Plasmin regulation of acute cytokine storm

Gómez-Salinero, Jesús M.; Rafii, Shahin

doi:10.1182/blood-2017-04-776385

Cited by 14 publications

(11 citation statements)

References 10 publications

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“…MMP9 is reported to relate with tertiary lumens for release of cytokines during neutrophil activation [ 53 ]. In monocytes and macrophages, MMP9 is over-activated by plasmin and reacts with ‘toll like receptor 9’ (TLR9) signaling to induce formation of tumour necrosis factor (TNF) that leads to the development of pro-inflammatory cytokine storm [ 54 , 55 ]. The involvement of MMP9 with serine protease activities was also noticed in Enrichr functional analysis with molecular function under gene ontology ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Matrix metallopeptidase 9 as a host protein target of chloroquine and melatonin for immunoregulation in COVID-19: A network-based meta-analysis

et al. 2020

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Aims The molecular pathogenesis of COVID-19 is similar to other coronavirus (CoV) infections viz. severe acute respiratory syndrome (SARS) in human. Due to scarcity of the suitable treatment strategy, the present study was undertaken to explore host protein(s) targeted by potent repurposed drug(s) in COVID-19. Materials and methods The differentially expressed genes (DEGs) were identified from microarray data repository of SARS-CoV patient blood. The repurposed drugs for COVID-19 were selected from available literature. Using DEGs and drugs, the protein-protein interaction (PPI) and chemo-protein interaction (CPI) networks were constructed and combined to develop an interactome model of PPI-CPI network. The top-ranked sub-network with its hub-bottleneck nodes were evaluated with their functional annotations. Key findings A total of 120 DEGs and 65 drugs were identified. The PPI-CPI network (118 nodes and 293 edges) exhibited a top-ranked sub-network (35 nodes and 174 connectivities) with 12 hub-bottleneck nodes having two drugs chloroquine and melatonin in association with 10 proteins corresponding to six upregulated and four downregulated genes. Two drugs interacted directly with the hub-bottleneck node i.e. matrix metallopeptidase 9 (MMP9), a host protein corresponding to its upregulated gene. MMP9 showed functional annotations associated with neutrophil mediated immunoinflammation. Moreover, literature survey revealed that angiotensin converting enzyme 2, a membrane receptor of SARS-CoV-2 virus, might have functional cooperativity with MMP9 and a possible interaction with both drugs. Significance The present study reveals that between chloroquine and melatonin, melatonin appears to be more promising repurposed drug against MMP9 for better immunocompromisation in COVID-19.

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Section: Discussionmentioning

confidence: 99%

Matrix metallopeptidase 9 as a host protein target of chloroquine and melatonin for immunoregulation in COVID-19: A network-based meta-analysis

et al. 2020

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“…In a study of 23 subjects with homozygous mutations in the PLG gene and little or no detectable plasmin, 96% had clinical inflammation of the conjunctivae (ligneous conjunctivitis) but 0% had experienced venous thrombosis [41]. New roles, however, have been recognized for plasmin regarding cytokine release [30,[42][43][44][45]. A "cytokine storm syndrome" is a form of systemic inflammatory response that can be triggered by a variety of factors such as severe infections.…”

Section: Discussionmentioning

confidence: 99%

Nrf2 Activator PB125^®as a Potential Therapeutic Agent Against COVID-19

McCord

Hybertson

Cota‐Gomez

et al. 2020

Preprint

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Nrf2 is a transcription factor that regulates cellular redox balance and the expression of a wide array of genes involved in immunity and inflammation, including antiviral actions. Nrf2 activity declines with age, making the elderly more susceptible to oxidative stress-mediated diseases, which include type 2 diabetes, chronic inflammation, and viral infections. Published evidence suggests that Nrf2 activity may regulate important mechanisms affecting viral susceptibility and replication. We examined gene expression levels by GeneChip microarray and by RNA-seq assays.We found that the potent Nrf2 activating composition PB125® downregulates ACE2 and TMPRSS2 mRNA expression in human liver-derived HepG2 cells. ACE2 is a surface receptor and TMPRSS2 activates the spike protein for SARS-Cov-2 entry into host cells. Furthermore, in endotoxin-stimulated primary human pulmonary artery endothelial cells we report the marked downregulation by PB125 of 36 genes encoding cytokines. These include IL1-beta, IL6, TNF- the cell adhesion molecules ICAM1, VCAM1, and E-selectin, and a group of IFN--induced genes. Many of these cytokines have been specifically identified in the "cytokine storm" observed in fatal cases of COVID-19, suggesting that Nrf2 activation may significantly decrease the intensity of the storm.

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“… 39 , 40 IL-6 and other inflammatory cytokines such as IL-8, TNF-α, interferon gamma (IFN-γ), and IL-1β induce the inactivation of cadherin, which mediate cell adhesion, leading to vascular leakage by increased capillary permeability; moreover, this induces the formation of tissue factor (thromboplastin) on the cell surface of monocytes, with subsequent activation of the extrinsic coagulation pathway. 41 , 42 The effects of inflammatory cytokines play a pathological role in the development of pain, tissue hypoxia, hypotension, myocardial dysfunction, and, eventually, disseminated intravascular coagulation (DIC) and multiorgan dysfunction. IL-6 is an excellent biomarker of cytokine storm reactions because of its correlation with the severity of the reaction and its longevity in blood serum.…”

Section: Phenotypes Endotypes and Biomarkers Of Anaphylaxismentioning

confidence: 99%

Anaphylaxis in the 21st century: phenotypes, endotypes, and biomarkers

Jiménez-Rodriguez

Garcia-Neuer

Alenazy

et al. 2018

JAA

107

131

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Anaphylaxis is the most serious of all allergic reactions and can be fatal. The diagnosis is frequently delayed, and misdiagnosis often occurs with asthma or urticaria. Biomarkers such as tryptase are not routinely checked, and appropriate treatment with epinephrine is not administered in a majority of cases, increasing the risk of poor outcomes. The objective of this review is to provide a better understanding of the pathophysiology of anaphylaxis with a description of phenotypes, endotypes, and biomarkers available in both the clinical and research settings. Expanding knowledge with regard to the presentation, causes, and triggers for anaphylaxis among health care providers will improve its diagnosis and management, increase patient safety, and decrease morbidity and mortality.

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Plasmin regulation of acute cytokine storm

Cited by 14 publications

References 10 publications

Matrix metallopeptidase 9 as a host protein target of chloroquine and melatonin for immunoregulation in COVID-19: A network-based meta-analysis

Matrix metallopeptidase 9 as a host protein target of chloroquine and melatonin for immunoregulation in COVID-19: A network-based meta-analysis

Nrf2 Activator PB125^®as a Potential Therapeutic Agent Against COVID-19

Anaphylaxis in the 21st century: phenotypes, endotypes, and biomarkers

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Plasmin regulation of acute cytokine storm

Cited by 14 publications

References 10 publications

Matrix metallopeptidase 9 as a host protein target of chloroquine and melatonin for immunoregulation in COVID-19: A network-based meta-analysis

Matrix metallopeptidase 9 as a host protein target of chloroquine and melatonin for immunoregulation in COVID-19: A network-based meta-analysis

Nrf2 Activator PB125®as a Potential Therapeutic Agent Against COVID-19

Anaphylaxis in the 21st century: phenotypes, endotypes, and biomarkers

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Product

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Nrf2 Activator PB125^®as a Potential Therapeutic Agent Against COVID-19