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1.
Inflammopharmacology ; 30(3): 811-820, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1802984

ABSTRACT

High-mobility group box 1 (HMGB1), a multifunctional nuclear protein, exists mainly within the nucleus of all mammal eukaryotic cells. It is actively secreted by the necrotic cells as a response to the inflammatory signaling pathway. HMGB1 binds to receptor ligands as RAGE, and TLR and becomes a pro-inflammatory cytokine with a robust capacity to trigger inflammatory response. It is a critical mediator of the pathogenesis of systemic inflammation in numerous inflammatory disorders. Release of HMGB1 is associated with different viral infections and strongly participates in the regulation of viral replication cycles. In COVID-19 era, high HMGB1 serum levels were observed in COVID-19 patients and linked with the disease severity, development of cytokine storm (CS), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). SARS-CoV-2-induced cytolytic effect may encourage release of HMGB1 due to nuclear damage. Besides, HMGB1 activates release of pro-inflammatory cytokines from immune cells and up-regulation of angiotensin I-converting enzyme 2 (ACE2). Therefore, targeting of the HMGB1 pathway by anti-HMGB1 agents, such as heparin, resveratrol and metformin, may decrease COVID-19 severity. HMGB1 signaling pathway has noteworthy role in the pathogenesis of SARS-CoV-2 infections and linked with development of ALI and ARDS in COVID-19 patients. Different endogenous and exogenous agents may affect release and activation of HMGB1 pathway. Targeting of HMGB1-mediated TLR2/TLR4, RAGE and MAPK signaling, might be a new promising drug candidate against development of ALI and/or ARDS in severely affected COVID-19 patients.


Subject(s)
Acute Lung Injury , COVID-19 , HMGB1 Protein , Respiratory Distress Syndrome , Acute Lung Injury/metabolism , Animals , COVID-19/drug therapy , Cytokine Release Syndrome , Cytokines , HMGB1 Protein/metabolism , Humans , Mammals/metabolism , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2
2.
Int J Mol Sci ; 23(3)2022 Feb 05.
Article in English | MEDLINE | ID: covidwho-1674671

ABSTRACT

Inflammation and thrombosis are closely intertwined in numerous disorders, including ischemic events and sepsis, as well as coronavirus disease 2019 (COVID-19). Thrombotic complications are markers of disease severity in both sepsis and COVID-19 and are associated with multiorgan failure and increased mortality. Immunothrombosis is driven by the complement/tissue factor/neutrophil axis, as well as by activated platelets, which can trigger the release of neutrophil extracellular traps (NETs) and release further effectors of immunothrombosis, including platelet factor 4 (PF4/CXCL4) and high-mobility box 1 protein (HMGB1). Many of the central effectors of deregulated immunothrombosis, including activated platelets and platelet-derived extracellular vesicles (pEVs) expressing PF4, soluble PF4, HMGB1, histones, as well as histone-decorated NETs, are positively charged and thus bind to heparin. Here, we provide evidence that adsorbents functionalized with endpoint-attached heparin efficiently deplete activated platelets, pEVs, PF4, HMGB1 and histones/nucleosomes. We propose that this elimination of central effectors of immunothrombosis, rather than direct binding of pathogens, could be of clinical relevance for mitigating thrombotic complications in sepsis or COVID-19 using heparin-functionalized adsorbents.


Subject(s)
Blood Proteins/isolation & purification , Heparin/pharmacology , /drug therapy , Blood Coagulation/physiology , Blood Platelets/metabolism , Blood Proteins/metabolism , COVID-19/metabolism , Extracellular Traps/immunology , Extracellular Traps/metabolism , HMGB Proteins/isolation & purification , HMGB Proteins/metabolism , HMGB1 Protein/isolation & purification , HMGB1 Protein/metabolism , Heparin/metabolism , Histones/isolation & purification , Histones/metabolism , Humans , Neutrophils/metabolism , Platelet Activation/immunology , Platelet Factor 4/isolation & purification , Platelet Factor 4/metabolism , SARS-CoV-2/pathogenicity , Sepsis/blood , Sepsis/metabolism , Thromboplastin/metabolism , Thrombosis/drug therapy
3.
Int Immunopharmacol ; 104: 108502, 2022 03.
Article in English | MEDLINE | ID: covidwho-1641351

ABSTRACT

BACKGROUND: SARS-CoV-2 infection can lead to the abnormal induction of cytokines and a dysregulated hyperinflammatory state that is implicated in disease severity and risk of death. There are several molecules present in blood associated with immune cellular response, inflammation, and oxidative stress that could be used as severity markers in respiratory viral infections such as COVID-19. However, there is a lack of clinical studies evaluating the role of oxidative stress-related molecules including glial fibrillary acidic protein (GFAP), the receptor for advanced glycation end products (RAGE), high mobility group box-1 protein (HMGB1) and cyclo-oxygenase-2 (COX-2) in COVID-19 pathogenesis. AIM: To evaluate the role of oxidative stress-related molecules in COVID-19. METHOD: An observational study with 93 Brazilian participants from September 2020 to April 2021, comprising 23 patients with COVID-19 admitted to intensive care unit (ICU), 19 outpatients with COVID-19 with mild to moderate symptoms, 17 individuals reporting a COVID-19 history, and 34 healthy controls. Blood samples were taken from all participants and western blot assay was used to determine the RAGE, HMGB1, GFAP, and COX-2 immunocontent. RESULTS: We found that GFAP levels were higher in patients with severe or critical COVID-19 compared to outpatients (p = 0.030) and controls (p < 0.001). A significant increase in immunocontents of RAGE (p < 0.001) and HMGB1 (p < 0.001) were also found among patients admitted to the ICU compared to healthy controls, as well as an overexpression of the inducible COX-2 (p < 0.001). In addition, we found a moderate to strong correlation between RAGE, GFAP and HMGB1 proteins. CONCLUSION: SARS-CoV-2 infection induces the upregulation of GFAP, RAGE, HMGB1, and COX-2 in patients with the most severe forms of COVID-19.


Subject(s)
COVID-19/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Case-Control Studies , Child , Cyclooxygenase 2/blood , Cyclooxygenase 2/metabolism , Female , Glial Fibrillary Acidic Protein/blood , Glial Fibrillary Acidic Protein/metabolism , HMGB1 Protein/blood , HMGB1 Protein/metabolism , Healthy Volunteers , Humans , Inflammation/blood , Inflammation/diagnosis , Inflammation/immunology , Inflammation/virology , Male , Middle Aged , Oxidative Stress/immunology , Receptor for Advanced Glycation End Products/blood , Receptor for Advanced Glycation End Products/metabolism , SARS-CoV-2/immunology , Severity of Illness Index , Up-Regulation/immunology , Young Adult
4.
Cells ; 10(12)2021 11 26.
Article in English | MEDLINE | ID: covidwho-1551567

ABSTRACT

High mobility group box 1 protein (HMGB1), a highly conserved nuclear DNA-binding protein, is a "damage-associated molecular pattern" molecule (DAMP) implicated in both stimulating and inhibiting innate immunity. As reviewed here, HMGB1 is an oxidation-reduction sensitive DAMP bearing three cysteines, and the post-translational modification of these residues establishes its proinflammatory and anti-inflammatory activities by binding to different extracellular cell surface receptors. The redox-sensitive signaling mechanisms of HMGB1 also occupy an important niche in innate immunity because HMGB1 may carry other DAMPs and pathogen-associated molecular pattern molecules (PAMPs). HMGB1 with DAMP/PAMP cofactors bind to the receptor for advanced glycation end products (RAGE) which internalizes the HMGB1 complexes by endocytosis for incorporation in lysosomal compartments. Intra-lysosomal HMGB1 disrupts lysosomal membranes thereby releasing the HMGB1-transported molecules to stimulate cytosolic sensors that mediate inflammation. This HMGB1-DAMP/PAMP cofactor pathway slowed the development of HMGB1-binding antagonists for diagnostic or therapeutic use. However, recent discoveries that HMGB1 released from neurons mediates inflammation via the TLR4 receptor system, and that cancer cells express fully oxidized HMGB1 as an immunosuppressive mechanism, offer new paths to targeting HMGB1 for inflammation, pain, and cancer.


Subject(s)
Disulfides/metabolism , HMGB1 Protein/metabolism , Inflammation/metabolism , Protein Processing, Post-Translational , Animals , COVID-19/metabolism , Humans , Sensory Receptor Cells/metabolism
5.
Inflammation ; 45(1): 172-179, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1474041

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) is associated with uncontrolled inflammatory responses. Loss of pulmonary angiotensin-converting enzyme 2 (ACE2) function has been associated with SARS-CoV-2 infection. The aberrant signalling and dysregulated inflammation characteristic of lung cancer have marked similarities with SARS-CoV-2 infection. Spearman's correlation analysis of The Cancer Genome Atlas (TCGA) datasets indicated an inverse correlation between ACE2 and IL6 in lung adenocarcinoma. qRT-PCR analysis revealed CoV-2-SRBD-mediated diminished ACE2 expression in lung cancer cells that was concomitant with increased IL6 expression. Western blot and qRT-PCR analysis suggested that treatment with methotrexate (MTx) dampened CoV-2-SRBD-mediated increase in JAK1/STAT3 phosphorylation, gp130, IL6, and folate-binding protein (FBP) expressions. MTx also rescued the diminished expression of ACE2 in CoV-2-SRBD transfected cells. As lung tissue injury in severely affected COVID-19 patients is characterised by aberrant inflammatory response, repurposing MTx as an effective therapy against critical regulators of inflammation in SARS-CoV-2 infection warrants investigation.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , Glycyrrhizic Acid/therapeutic use , Immunosuppressive Agents/therapeutic use , Interleukin-6/biosynthesis , Methotrexate/therapeutic use , A549 Cells , Adenocarcinoma of Lung/pathology , Anti-Inflammatory Agents/therapeutic use , COVID-19/immunology , COVID-19/pathology , Cell Line, Tumor , Cytokine Receptor gp130/biosynthesis , Folate Receptor 2/biosynthesis , HMGB1 Protein/antagonists & inhibitors , HMGB1 Protein/metabolism , Humans , Interleukin-6/immunology , Janus Kinase 1/metabolism , Lung Neoplasms/pathology , Phosphorylation/drug effects , SARS-CoV-2/drug effects , STAT3 Transcription Factor/metabolism , Spike Glycoprotein, Coronavirus/immunology
6.
J Immunol Res ; 2021: 4414544, 2021.
Article in English | MEDLINE | ID: covidwho-1443671

ABSTRACT

COVID-19 is a respiratory infection caused by the SARS-CoV-2 virus that can rapidly escalate to life-threatening pneumonia and acute respiratory distress syndrome (ARDS). Recently, extracellular high mobility group box 1 (HMGB1) has been identified as an essential component of cytokine storms that occur with COVID-19; HMGB1 levels correlate significantly with disease severity. Thus, the modulation of HMGB1 release may be vital for treating COVID-19. HMGB1 is a ubiquitous nuclear DNA-binding protein whose biological function depends on posttranslational modifications, its redox state, and its cellular localization. The acetylation of HMGB1 is a prerequisite for its translocation from the nucleus to the cytoplasm and then to the extracellular milieu. When released, HMGB1 acts as a proinflammatory cytokine that binds primarily to toll-like receptor 4 (TLR4) and RAGE, thereby stimulating immune cells, endothelial cells, and airway epithelial cells to produce cytokines, chemokines, and other inflammatory mediators. In this study, we demonstrate that inhaled [D-Ala2]-dynorphin 1-6 (leytragin), a peptide agonist of δ-opioid receptors, significantly inhibits HMGB1 secretion in mice with lipopolysaccharide- (LPS-) induced acute lung injury. The mechanism of action involves preventing HMGB1's hyperacetylation at critical lysine residues within nuclear localization sites, as well as promoting the expression of sirtuin 1 (SIRT1), an enzyme known to deacetylate HMGB1. Leytragin's effects are mediated by opioid receptors, since naloxone, an antagonist of opioid receptors, abrogates the leytragin effect on SIRT1 expression. Overall, our results identify leytragin as a promising therapeutic agent for the treatment of pulmonary inflammation associated with HMGB1 release. In a broader context, we demonstrate that the opioidergic system in the lungs may represent a promising target for the treatment of inflammatory lung diseases.


Subject(s)
Acute Lung Injury/drug therapy , Dynorphins/pharmacology , HMGB1 Protein/metabolism , Acetylation , Acute Lung Injury/metabolism , Animals , COVID-19/drug therapy , COVID-19/metabolism , Disease Models, Animal , Mice , Mice, Inbred C57BL , Receptors, Opioid/metabolism , Sirtuin 1/metabolism
7.
Biomolecules ; 11(8)2021 08 16.
Article in English | MEDLINE | ID: covidwho-1360720

ABSTRACT

The SARS-CoV-2 pandemic has completely disrupted the health systems of the entire planet. From the earliest months, it became increasingly clear that in addition to affecting the upper airways and lungs, there were other organs that could be affected. Among these, the skin became a real "sentinel signal" to be able to even suspect COVID-19. Background: this study deals with a little-explored issue for now: the study of skin immunopathology in SARS-CoV-2 positive subjects ascertained using the most reliable methods available. Methods: we used skin biopsy samples from SARS-CoV-2 positive and negative patients, studying morphology (Hematoxylin-Eosin), T lymphocyte population (CD4 and CD8), three markers such as HMGB-1, TIM-3 and HO-1 by immunohistochemistry. Results: although the presence of the CD4 and CD8 T population did not differ statistically significantly, we found greater activation and release of HMGB-1 in skin samples from SARS-CoV-2 positive patients, greater immunolabeling for TIM-3 at the level of CD4 and CD8 and a reduced expression of Heme oxygenase 1. Conclusions: these results support the possibility that there is immune deregulation in SARS-CoV-2 positive patients who develop skin manifestations of various kinds.


Subject(s)
COVID-19/complications , HMGB1 Protein/metabolism , Heme Oxygenase (Decyclizing)/metabolism , Hepatitis A Virus Cellular Receptor 2/metabolism , Skin Diseases/metabolism , Skin/metabolism , Adult , Aged , Female , Humans , Male , Middle Aged , Skin/pathology , Skin Diseases/etiology , Skin Diseases/pathology , T-Lymphocytes/metabolism
8.
J Med Virol ; 93(4): 2396-2405, 2021 04.
Article in English | MEDLINE | ID: covidwho-1217389

ABSTRACT

SARS-CoV-2 triggers a dysregulated innate immune system activation. As the mevalonate pathway (MVP) prevents the activation of inflammasomes and cytokine release and regulates endosomal transport, compromised signaling could be associated with the pathobiology of COVID-19. Prior transcriptomic studies of host cells in response to SARS-CoV-2 infection have not reported to date the effects of SARS-CoV-2 on the MVP. In this study, we accessed public data sets to report in silico investigations into gene expression. In addition, we proposed candidate genes that are thought to have a direct association with the pathogenesis of COVID-19, and which may be dependent on signals derived from the MVP. Our results revealed dysregulation of genes involved in the MVP. These results were not found when investigating the gene expression data from host cells infected with H3N2 influenza virus, H1N1 influenza virus, or respiratory syncytial virus. Our manually curated gene set showed significant gene expression variability in A549 cells infected with SARS-CoV-2, as per Blanco-Melo et al. data set (GSE147507). In light of the present findings, SARS-CoV-2 could hijack the MVP, leading to hyperinflammatory responses. Prompt reconstitution of this pathway with available agents should be considered in future studies.


Subject(s)
COVID-19/metabolism , Mevalonic Acid/metabolism , SARS-CoV-2/metabolism , A549 Cells , Autophagy , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Computer Simulation , Cytokines/immunology , Cytokines/metabolism , HMGB1 Protein/genetics , HMGB1 Protein/metabolism , Host-Pathogen Interactions , Humans , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/metabolism , Influenza A Virus, H3N2 Subtype/genetics , Influenza A Virus, H3N2 Subtype/metabolism , Influenza, Human/immunology , Influenza, Human/metabolism , SAM Domain and HD Domain-Containing Protein 1/genetics , SAM Domain and HD Domain-Containing Protein 1/metabolism , SARS-CoV-2/genetics , Signal Transduction , Transcriptome , Virus Replication
9.
Am J Trop Med Hyg ; 105(1): 73-80, 2021 05 03.
Article in English | MEDLINE | ID: covidwho-1212055

ABSTRACT

Exuberant inflammation manifesting as a "cytokine storm" has been suggested as a central feature in the pathogenesis of severe coronavirus disease 2019 (COVID-19). This study investigated two prognostic biomarkers, the high mobility group box 1 (HMGB1) and interleukin-6 (IL-6), in patients with severe COVID-19 at the time of admission in the intensive care unit (ICU). Of 60 ICU patients with COVID-19 enrolled and analyzed in this prospective cohort study, 48 patients (80%) were alive at ICU discharge. HMGB1 and IL-6 plasma levels at ICU admission were elevated compared with a healthy control, both in ICU nonsurvivors and ICU survivors. HMGB1 and IL-6 plasma levels were higher in patients with a higher Sequential Organ Failure Assessment (SOFA) score (> 10), and the presence of septic shock or acute kidney injury. HMGB1 and IL-6 plasma levels were also higher in patients with a poor oxygenation status (PaO2/FiO2 < 150 mm Hg) and a longer duration of ventilation (> 7 days). Plasma HMGB1 and IL-6 levels at ICU admission also correlated with other prognostic markers, including the maximum neutrophil/lymphocyte ratio, D-dimer levels, and C-reactive protein levels. Plasma HMGB1 and IL-6 levels at ICU admission predicted ICU mortality with comparable accuracy to the SOFA score and the COVID-GRAM risk score. Higher HMGB1 and IL-6 were not independently associated with ICU mortality after adjustment for age, gender, and comorbidities in multivariate analysis models. In conclusion, plasma HMGB1 and IL6 at ICU admission may serve as prognostic biomarkers in critically ill COVID-19 patients.


Subject(s)
COVID-19/metabolism , COVID-19/pathology , Critical Illness , HMGB1 Protein/metabolism , Interleukin-6/metabolism , SARS-CoV-2 , Biomarkers/blood , Gene Expression Regulation/immunology , HMGB1 Protein/genetics , Humans , Intensive Care Units , Interleukin-6/genetics
10.
Cytokine ; 142: 155496, 2021 06.
Article in English | MEDLINE | ID: covidwho-1152317

ABSTRACT

Efforts to understand host factors critical for COVID-19 pathogenesis have identified high mobility group box 1 (HMGB1) to be crucial for regulating susceptibility to SARS-CoV-2. COVID-19 disease severity is correlated with heightened inflammatory responses, and HMGB1 is an important extracellular mediator in inflammation processes.In this study, we evaluated the effect of HMGB1 inhibitor Glycyrrhizin on the cellular perturbations in lung cells expressing SARS-CoV-2 viral proteins. Pyroptosis in lung cells transfected with SARS-CoV-2 S-RBD and Orf3a, was accompanied by elevation of IL-1ß and extracellular HMGB1 levels. Glycyrrhizin mitigated viral proteins-induced lung cell pyroptosis and activation of macrophages. Heightened release of proinflammatory cytokines IL-1ß, IL-6 and IL-8, as well as ferritin from macrophages cultured in conditioned media from lung cells expressing SARS-CoV-2 S-RBD and Orf3a was attenuated by glycyrrhizin. Importantly, Glycyrrhizin inhibited SARS-CoV-2 replication in Vero E6 cells without exhibiting cytotoxicity at high doses. The dual ability of Glycyrrhizin to concomitantly halt virus replication and dampen proinflammatory mediators might constitute a viable therapeutic option in patients with SARS-CoV-2 infection.


Subject(s)
COVID-19/metabolism , Glycyrrhizic Acid/pharmacology , HMGB1 Protein/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Viroporin Proteins/metabolism , Virus Replication/drug effects , A549 Cells , COVID-19/drug therapy , COVID-19/genetics , HMGB1 Protein/genetics , Humans , Spike Glycoprotein, Coronavirus/genetics , U937 Cells , Viroporin Proteins/genetics
11.
Cell ; 184(1): 76-91.e13, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1064906

ABSTRACT

Identification of host genes essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may reveal novel therapeutic targets and inform our understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here we performed genome-wide CRISPR screens in Vero-E6 cells with SARS-CoV-2, Middle East respiratory syndrome CoV (MERS-CoV), bat CoV HKU5 expressing the SARS-CoV-1 spike, and vesicular stomatitis virus (VSV) expressing the SARS-CoV-2 spike. We identified known SARS-CoV-2 host factors, including the receptor ACE2 and protease Cathepsin L. We additionally discovered pro-viral genes and pathways, including HMGB1 and the SWI/SNF chromatin remodeling complex, that are SARS lineage and pan-coronavirus specific, respectively. We show that HMGB1 regulates ACE2 expression and is critical for entry of SARS-CoV-2, SARS-CoV-1, and NL63. We also show that small-molecule antagonists of identified gene products inhibited SARS-CoV-2 infection in monkey and human cells, demonstrating the conserved role of these genetic hits across species. This identifies potential therapeutic targets for SARS-CoV-2 and reveals SARS lineage-specific and pan-CoV host factors that regulate susceptibility to highly pathogenic CoVs.


Subject(s)
Coronavirus Infections/genetics , Genome-Wide Association Study , Host-Pathogen Interactions , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , COVID-19/virology , Cell Line , Chlorocebus aethiops , Clustered Regularly Interspaced Short Palindromic Repeats , Coronavirus/classification , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Gene Knockout Techniques , Gene Regulatory Networks , HEK293 Cells , HMGB1 Protein/genetics , HMGB1 Protein/metabolism , Host-Pathogen Interactions/drug effects , Humans , Vero Cells , Virus Internalization
12.
Mol Med ; 26(1): 98, 2020 10 30.
Article in English | MEDLINE | ID: covidwho-894987

ABSTRACT

BACKGROUND: Mechanical ventilation, in combination with supraphysiological concentrations of oxygen (i.e., hyperoxia), is routinely used to treat patients with respiratory distress, such as COVID-19. However, prolonged exposure to hyperoxia compromises the clearance of invading pathogens by impairing macrophage phagocytosis. Previously, we have shown that the exposure of mice to hyperoxia induces the release of the nuclear protein high mobility group box-1 (HMGB1) into the pulmonary airways. Furthermore, extracellular HMGB1 impairs macrophage phagocytosis and increases the mortality of mice infected with Pseudomonas aeruginosa (PA). The aim of this study was to determine whether GTS-21 (3-(2,4-dimethoxybenzylidene) anabaseine), an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, could (1) inhibit hyperoxia-induced HMGB1 release into the airways; (2) enhance macrophage phagocytosis and (3) increase bacterial clearance from the lungs in a mouse model of ventilator-associated pneumonia. METHOD: GTS-21 (0.04, 0.4, and 4 mg/kg) or saline were administered by intraperitoneal injection to mice that were exposed to hyperoxia (≥ 99% O2) and subsequently challenged with PA. RESULTS: The systemic administration of 4 mg/kg i.p. of GTS-21 significantly increased bacterial clearance, decreased acute lung injury and decreased accumulation of airway HMGB1 compared to the saline control. To determine the mechanism of action of GTS-21, RAW 264.7 cells, a macrophage-like cell line, were incubated with different concentrations of GTS-21 in the presence of 95% O2. The phagocytic activity of macrophages was significantly increased by GTS-21 in a dose-dependent manner. In addition, GTS-21 significantly inhibited the cytoplasmic translocation and release of HMGB1 from RAW 264.7 cells and attenuated hyperoxia-induced NF-κB activation in macrophages and mouse lungs exposed to hyperoxia and infected with PA. CONCLUSIONS: Our results indicate that GTS-21 is efficacious in improving bacterial clearance and reducing acute lung injury via enhancing macrophage function by inhibiting the release of nuclear HMGB1. Therefore, the α7nAChR represents a possible pharmacological target to improve the clinical outcome of patients on ventilators by augmenting host defense against bacterial infections.


Subject(s)
Benzylidene Compounds/pharmacology , Hyperoxia/immunology , Macrophages, Alveolar/drug effects , Pseudomonas Infections/drug therapy , Pyridines/pharmacology , Ventilator-Induced Lung Injury/drug therapy , alpha7 Nicotinic Acetylcholine Receptor/antagonists & inhibitors , Animals , Disease Models, Animal , HMGB1 Protein/metabolism , Hyperoxia/diet therapy , Macrophages, Alveolar/immunology , Macrophages, Alveolar/metabolism , Male , Mice , Mice, Inbred C57BL , Phagocytosis/drug effects , Pseudomonas aeruginosa , RAW 264.7 Cells
13.
Immunol Lett ; 217: 25-30, 2020 01.
Article in English | MEDLINE | ID: covidwho-888577

ABSTRACT

In a previous work we demonstrated that inhibition of mouse indoleamine 2,3-dioxygenase (IDO) by methyltryptophan (MT) exacerbated the pathological actions of mouse hepatitis virus (MHV-A59) infection, suggesting that tryptophan (TRP) catabolism was involved in viral effects. Since there is a second enzyme that dioxygenates TRP, tryptophan-2, 3-dioxygenase (TDO), which is mainly located in liver, we decided to study its role in our model of MHV-infection. Results showed that in vivo TDO inhibition by LM10, a derivative of 3-(2-(pyridyl) ethenyl) indole, resulted in a decrease of anti- MHV Ab titers induced by the virus infection. Besides, a reduction of some alarmin release, i.e, uric acid and high-mobility group box1 protein (HMGB1), was observed. Accordingly, since alarmin liberation was related to the expression of autoantibodies (autoAb) to fumarylacetoacetate hydrolase (FAH), these autoAb also diminished. Moreover, PCR results indicated that TDO inhibition did not abolish viral replication. Furthermore, histological liver examination did not reveal strong pathologies, whereas mouse survival was hundred percent in control as well as in MHV-infected mice treated with LM10. Data presented in this work indicate that in spite of the various TDO actions already described, specific TDO blockage could also restrain some MHV actions, mainly suppressing autoimmune reactions. Such results should prompt further experiments with various viruses to confirm the possible use of a TDO inhibitor such as LM-10 to treat either viral infections or even autoimmune diseases triggered by a viral infection.


Subject(s)
Autoimmune Diseases/enzymology , Autoimmunity/drug effects , Coronavirus Infections/enzymology , Coronavirus Infections/immunology , Liver/enzymology , Murine hepatitis virus/immunology , Tryptophan Oxygenase/antagonists & inhibitors , Tryptophan Oxygenase/metabolism , Alarmins/metabolism , Animals , Autoantibodies/drug effects , Autoantibodies/immunology , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , Autoimmune Diseases/virology , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Female , HMGB1 Protein/blood , HMGB1 Protein/metabolism , Hydrolases/immunology , Indoles/therapeutic use , Liver/drug effects , Liver/immunology , Liver/pathology , Mice , Mice, Inbred BALB C , Murine hepatitis virus/drug effects , Murine hepatitis virus/growth & development , Tryptophan/metabolism , Tryptophan Oxygenase/genetics , Uric Acid/blood , Uric Acid/metabolism , Virus Replication/drug effects , Virus Replication/immunology
14.
Life Sci ; 263: 118601, 2020 Dec 15.
Article in English | MEDLINE | ID: covidwho-866958

ABSTRACT

Dimethyl cardamonin (DMC) has been isolated from diverse plants, notably from Cleistocalyx operculatus. We have reviewed the pharmacological properties of this natural product which displays anti-inflammatory, anti-hyperglycemic and anti-cancer properties. The pharmacological activities essentially derive from the capacity of DMC to interact with the protein targets HMGB1 and AMPK. Upon binding to HMGB1, DMC inhibits the nucleocytoplasmic transfer of the protein and its extracellular secretion, thereby blocking its alarmin function. DMC also binds to the AMP site of AMPK to activate phospho-AMPK and then to trigger downstream signals leading to the anti-inflammatory and anti-hyperglycemic effects. AMPK activation by DMC reinforces inhibition of HMGB1, to further reduce the release of the alarmin protein, likely contributing to the anticancer effects. The characterization of a tight control of DMC over the AMPK-HMGB1 axis not only helps to explain the known activities of DMC but also suggests opportunities to use this chalcone to treat other pathological conditions such as the acute respiratory distress syndrome (which affects patients with COVID-19). DMC structural analogues are also evoked.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Chalcones/pharmacology , AMP-Activated Protein Kinases/metabolism , Animals , COVID-19/complications , COVID-19/drug therapy , HMGB1 Protein/metabolism , Humans , Hypoglycemic Agents/pharmacology , Respiratory Distress Syndrome/drug therapy , Signal Transduction/drug effects
15.
Int J Mol Sci ; 21(8)2020 Apr 23.
Article in English | MEDLINE | ID: covidwho-825269

ABSTRACT

Our previous study showed that glycyrrhizin (GLY) inhibited porcine epidemic diarrhea virus (PEDV) infection, but the mechanisms of GLY anti-PEDV action remain unclear. In this study, we focused on the anti-PEDV and anti-proinflammatory cytokine secretion mechanisms of GLY. We found that PEDV infection had no effect on toll-like receptor 4 (TLR4) protein and mRNA levels, but that TLR4 regulated PEDV infection and the mRNA levels of proinflammatory cytokines. In addition, we demonstrated that TLR4 regulated p38 phosphorylation but not extracellular regulated protein kinases1/2 (Erk1/2) and c-Jun N-terminal kinases (JNK) phosphorylation, and that GLY inhibited p38 phosphorylation but not Erk1/2 and JNK phosphorylation. Therefore, we further explored the relationship between high mobility group box-1 (HMGB1) and p38. We demonstrated that inhibition of HMGB1 using an antibody, mutation, or knockdown decreased p38 phosphorylation. Thus, HMGB1 participated in activation of p38 through TLR4. Collectively, our data indicated that GLY inhibited PEDV infection and decreased proinflammatory cytokine secretion via the HMGB1/TLR4-mitogen-activated protein kinase (MAPK) p38 pathway.


Subject(s)
Glycyrrhizic Acid/pharmacology , HMGB1 Protein/metabolism , Porcine epidemic diarrhea virus/drug effects , Porcine epidemic diarrhea virus/physiology , Signal Transduction/drug effects , Toll-Like Receptor 4/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Cells, Cultured , Chlorocebus aethiops , Coronavirus Infections/veterinary , Swine , Swine Diseases/metabolism , Swine Diseases/virology , Vero Cells
16.
Front Immunol ; 11: 1580, 2020.
Article in English | MEDLINE | ID: covidwho-647056

ABSTRACT

SARS-CoV-2 might directly activate NLRP3 inflammasome resulting in an endogenous adjuvant activity necessary to mount a proper adaptive immune response against the virus. Heterogeneous response of COVID-19 patients could be attributed to differences in not being able to properly downregulate NLRP3 inflammasome activation. This relates to the fitness of the immune system of the individual challenged by the virus. Patients with a reduced immune fitness can demonstrate a dysregulated NLRP3 inflammasome activity resulting in severe COVID-19 with tissue damage and a cytokine storm. We sketch the outlines of five possible scenarios for COVID-19 in medical practice and provide potential treatment options targeting dysregulated endogenous adjuvant activity in severe COVID-19 patients.


Subject(s)
Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , HMGB1 Protein/metabolism , Inflammasomes/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/pathology , Cytokines/metabolism , Humans , Macrophage Activation/immunology , Macrophages/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Neutrophil Infiltration/immunology , Neutrophils/immunology , Pandemics , Pneumonia, Viral/pathology , SARS-CoV-2
17.
Int J Mol Sci ; 21(13)2020 Jun 30.
Article in English | MEDLINE | ID: covidwho-635461

ABSTRACT

By attaching to the angiotensin converting enzyme 2 (ACE2) protein on lung and intestinal cells, Sudden Acute Respiratory Syndrome (SARS-CoV-2) can cause respiratory and homeostatic difficulties leading to sepsis. The progression from acute respiratory failure to sepsis has been correlated with the release of high-mobility group box 1 protein (HMGB1). Lack of effective conventional treatment of this septic state has spiked an interest in alternative medicine. This review of herbal extracts has identified multiple candidates which can target the release of HMGB1 and potentially reduce mortality by preventing progression from respiratory distress to sepsis. Some of the identified mixtures have also been shown to interfere with viral attachment. Due to the wide variability in chemical superstructure of the components of assorted herbal extracts, common motifs have been identified. Looking at the most active compounds in each extract it becomes evident that as a group, phenolic compounds have a broad enzyme inhibiting function. They have been shown to act against the priming of SARS-CoV-2 attachment proteins by host and viral enzymes, and the release of HMGB1 by host immune cells. An argument for the value in a nonspecific inhibitory action has been drawn. Hopefully these findings can drive future drug development and clinical procedures.


Subject(s)
Betacoronavirus/physiology , HMGB1 Protein/metabolism , Respiratory Insufficiency/pathology , Sepsis/pathology , Angiotensin-Converting Enzyme 2 , HMGB1 Protein/antagonists & inhibitors , Humans , Macrophages/cytology , Macrophages/metabolism , Macrophages/virology , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Plant Exudates/chemistry , Plant Exudates/pharmacology , Plants, Medicinal/chemistry , Plants, Medicinal/metabolism , Respiratory Insufficiency/metabolism , Respiratory Insufficiency/prevention & control , SARS-CoV-2 , Sepsis/metabolism , Sepsis/prevention & control , Virus Internalization/drug effects
18.
Mol Med ; 26(1): 63, 2020 06 29.
Article in English | MEDLINE | ID: covidwho-617382

ABSTRACT

BACKGROUND: Oxygen therapy, using supraphysiological concentrations of oxygen (hyperoxia), is routinely administered to patients who require respiratory support including mechanical ventilation (MV). However, prolonged exposure to hyperoxia results in acute lung injury (ALI) and accumulation of high mobility group box 1 (HMGB1) in the airways. We previously showed that airway HMGB1 mediates hyperoxia-induced lung injury in a mouse model of ALI. Cholinergic signaling through the α7 nicotinic acetylcholine receptor (α7nAChR) attenuates several inflammatory conditions. The aim of this study was to determine whether 3-(2,4 dimethoxy-benzylidene)-anabaseine dihydrochloride, GTS-21, an α7nAChR partial agonist, inhibits hyperoxia-induced HMGB1 accumulation in the airways and circulation, and consequently attenuates inflammatory lung injury. METHODS: Mice were exposed to hyperoxia (≥99% O2) for 3 days and treated concurrently with GTS-21 (0.04, 0.4 and 4 mg/kg, i.p.) or the control vehicle, saline. RESULTS: The systemic administration of GTS-21 (4 mg/kg) significantly decreased levels of HMGB1 in the airways and the serum. Moreover, GTS-21 (4 mg/kg) significantly reduced hyperoxia-induced acute inflammatory lung injury, as indicated by the decreased total protein content in the airways, reduced infiltration of inflammatory monocytes/macrophages and neutrophils into the lung tissue and airways, and improved lung injury histopathology. CONCLUSIONS: Our results indicate that GTS-21 can attenuate hyperoxia-induced ALI by inhibiting extracellular HMGB1-mediated inflammatory responses. This suggests that the α7nAChR represents a potential pharmacological target for the treatment regimen of oxidative inflammatory lung injury in patients receiving oxygen therapy.


Subject(s)
Acute Lung Injury/etiology , Acute Lung Injury/metabolism , Benzylidene Compounds/pharmacology , HMGB1 Protein/metabolism , Hyperoxia/complications , Nicotinic Agonists/pharmacology , Pyridines/pharmacology , Acute Lung Injury/drug therapy , Acute Lung Injury/pathology , Animals , Biomarkers , Disease Susceptibility , HMGB1 Protein/blood , HMGB1 Protein/genetics , Immunohistochemistry , Male , Mice , Models, Biological
20.
Mol Med ; 26(1): 42, 2020 05 07.
Article in English | MEDLINE | ID: covidwho-197895

ABSTRACT

BACKGROUND: The 2019 novel coronavirus disease (COVID-19) causes for unresolved reasons acute respiratory distress syndrome in vulnerable individuals. There is a need to identify key pathogenic molecules in COVID-19-associated inflammation attainable to target with existing therapeutic compounds. The endogenous damage-associated molecular pattern (DAMP) molecule HMGB1 initiates inflammation via two separate pathways. Disulfide-HMGB1 triggers TLR4 receptors generating pro-inflammatory cytokine release. Extracellular HMGB1, released from dying cells or secreted by activated innate immunity cells, forms complexes with extracellular DNA, RNA and other DAMP or pathogen-associated molecular (DAMP) molecules released after lytic cell death. These complexes are endocytosed via RAGE, constitutively expressed at high levels in the lungs only, and transported to the endolysosomal system, which is disrupted by HMGB1 at high concentrations. Danger molecules thus get access to cytosolic proinflammatory receptors instigating inflammasome activation. It is conceivable that extracellular SARS-CoV-2 RNA may reach the cellular cytosol via HMGB1-assisted transfer combined with lysosome leakage. Extracellular HMGB1 generally exists in vivo bound to other molecules, including PAMPs and DAMPs. It is plausible that these complexes are specifically removed in the lungs revealed by a 40% reduction of HMGB1 plasma levels in arterial versus venous blood. Abundant pulmonary RAGE expression enables endocytosis of danger molecules to be destroyed in the lysosomes at physiological HMGB1 levels, but causing detrimental inflammasome activation at high levels. Stress induces apoptosis in pulmonary endothelial cells from females but necrosis in cells from males. CONCLUSION: Based on these observations we propose extracellular HMGB1 to be considered as a therapeutic target for COVID-19.


Subject(s)
Betacoronavirus , Coronavirus Infections , HMGB1 Protein/metabolism , Pandemics , Pneumonia, Viral , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Coronavirus Infections/physiopathology , Humans , Inflammation/metabolism , Inflammation/prevention & control , Lung/metabolism , Lung/physiopathology , Molecular Targeted Therapy , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Pneumonia, Viral/physiopathology , RNA, Viral/metabolism , SARS-CoV-2 , Toll-Like Receptor 4/metabolism
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