered by SARS-CoV-2 infection. The diffuse inflammation leads to endothelium dysfunction in pulmonary blood vessels, uncoupling eNOS activity, lowering NO production, causing pulmonary physiological alterations and coagulopathy. On the other hand, iNOS activity is increased, which may be advantageous for host defense, once NO plays antiviral effects. However, overproduction of NO may be deleterious, generating a pro-inflammatory effect. In this review, we discussed the role of endogenous NO as a protective or deleterious agent of the respiratory and vascular systems, the most affected in COVID-19 patients, focusing on eNOS and iNOS roles. We also reviewed the currently available NO therapies and pointed out possible alternative treatments targeting NO metabolism, which could help mitigate health crises in the present and future CoV's spillovers.


Subject(s)
COVID-19/metabolism , Nitric Oxide Synthase Type III/metabolism , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide/metabolism , SARS-CoV-2 , Blood Vessels/metabolism , Gene Expression Regulation, Enzymologic , Humans , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type III/genetics , Respiratory System/metabolism
10.
Adv Sci (Weinh) ; 8(7): 2003895, 2021 04.
Article in English | MEDLINE | ID: covidwho-1103262

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that has quickly and deeply affected the world, with over 60 million confirmed cases. There has been a great effort worldwide to contain the virus and to search for an effective treatment for patients who become critically ill with COVID-19. A promising therapeutic compound currently undergoing clinical trials for COVID-19 is nitric oxide (NO), which is a free radical that has been previously reported to inhibit the replication of several DNA and RNA viruses, including coronaviruses. Although NO has potent antiviral activity, it has a complex role in the immunological host responses to viral infections, i.e., it can be essential for pathogen control or detrimental for the host, depending on its concentration and the type of virus. In this Essay, the antiviral role of NO against SARS-CoV, SARS-CoV-2, and other human viruses is highlighted, current development of NO-based therapies used in the clinic is summarized, existing challenges are discussed and possible further developments of NO to fight viral infections are suggested.


Subject(s)
Antiviral Agents/therapeutic use , Nitric Oxide/therapeutic use , Virus Diseases/drug therapy , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/virology , Clinical Trials as Topic , Humans , Nitric Oxide/pharmacology , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide Synthase Type II/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Virus Diseases/pathology , Virus Replication/drug effects
11.
Eur J Clin Invest ; 51(1): e13443, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-901035

ABSTRACT

BACKGROUND: To reveal detailed histopathological changes, virus distributions, immunologic properties and multi-omic features caused by SARS-CoV-2 in the explanted lungs from the world's first successful lung transplantation of a COVID-19 patient. MATERIALS AND METHODS: A total of 36 samples were collected from the lungs. Histopathological features and virus distribution were observed by optical microscope and transmission electron microscope (TEM). Immune cells were detected by flow cytometry and immunohistochemistry. Transcriptome and proteome approaches were used to investigate main biological processes involved in COVID-19-associated pulmonary fibrosis. RESULTS: The histopathological changes of the lung tissues were characterized by extensive pulmonary interstitial fibrosis and haemorrhage. Viral particles were observed in the cytoplasm of macrophages. CD3+ CD4- T cells, neutrophils, NK cells, γ/δ T cells and monocytes, but not B cells, were abundant in the lungs. Higher levels of proinflammatory cytokines iNOS, IL-1ß and IL-6 were in the area of mild fibrosis. Multi-omics analyses revealed a total of 126 out of 20,356 significant different transcription and 114 out of 8,493 protein expression in lung samples with mild and severe fibrosis, most of which were related to fibrosis and inflammation. CONCLUSIONS: Our results provide novel insight that the significant neutrophil/ CD3+ CD4- T cell/ macrophage activation leads to cytokine storm and severe fibrosis in the lungs of COVID-19 patient and may contribute to a better understanding of COVID-19 pathogenesis.


Subject(s)
COVID-19/pathology , Hemorrhage/pathology , Lung Transplantation , Lung/pathology , Lymph Nodes/pathology , Pulmonary Fibrosis/pathology , B-Lymphocytes/pathology , B-Lymphocytes/ultrastructure , B-Lymphocytes/virology , COVID-19/genetics , COVID-19/metabolism , COVID-19/surgery , Chromatography, Liquid , Flow Cytometry , Gene Expression Profiling , Humans , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Killer Cells, Natural/pathology , Killer Cells, Natural/ultrastructure , Killer Cells, Natural/virology , Lung/metabolism , Lung/ultrastructure , Lung/virology , Lymph Nodes/metabolism , Lymph Nodes/ultrastructure , Lymph Nodes/virology , Macrophages, Alveolar/pathology , Macrophages, Alveolar/ultrastructure , Macrophages, Alveolar/virology , Male , Middle Aged , Monocytes/pathology , Monocytes/ultrastructure , Monocytes/virology , Neutrophils/pathology , Neutrophils/ultrastructure , Neutrophils/virology , Nitric Oxide Synthase Type II/metabolism , Proteomics , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/surgery , RNA-Seq , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes/pathology , T-Lymphocytes/ultrastructure , T-Lymphocytes/virology , Tandem Mass Spectrometry
12.
Cell Death Dis ; 11(10): 921, 2020 10 27.
Article in English | MEDLINE | ID: covidwho-894382

ABSTRACT

The immunological mechanisms underlying the clinical presentation of SARS-CoV-2 infection and those influencing the disease outcome remain to be defined. Myeloid-derived suppressor cells (MDSC) have been described to be highly increased during COVID-19, however, their role remains elusive. We performed an in depth analysis of MDSC in 128 SARS-CoV-2 infected patients. Polymorphonuclear (PMN)-MDSC expanded during COVID-19, in particular in patients who required intensive care treatments, and correlated with IL-1ß, IL-6, IL-8, and TNF-α plasma levels. PMN-MDSC inhibited T-cells IFN-γ production upon SARS-CoV-2 peptides stimulation, through TGF-ß- and iNOS-mediated mechanisms, possibly contrasting virus elimination. Accordingly, a multivariate regression analysis found a strong association between PMN-MDSC percentage and fatal outcome of the disease. The PMN-MDSC frequency was higher in non-survivors than survivors at the admission time, followed by a decreasing trend. Interestingly, this trend was associated with IL-6 increase in non-survivors but not in survivors. In conclusion, this study indicates PMN-MDSC as a novel factor in the pathogenesis of SARS-CoV2 infection, and open up to new therapeutic options.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/pathology , Myeloid-Derived Suppressor Cells/immunology , Pneumonia, Viral/pathology , T-Lymphocytes/immunology , Aged , Area Under Curve , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Coronavirus Infections/virology , Female , Humans , Interferon-gamma/metabolism , Interleukin-1beta/blood , Interleukin-6/blood , Male , Middle Aged , Myeloid-Derived Suppressor Cells/cytology , Neutrophils/cytology , Neutrophils/immunology , Neutrophils/metabolism , Nitric Oxide Synthase Type II/metabolism , Pandemics , Peptides/immunology , Peptides/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Proportional Hazards Models , ROC Curve , SARS-CoV-2 , Survival Rate , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Transforming Growth Factor beta/blood , Transforming Growth Factor beta/metabolism
13.
Neuromolecular Med ; 23(1): 184-198, 2021 03.
Article in English | MEDLINE | ID: covidwho-871558

ABSTRACT

Ergothioneine (ET) is a naturally occurring antioxidant that is synthesized by non-yeast fungi and certain bacteria. ET is not synthesized by animals, including humans, but is avidly taken up from the diet, especially from mushrooms. In the current study, we elucidated the effect of ET on the hCMEC/D3 human brain endothelial cell line. Endothelial cells are exposed to high levels of the cholesterol oxidation product, 7-ketocholesterol (7KC), in patients with cardiovascular disease and diabetes, and this process is thought to mediate pathological inflammation. 7KC induces a dose-dependent loss of cell viability and an increase in apoptosis and necrosis in the endothelial cells. A relocalization of the tight junction proteins, zonula occludens-1 (ZO-1) and claudin-5, towards the nucleus of the cells was also observed. These effects were significantly attenuated by ET. In addition, 7KC induces marked increases in the mRNA expression of pro-inflammatory cytokines, IL-1ß IL-6, IL-8, TNF-α and cyclooxygenase-2 (COX2), as well as COX2 enzymatic activity, and these were significantly reduced by ET. Moreover, the cytoprotective and anti-inflammatory effects of ET were significantly reduced by co-incubation with an inhibitor of the ET transporter, OCTN1 (VHCL). This shows that ET needs to enter the endothelial cells to have a protective effect and is unlikely to act via extracellular neutralizing of 7KC. The protective effect on inflammation in brain endothelial cells suggests that ET might be useful as a nutraceutical for the prevention or management of neurovascular diseases, such as stroke and vascular dementia. Moreover, the ability of ET to cross the blood-brain barrier could point to its usefulness in combatting 7KC that is produced in the CNS during neuroinflammation, e.g. after excitotoxicity, in chronic neurodegenerative diseases, and possibly COVID-19-related neurologic complications.


Subject(s)
Antioxidants/pharmacology , COVID-19/complications , Endothelial Cells/drug effects , Ergothioneine/pharmacology , Ketocholesterols/toxicity , Nervous System Diseases/prevention & control , Neuroprotective Agents/pharmacology , Antioxidants/pharmacokinetics , Apoptosis/drug effects , Biological Transport , Blood-Brain Barrier , Brain/blood supply , Brain/cytology , Cell Line , Cholesterol/metabolism , Claudin-5 , Cyclooxygenase 2/biosynthesis , Cyclooxygenase 2/genetics , Cytokines/biosynthesis , Cytokines/genetics , Drug Evaluation, Preclinical , Ergothioneine/pharmacokinetics , Humans , Microvessels/cytology , Nervous System Diseases/etiology , Neuroprotective Agents/pharmacokinetics , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type III/metabolism , Organic Cation Transport Proteins , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Symporters , Zonula Occludens-1 Protein
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