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1.
Iran J Immunol ; 19(3): 330-336, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-2111332

ABSTRACT

Pregnant women with coronavirus disease 2019 (COVID-19) have a higher risk of morbidity and mortality compared with the general population. Possible pathways are: I) in patients with COVID-19, cytokine storm defined as the excess release of pro-inflammatory cytokines such as interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) has been associated with morbidities and an even higher rate of mortality. II) Labor, despite being a term/preterm, has an inflammatory nature, although, inflammation is more prominent in preterm delivery. During labor, different pro-inflammatory cytokines such as IL-1ß, IL-6, and TNF-α are involved which as mentioned, all are crucial role players in the cytokine storm. III) Tissue injury, and during labor, (especially cesarean section) is shown to cause inflammation via pro-inflammatory cytokines release including those involved in the cytokine storm through the activation of nuclear factor κB (NFκB). IV) post-partum hemorrhage with a notable amount of blood loss which can cause significant hypoxemia. In this condition, hypoxia-inducible factor 1α which has a cross-talk with NFκB, leads to the expression of IL-1ß, IL-6, and TNF-α as both angiogenic and pro-inflammatory factors. Considering all the mentioned issues and pathways, we suggest that clinicians be careful about the escalation of the inflammatory status in their pregnant COVID-19 patients during/following labor.


Subject(s)
COVID-19 , Tumor Necrosis Factor-alpha , Cesarean Section , Cytokine Release Syndrome , Cytokines/metabolism , Female , Humans , Infant, Newborn , Inflammation/pathology , Interleukin-1beta/metabolism , Interleukin-6 , NF-kappa B/metabolism , Pregnancy , Tumor Necrosis Factor-alpha/metabolism
2.
Front Immunol ; 13: 842468, 2022.
Article in English | MEDLINE | ID: covidwho-2080127

ABSTRACT

The role of the mucosal pulmonary antibody response in coronavirus disease 2019 (COVID-19) outcome remains unclear. Here, we found that in bronchoalveolar lavage (BAL) samples from 48 patients with severe COVID-19-infected with the ancestral Wuhan virus, mucosal IgG and IgA specific for S1, receptor-binding domain (RBD), S2, and nucleocapsid protein (NP) emerged in BAL containing viruses early in infection and persist after virus elimination, with more IgA than IgG for all antigens tested. Furthermore, spike-IgA and spike-IgG immune complexes were detected in BAL, especially when the lung virus has been cleared. BAL IgG and IgA recognized the four main RBD variants. BAL neutralizing titers were higher early in COVID-19 when virus replicates in the lung than later in infection after viral clearance. Patients with fatal COVID-19, in contrast to survivors, developed higher levels of mucosal spike-specific IgA than IgG but lost neutralizing activities over time and had reduced IL-1ß in the lung. Altogether, mucosal spike and NP-specific IgG and S1-specific IgA persisting after lung severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance and low pulmonary IL-1ß correlate with COVID-19 fatal outcome. Thus, mucosal SARS-CoV-2-specific antibodies may have adverse functions in addition to protective neutralization. Highlights: Mucosal pulmonary antibody response in COVID-19 outcome remains unclear. We show that in severe COVID-19 patients, mucosal pulmonary non-neutralizing SARS-CoV-2 IgA persit after viral clearance in the lung. Furthermore, low lung IL-1ß correlate with fatal COVID-19. Altogether, mucosal IgA may exert harmful functions beside protective neutralization.


Subject(s)
COVID-19 , Interleukin-1beta/metabolism , SARS-CoV-2 , Antibodies, Viral , Antigen-Antibody Complex , Cross-Sectional Studies , Humans , Immunoglobulin A , Immunoglobulin G , Lung , Nucleocapsid Proteins , Spike Glycoprotein, Coronavirus
3.
EBioMedicine ; 85: 104299, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2061075

ABSTRACT

A hyperinflammatory response during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection crucially worsens clinical evolution of coronavirus disease 2019 (COVID-19). The interaction between SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) triggers the activation of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Enhanced inflammasome activity has been associated with increased disease severity and poor prognosis. Evidence suggests that inflammasome activation and interleukin-1ß (IL-1ß) release aggravate pulmonary injury and induce hypercoagulability, favoring progression to respiratory failure and widespread thrombosis eventually leading to multiorgan failure and death. Observational studies with the IL-1 blockers anakinra and canakinumab provided promising results. In the SAVE-MORE trial, early treatment with anakinra significantly shortened hospital stay and improved survival in patients with moderate-to-severe COVID-19. In this review, we summarize current evidence supporting the pathogenetic role of the NLRP3 inflammasome and IL-1ß in COVID-19, and discuss clinical trials testing IL-1 inhibition in COVID-19.


Subject(s)
COVID-19 , Inflammasomes , Humans , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , COVID-19/complications , COVID-19/drug therapy , Interleukin 1 Receptor Antagonist Protein , SARS-CoV-2 , Interleukin-1beta/metabolism
4.
Medicine (Baltimore) ; 101(35): e29554, 2022 Sep 02.
Article in English | MEDLINE | ID: covidwho-2008659

ABSTRACT

BACKGROUND: Coronavirus (CoV) disease (COVID-19) identified in Wuhan, China, in 2019, is mainly characterized by atypical pneumonia and severe acute respiratory syndrome (SARS) and is caused by SARS CoV-2, which belongs to the Coronaviridae family. Determining the underlying disease mechanisms is central to the identification and development of COVID-19-specific drugs for effective treatment and prevention of human-to-human transmission, disease complications, and deaths. METHODS: Here, next-generation RNA sequencing (RNA Seq) data were obtained using Illumina Next Seq 500 from SARS CoV-infected A549 cells and mock-treated A549 cells from the Gene Expression Omnibus (GEO) (GSE147507), and quality control (QC) was assessed before RNA Seq analysis using CLC Genomics Workbench 20.0. Differentially expressed genes (DEGs) were imported into BioJupies to decipher COVID-19 induced signaling pathways and small molecules derived from chemical synthesis or natural sources to mimic or reverse COVID -19 specific gene signatures. In addition, iPathwayGuide was used to identify COVID-19-specific signaling pathways, as well as drugs and natural products with anti-COVID-19 potential. RESULTS: Here, we identified the potential activation of upstream regulators such as signal transducer and activator of transcription 2 (STAT2), interferon regulatory factor 9 (IRF9), and interferon beta (IFNß), interleukin-1 beta (IL-1ß), and interferon regulatory factor 3 (IRF3). COVID-19 infection activated key infectious disease-specific immune-related signaling pathways such as influenza A, viral protein interaction with cytokine and cytokine receptors, measles, Epstein-Barr virus infection, and IL-17 signaling pathway. Besides, we identified drugs such as prednisolone, methylprednisolone, diclofenac, compound JQ1, and natural products such as Withaferin-A and JinFuKang as candidates for further experimental validation of COVID-19 therapy. CONCLUSIONS: In conclusion, we have used the in silico next-generation knowledge discovery (NGKD) methods to discover COVID-19-associated pathways and specific therapeutics that have the potential to ameliorate the disease pathologies associated with COVID-19.


Subject(s)
Biological Products , COVID-19 , Epstein-Barr Virus Infections , A549 Cells , COVID-19/drug therapy , Cytokines/metabolism , Diclofenac , Herpesvirus 4, Human/genetics , Humans , Interferon Regulatory Factor-3/genetics , Interferon Regulatory Factor-3/metabolism , Interferon-Stimulated Gene Factor 3, gamma Subunit/genetics , Interferon-Stimulated Gene Factor 3, gamma Subunit/metabolism , Interferon-beta , Interleukin-17/metabolism , Interleukin-1beta/metabolism , Methylprednisolone , RNA , Receptors, Cytokine/genetics , SARS-CoV-2/genetics , STAT2 Transcription Factor , Sequence Analysis, RNA , Viral Proteins/genetics
5.
Turk Neurosurg ; 32(4): 680-687, 2022.
Article in English | MEDLINE | ID: covidwho-2006417

ABSTRACT

AIM: To evaluate the effects of favipiravir (FVP) on cell viability and cytotoxicity in human degenerated primary intervertebral disc (IVD) tissue cell cultures. Furthermore, the protein expressions of hypoxia-inducible factor 1 alpha (HIF-1α), nuclear factor-kappa-b (NF-kB), and interleukin-1 beta (IL-1ß) were also examined. MATERIAL AND METHODS: Untreated cell cultures served as the control group, named group 1. Cell cultures treated with FVP served as the study group, named group 2. Pharmacomolecular analyses were performed in all groups at 0, 24, 48, and 72 hours (h). Obtained data were evaluated statistically. RESULTS: Cell proliferation was suppressed in the FVP-treated samples compared to the control group samples at 24 and 72 h, and this was statistically significant (p < 0.05). Decreased or increased protein expression levels of HIF-1α, NF-κB, and IL-1ß in FVPtreated samples may be an indication of suppression in anabolic events as well as proliferation in IVD cultures. FVP administration showed that AF/NP cells in a culture medium may induce a strong inflammatory response to FVP. This strong inflammatory response is likely to cause slowed proliferation. It may also be a trigger for many catabolic events. NF-κB expression increased within the first 24 h and then decreased rapidly. Based on the data obtained, it may be suggested that the rapidly increasing NF-kB may have stimulated the expression of many antiproliferative genes. CONCLUSION: The suppression of IL-1ß and NF-kB protein expressions in IVD cells treated with FVP is important in the treatment of IVD degeneration (IDD). If the protein expression of HIF-1α could be increased along with the suppression of IL-1ß and NF-kB, FVP would perhaps be a promising pharmacological agent in the treatment of IDD.


Subject(s)
Intervertebral Disc Degeneration , Intervertebral Disc , Amides , Apoptosis , Autophagy , Cells, Cultured , Humans , Interleukin-1beta/metabolism , Intervertebral Disc Degeneration/genetics , NF-kappa B/metabolism , Pyrazines
6.
J Allergy Clin Immunol ; 150(4): 796-805, 2022 10.
Article in English | MEDLINE | ID: covidwho-1991092

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in a severe pneumonia associated with elevation of blood inflammatory parameters, reminiscent of cytokine storm syndrome. Steroidal anti-inflammatory therapies have shown efficacy in reducing mortality in critically ill patients; however, the mechanisms by which SARS-CoV-2 triggers such an extensive inflammation remain unexplained. OBJECTIVES: To dissect the mechanisms underlying SARS-CoV-2-associated inflammation in patients with severe coronavirus disease 2019 (COVID-19), we studied the role of IL-1ß, a pivotal cytokine driving inflammatory phenotypes, whose maturation and secretion are regulated by inflammasomes. METHODS: We analyzed nod-like receptor protein 3 pathway activation by means of confocal microscopy, plasma cytokine measurement, cytokine secretion following in vitro stimulation of blood circulating monocytes, and whole-blood RNA sequencing. The role of open reading frame 3a SARS-CoV-2 protein was assessed by confocal microscopy analysis following nucleofection of a monocytic cell line. RESULTS: We found that circulating monocytes from patients with COVID-19 display ASC (adaptor molecule apoptotic speck like protein-containing a CARD) specks that colocalize with nod-like receptor protein 3 inflammasome and spontaneously secrete IL-1ß in vitro. This spontaneous activation reverts following patient's treatment with the IL-1 receptor antagonist anakinra. Transfection of a monocytic cell line with cDNA coding for the ORF3a SARS-CoV-2 protein resulted in ASC speck formation. CONCLUSIONS: These results provide further evidence that IL-1ß targeting could represent an effective strategy in this disease and suggest a mechanistic explanation for the strong inflammatory manifestations associated with COVID-19.


Subject(s)
COVID-19 , Inflammasomes , Anti-Inflammatory Agents , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokines/metabolism , DNA, Complementary , Humans , Inflammasomes/metabolism , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-1beta/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Proteins , Receptors, Interleukin-1 , SARS-CoV-2
7.
Med Sci (Paris) ; 38(6-7): 545-552, 2022.
Article in French | MEDLINE | ID: covidwho-1908318

ABSTRACT

NLRP3 is one of the best characterized innate immune cytosolic sensor. As part of the innate immune response, the NLRP3 inflammasome detects a wide range of danger signals such as pathogens, tissue damages, cellular stress. The priming and activation of NLRP3 lead to the formation of an oligomeric intracellular complex and to the recruitment and activation of caspase-1. Once activated, not only this inflammasome complex controls the processing and release of pro-inflammatory factors including IL-1ß and IL-18, but also the inflammatory cell death pyroptosis mediated by gasdermin D pores. In this review, we describe the role of the NLRP3 inflammasome activation in viral infections with a particular interest on SARS-CoV-2 infection. In addition, we present therapies evaluated or under evaluation targeting the NLRP3 inflammasome pathway as COVID-19 treatment.


Title: L'inflammasome NLRP3 dans la physiopathologie des infections virales - Un focus sur la COVID-19. Abstract: L'inflammasome NLRP3 est un complexe multiprotéique intracellulaire impliqué dans la réponse immunitaire innée. Après la détection de signaux de dangers, tels que ceux provenant d'agents pathogènes, ce complexe s'assemble afin d'initier la production et la sécrétion de molécules pro-inflammatoires, comme l'IL(interleukine)-1ß et l'IL-18. L'inflammasome NLRP3 régule aussi l'activation de la gasdermine D, une protéine impliquée dans la mort cellulaire inflammatoire, ou pyroptose. Cette revue s'intéresse à l'activation et aux rôles de l'inflammasome NLRP3 dans les infections virales et plus particulièrement dans le cas de l'infection par le SARS-CoV-2. Une attention particulière est portée dans cette revue aux traitements évalués, ou en cours d'évaluation, ciblant la voie de l'inflammasome NLRP3 activée au cours de la COVID-19.


Subject(s)
COVID-19 , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , COVID-19/drug therapy , COVID-19/immunology , Humans , Inflammasomes/immunology , Inflammasomes/metabolism , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2
8.
Blood Adv ; 6(17): 5085-5099, 2022 09 13.
Article in English | MEDLINE | ID: covidwho-1789100

ABSTRACT

Accumulating evidence into the pathogenesis of COVID-19 highlights a hypercoagulability state with high risk of life-threatening thromboembolic complications. However, the mechanisms of hypercoagulability and their link to hyperinflammation remain poorly understood. Here, we investigate functions and mechanisms of platelet activation and platelet-monocyte interactions in inflammatory amplification during SARS-CoV-2 infection. We used a combination of immunophenotyping, single-cell analysis, functional assays, and pharmacological approaches to gain insights on mechanisms. Critically ill patients with COVID-19 exhibited increased platelet-monocyte aggregates formation. We identified a subset of inflammatory monocytes presenting high CD16 and low HLA-DR expression as the subset mainly interacting with platelets during severe COVID-19. Single-cell RNA-sequencing analysis indicated enhanced fibrinogen receptor Mac-1 in monocytes from patients with severe COVID-19. Monocytes from patients with severe COVID-19 displayed increased platelet binding and hyperresponsiveness to P-selectin and fibrinogen with respect to tumor necrosis factor-α and interleukin-1ß secretion. Platelets were able to orchestrate monocyte responses driving tissue factor (TF) expression, inflammatory activation, and inflammatory cytokines secretion in SARS-CoV-2 infection. Platelet-monocyte interactions ex vivo and in SARS-CoV-2 infection model in vitro reciprocally activated monocytes and platelets, inducing the heightened secretion of a wide panel of inflammatory mediators. We identified platelet adhesion as a primary signaling mechanism inducing mediator secretion and TF expression, whereas TF signaling played major roles in amplifying inflammation by inducing proinflammatory cytokines, especially tumor necrosis factor-α and interleukin-1ß. Our data identify platelet-induced TF expression and activity at the crossroad of coagulation and inflammation in severe COVID-19.


Subject(s)
COVID-19 , Thrombophilia , Thrombosis , Blood Platelets/metabolism , Cytokines/metabolism , Humans , Inflammation/pathology , Interleukin-1beta/metabolism , Monocytes/metabolism , SARS-CoV-2 , Thromboinflammation , Thromboplastin/metabolism , Thrombosis/metabolism , Tumor Necrosis Factor-alpha/metabolism
9.
Stem Cell Reports ; 17(3): 538-555, 2022 03 08.
Article in English | MEDLINE | ID: covidwho-1692861

ABSTRACT

To date, the direct causative mechanism of SARS-CoV-2-induced endotheliitis remains unclear. Here, we report that human ECs barely express surface ACE2, and ECs express less intracellular ACE2 than non-ECs of the lungs. We ectopically expressed ACE2 in hESC-ECs to model SARS-CoV-2 infection. ACE2-deficient ECs are resistant to the infection but are more activated than ACE2-expressing ones. The virus directly induces endothelial activation by increasing monocyte adhesion, NO production, and enhanced phosphorylation of p38 mitogen-associated protein kinase (MAPK), NF-κB, and eNOS in ACE2-expressing and -deficient ECs. ACE2-deficient ECs respond to SARS-CoV-2 through TLR4 as treatment with its antagonist inhibits p38 MAPK/NF-κB/ interleukin-1ß (IL-1ß) activation after viral exposure. Genome-wide, single-cell RNA-seq analyses further confirm activation of the TLR4/MAPK14/RELA/IL-1ß axis in circulating ECs of mild and severe COVID-19 patients. Circulating ECs could serve as biomarkers for indicating patients with endotheliitis. Together, our findings support a direct role for SARS-CoV-2 in mediating endothelial inflammation in an ACE2-dependent or -independent manner.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Models, Biological , SARS-CoV-2/physiology , Toll-Like Receptor 4/metabolism , Angiotensin-Converting Enzyme 2/genetics , COVID-19/pathology , COVID-19/virology , Endothelial Cells/cytology , Endothelial Cells/metabolism , Gene Expression Profiling , Human Umbilical Vein Endothelial Cells , Humans , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , NF-kappa B/metabolism , Pluripotent Stem Cells/cytology , Pluripotent Stem Cells/metabolism , SARS-CoV-2/isolation & purification , Severity of Illness Index , Single-Cell Analysis , Toll-Like Receptor 4/antagonists & inhibitors , Toll-Like Receptor 4/genetics , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolism
10.
Front Immunol ; 12: 799558, 2021.
Article in English | MEDLINE | ID: covidwho-1662582

ABSTRACT

The poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome and oxidative stress have independently been implicated in COVID-19, it is poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment of CD14highCD16- monocytes displaying inflammasome activation evidenced by caspase-1/ASC-speck formation in severe COVID-19 patients when compared to mild ones and healthy controls, respectively. Those cells also showed aberrant levels of mitochondrial superoxide and lipid peroxidation, both hallmarks of the oxidative stress response, which strongly correlated with caspase-1 activity. In addition, we found that NLRP3 inflammasome-derived IL-1ß secretion by SARS-CoV-2-exposed monocytes in vitro was partially dependent on lipid peroxidation. Importantly, altered inflammasome and stress responses persisted after short-term patient recovery. Collectively, our findings suggest oxidative stress/NLRP3 signaling pathway as a potential target for host-directed therapy to mitigate early COVID-19 hyperinflammation and also its long-term outcomes.


Subject(s)
COVID-19/metabolism , Inflammasomes/metabolism , Lipopolysaccharide Receptors/metabolism , Monocytes/metabolism , Oxidative Stress/physiology , Receptors, IgG/metabolism , Aged , COVID-19/pathology , Caspase 1/metabolism , Female , GPI-Linked Proteins/metabolism , Humans , Interleukin-1beta/metabolism , Male , Middle Aged , Mitochondria/metabolism , Mitochondria/pathology , Monocytes/pathology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/metabolism , Signal Transduction/physiology
11.
Autophagy ; 18(9): 2246-2248, 2022 09.
Article in English | MEDLINE | ID: covidwho-1650708

ABSTRACT

As the coronavirus disease 2019 (COVID-19) pandemic continues to wreak havoc, researchers around the globe are working together to understand how the responsible agent - severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) damages the respiratory system and other organs. Macroautophagy/autophagy is an innate immune response against viral infection and is known to be manipulated by positive-strand RNA viruses, including SARS-CoV-2. Nevertheless, the link between autophagic subversion and cell death or inflammation in COVID-19 remains unclear. Emerging evidence suggests that SARS-CoV-2 could trigger pyroptosis, a form of inflammatory programmed cell death characterized by the activation of inflammasomes and CASP1 (caspase 1) and the formation of transmembrane pores by GSDMD (gasdermin D). In this connection, autophagic flux impairment is a known activator of inflammasomes. This prompted us to investigate if SARS-CoV-2 could target autophagy to induce inflammasome-dependent pyroptosis in lung epithelial cells.Abbreviations: ATP6AP1: ATPase H+ transporting accessory protein 1; CASP1: caspase 1; COVID-19: coronavirus disease 2019; GSDMD: gasdermin D; IL1B: interleukin 1 beta; IL18: interleukin 18; KRT 18: keratin 18; NLRP3: NLR family pyrin domain containing 3; NOD: nucleotide oligomerization domain; NSP6: non-structural protein 6; TFEB: transcription factor EB; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.


Subject(s)
COVID-19 , Vacuolar Proton-Translocating ATPases , Autophagy , Caspase 1/metabolism , Humans , Inflammasomes/metabolism , Interleukin-1beta/metabolism , Lung/metabolism , Lysosomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pyroptosis , SARS-CoV-2 , Vacuolar Proton-Translocating ATPases/metabolism
12.
Nutrients ; 14(2)2022 Jan 07.
Article in English | MEDLINE | ID: covidwho-1613925

ABSTRACT

Despite the ongoing vaccination efforts, there is still an urgent need for safe and effective treatments to help curb the debilitating effects of COVID-19 disease. This systematic review aimed to investigate the efficacy of supplemental curcumin treatment on clinical outcomes and inflammation-related biomarker profiles in COVID-19 patients. We searched PubMed, Scopus, Web of Science, EMBASE, ProQuest, and Ovid databases up to 30 June 2021 to find studies that assessed the effects of curcumin-related compounds in mild to severe COVID-19 patients. Six studies were identified which showed that curcumin supplementation led to a significant decrease in common symptoms, duration of hospitalization and deaths. In addition, all of these studies showed that the intervention led to amelioration of cytokine storm effects thought to be a driving force in severe COVID-19 cases. This was seen as a significant (p < 0.05) decrease in proinflammatory cytokines such as IL1ß and IL6, with a concomitant significant (p < 0.05) increase in anti-inflammatory cytokines, including IL-10, IL-35 and TGF-α. Taken together, these findings suggested that curcumin exerts its beneficial effects through at least partial restoration of pro-inflammatory/anti-inflammatory balance. In conclusion, curcumin supplementation may offer an efficacious and safe option for improving COVID-19 disease outcomes. We highlight the point that future clinical studies of COVID-19 disease should employ larger cohorts of patients in different clinical settings with standardized preparations of curcumin-related compounds.


Subject(s)
COVID-19/drug therapy , Curcumin/administration & dosage , Dietary Supplements , Hospitalization , Phytotherapy/methods , Curcumin/pharmacology , Cytokines/metabolism , Female , Humans , Inflammation Mediators/metabolism , Interleukin-10/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Interleukins/metabolism , Male , Patient Acuity , Transforming Growth Factor alpha/metabolism , Treatment Outcome
13.
Front Immunol ; 12: 781352, 2021.
Article in English | MEDLINE | ID: covidwho-1613552

ABSTRACT

After the outburst of the SARS-CoV-2 pandemic, a worldwide research effort has led to the uncovering of many aspects of the COVID-19, among which we can count the outstanding role played by inflammatory cytokine milieu in the disease progression. Despite that, molecular mechanisms that regulate SARS-CoV-2 pathogenesis are still almost unidentified. In this study, we investigated whether the pro-inflammatory milieu of the host affects the susceptibility of SARS-CoV-2 infection by modulating ACE2 and TMPRSS2 expression. Our results indicated that the host inflammatory milieu favors SARS-CoV-2 infection by directly increasing TMPRSS2 expression. We unveiled the molecular mechanism that regulates this process and that can be therapeutically advantageously targeted.


Subject(s)
GATA2 Transcription Factor/metabolism , Interleukin-1beta/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/metabolism , Virus Internalization , A549 Cells , COVID-19 , Humans , p38 Mitogen-Activated Protein Kinases/metabolism
14.
Cell Death Differ ; 29(6): 1240-1254, 2022 06.
Article in English | MEDLINE | ID: covidwho-1612182

ABSTRACT

A recent mutation analysis suggested that Non-Structural Protein 6 (NSP6) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a key determinant of the viral pathogenicity. Here, by transcriptome analysis, we demonstrated that the inflammasome-related NOD-like receptor signaling was activated in SARS-CoV-2-infected lung epithelial cells and Coronavirus Disease 2019 (COVID-19) patients' lung tissues. The induction of inflammasomes/pyroptosis in patients with severe COVID-19 was confirmed by serological markers. Overexpression of NSP6 triggered NLRP3/ASC-dependent caspase-1 activation, interleukin-1ß/18 maturation, and pyroptosis of lung epithelial cells. Upstream, NSP6 impaired lysosome acidification to inhibit autophagic flux, whose restoration by 1α,25-dihydroxyvitamin D3, metformin or polydatin abrogated NSP6-induced pyroptosis. NSP6 directly interacted with ATP6AP1, a vacuolar ATPase proton pump component, and inhibited its cleavage-mediated activation. L37F NSP6 variant, which was associated with asymptomatic COVID-19, exhibited reduced binding to ATP6AP1 and weakened ability to impair lysosome acidification to induce pyroptosis. Consistently, infection of cultured lung epithelial cells with live SARS-CoV-2 resulted in autophagic flux stagnation, inflammasome activation, and pyroptosis. Overall, this work supports that NSP6 of SARS-CoV-2 could induce inflammatory cell death in lung epithelial cells, through which pharmacological rectification of autophagic flux might be therapeutically exploited.


Subject(s)
COVID-19 , Coronavirus Nucleocapsid Proteins , NLR Family, Pyrin Domain-Containing 3 Protein , SARS-CoV-2 , Vacuolar Proton-Translocating ATPases , COVID-19/metabolism , COVID-19/virology , Coronavirus Nucleocapsid Proteins/genetics , Coronavirus Nucleocapsid Proteins/metabolism , Humans , Inflammasomes/metabolism , Interleukin-1beta/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pyroptosis , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Vacuolar Proton-Translocating ATPases/metabolism
15.
Sci Rep ; 11(1): 24432, 2021 12 24.
Article in English | MEDLINE | ID: covidwho-1585772

ABSTRACT

Despite the initial success of some drugs and vaccines targeting COVID-19, understanding the mechanism underlying SARS-CoV-2 disease pathogenesis remains crucial for the development of further approaches to treatment. Some patients with severe Covid-19 experience a cytokine storm and display evidence of inflammasome activation leading to increased levels of IL-1ß and IL-18; however, other reports have suggested reduced inflammatory responses to Sars-Cov-2. In this study we have examined the effects of the Sars-Cov-2 envelope (E) protein, a virulence factor in coronaviruses, on inflammasome activation and pulmonary inflammation. In cultured macrophages the E protein suppressed inflammasome priming and NLRP3 inflammasome activation. Similarly, in mice transfected with E protein and treated with poly(I:C) to simulate the effects of viral RNA, the E protein, in an NLRP3-dependent fashion, reduced expression of pro-IL-1ß, levels of IL-1ß and IL-18 in broncho-alveolar lavage fluid, and macrophage infiltration in the lung. To simulate the effects of more advanced infection, macrophages were treated with both LPS and poly(I:C). In this setting the E protein increased NLRP3 inflammasome activation in both murine and human macrophages. Thus, the Sars-Cov-2 E protein may initially suppress the host NLRP3 inflammasome response to viral RNA while potentially increasing NLRP3 inflammasome responses in the later stages of infection. Targeting the Sars-Cov-2 E protein especially in the early stages of infection may represent a novel approach to Covid-19 therapy.


Subject(s)
Coronavirus Envelope Proteins/metabolism , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/metabolism , Animals , Bronchoalveolar Lavage Fluid/chemistry , COVID-19/pathology , COVID-19/virology , Coronavirus Envelope Proteins/genetics , Down-Regulation/drug effects , Endoplasmic Reticulum Stress , Humans , Inflammasomes/drug effects , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Janus Kinases/genetics , Janus Kinases/metabolism , Lipopolysaccharides/pharmacology , Macrophages/cytology , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/deficiency , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Poly I-C/pharmacology , RNA, Viral/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification
17.
Sci Rep ; 11(1): 23695, 2021 12 08.
Article in English | MEDLINE | ID: covidwho-1561520

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread across the world. Inactivating the virus in saliva and the oral cavity represents a reasonable approach to prevent human-to-human transmission because the virus is easily transmitted through oral routes by dispersed saliva. Persimmon-derived tannin is a condensed type of tannin that has strong antioxidant and antimicrobial activity. In this study, we investigated the antiviral effects of persimmon-derived tannin against SARS-CoV-2 in both in vitro and in vivo models. We found that persimmon-derived tannin suppressed SARS-CoV-2 titers measured by plaque assay in vitro in a dose- and time-dependent manner. We then created a Syrian hamster model by inoculating SARS-CoV-2 into hamsters' mouths. Oral administration of persimmon-derived tannin dissolved in carboxymethyl cellulose before virus inoculation dramatically reduced the severity of pneumonia with lower virus titers compared with a control group inoculated with carboxymethyl cellulose alone. In addition, pre-administration of tannin to uninfected hamsters reduced hamster-to-hamster transmission of SARS-CoV-2 from a cohoused, infected donor cage mate. These data suggest that oral administration of persimmon-derived tannin may help reduce the severity of SARS-CoV-2 infection and transmission of the virus.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Diospyros/chemistry , Tannins/therapeutic use , Administration, Oral , Animals , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , COVID-19/pathology , COVID-19/transmission , COVID-19/virology , Cricetinae , Diospyros/metabolism , Disease Models, Animal , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Lung/pathology , Lung/virology , Male , Mesocricetus , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Severity of Illness Index , Tannins/chemistry , Tannins/isolation & purification , Tannins/pharmacology , Viral Load/drug effects
18.
Eur Rev Med Pharmacol Sci ; 25(21): 6797-6812, 2021 11.
Article in English | MEDLINE | ID: covidwho-1524867

ABSTRACT

Cytokines in cardiac tissue plays a key role in progression of cardiometabolic diseases and cardiotoxicity induced by several anticancer drugs. Interleukin-1ß is one on the most studied regulator of cancer progression, survival and resistance to anticancer treatments. Recent findings indicate that interleukin1-ß exacerbates myocardial damages in cancer patients treated with chemotherapies and immune check-point inhibitors. Interleukin1-ß blocking agent canakinumab reduces major adverse cardiovascular events and cardiovascular death in recent cardiovascular trials. We focalized on the main biological functions of interleukin1-ß in cancer and cardiovascular diseases, summarizing the main clinical evidence available to date in literature. Especially in the era of SARS-CoV-2 infection, associated to coagulopathies, myocarditis and heart failure, cancer patients have an increased risk of cardiovascular complications compared to general population, therefore, the pharmacological inhibition of interleukin1-ß should be discussed and considered.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/adverse effects , COVID-19/complications , Cardiotoxicity/prevention & control , Interleukin-1beta/metabolism , Neoplasms/drug therapy , Anthracyclines/adverse effects , Anthracyclines/therapeutic use , Antibodies, Monoclonal, Humanized/immunology , Antineoplastic Agents/therapeutic use , COVID-19/virology , Cardiotoxicity/etiology , Cardiovascular Diseases/prevention & control , Humans , Interleukin-1beta/immunology , Neoplasms/complications , SARS-CoV-2/isolation & purification
19.
Eur J Med Chem ; 229: 114002, 2022 Feb 05.
Article in English | MEDLINE | ID: covidwho-1517139

ABSTRACT

Compounds targeting the inflammasome-caspase-1 pathway could be of use for the treatment of inflammation and inflammatory diseases. Previous caspase-1 inhibitors were in great majority covalent inhibitors and failed in clinical trials. Using a mixed modelling, computational screening, synthesis and in vitro testing approach, we identified a novel class of non-covalent caspase-1 non cytotoxic inhibitors which are able to inhibit IL-1ß release in activated macrophages in the low µM range, in line with the best activities observed for the known covalent inhibitors. Our compounds could form the basis of further optimization towards potent drugs for the treatment of inflammation and inflammatory disorders including also dysregulated inflammation in Covid 19.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Autoimmune Diseases/drug therapy , Caspase 1/drug effects , Inflammasomes/drug effects , Inflammation/drug therapy , Serpins/chemical synthesis , Serpins/pharmacology , Tetrazoles/chemical synthesis , Tetrazoles/therapeutic use , Viral Proteins/chemical synthesis , Viral Proteins/pharmacology , COVID-19 , Cell Division/drug effects , Drug Design , Drug Evaluation, Preclinical , Humans , Interleukin-1beta/metabolism , Macrophages/drug effects , Macrophages/metabolism , Tetrazoles/pharmacology , U937 Cells
20.
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
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