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Highlights REVIVAL is a multicenter, open-label, randomized, controlled study to compare the standard low doses of intravenous dexamethasone with weight-adjusted low doses of intranasal dexamethasone. Intranasal dexamethasone can reach the respiratory tract more effectively than intravenous administration. Intranasal dexamethasone can reach the central nervous system in therapeutic concentrations, even at low doses. REVIVAL aims to reduce central failures and sequelae by controlling not only systemic inflammation but also neuroinflammation.

Staphylococcal enterotoxin B (SEB) is a protein produced by Staphylococcus aureus, which is toxic to humans. It is well known for its ability to stimulate the exacerbated activation of proinflammatory CD4+ T cells (Th1 profile), and in vitro studies have been conducted to understand its mechanism of action and its potential use as an immune therapy. However, the efficiency of the SEB1741 aptamer in blocking SEB has not been experimentally demonstrated. Methods: Enrichment CD4+ T cells were stimulated with SEB, and as a blocker, we used the SEB1741 aptamer, which was previously synthesised by an “in silico” analysis, showing high affinity and specificity to SEB. The efficiency of the SEB1741 aptamer in blocking CD4+ T cell activation was compared with that of an anti-SEB monoclonal antibody. Flow cytometry and Bio-Plex were used to evaluate the T-cell function. Results: In vitro, SEB induced the activation of CD4+ T cells and favoured a Th1 profile; however, the SEB1741 aptamer was highly efficient in decreasing the frequency of CD4+ T cells positive to ki-67 and CD69 cells, this means that proliferation and activation of CD4+ T cells was decreased. Moreover, the production of interleukin 2 (IL-2) and interferon-gamma (IFN-γ) was affected, suggesting that the Th1 profile is not present when the SEB1441 aptamer is used. Thus, the SEB1741 function was similar to that of anti-SEB. Conclusions: The SEB1741 aptamer is a valuable tool for blocking CD4+ T cell activation and the subsequent release of proinflammatory cytokines by SEB stimulation.

Staphylococcal enterotoxin B (SEB) is a protein produced by Staphylococcus aureus, which is toxic to humans. It is well known for its ability to stimulate the exacerbated activation of proinflammatory CD4+ T cells (Th1 profile), and in vitro studies have been conducted to understand its mechanism of action and its potential use as an immune therapy. However, the efficiency of the SEB1741 aptamer in blocking SEB has not been experimentally demonstrated. Methods: Enrichment CD4+ T cells were stimulated with SEB, and as a blocker, we used the SEB1741 aptamer, which was previously synthesised by an "in silico" analysis, showing high affinity and specificity to SEB. The efficiency of the SEB1741 aptamer in blocking CD4+ T cell activation was compared with that of an anti-SEB monoclonal antibody. Flow cytometry and Bio-Plex were used to evaluate the T-cell function. Results: In vitro, SEB induced the activation of CD4+ T cells and favoured a Th1 profile; however, the SEB1741 aptamer was highly efficient in decreasing the frequency of CD4+ T cells positive to ki-67 and CD69 cells, this means that proliferation and activation of CD4+ T cells was decreased. Moreover, the production of interleukin 2 (IL-2) and interferon-gamma (IFN-γ) was affected, suggesting that the Th1 profile is not present when the SEB1441 aptamer is used. Thus, the SEB1741 function was similar to that of anti-SEB. Conclusions: The SEB1741 aptamer is a valuable tool for blocking CD4+ T cell activation and the subsequent release of proinflammatory cytokines by SEB stimulation. [ABSTRACT FROM AUTHOR]

Overproduction of inflammatory cytokines is a keystone event in COVID-19 pathogenesis; TNF and its receptors (TNFR1 and TNFR2) are critical pro-inflammatory molecules. ADAM17 releases the soluble (sol) forms of TNF, TNFR1, and TNFR2. This study evaluated TNF, TNFRs, and ADAM17 at the protein, transcriptional, and gene levels in COVID-19 patients with different levels of disease severity. In total, 102 patients were divided into mild, moderate, and severe condition groups. A group of healthy donors (HD; n = 25) was included. Our data showed that solTNFR1 and solTNFR2 were elevated among the COVID-19 patients (p < 0.0001), without increasing the transcriptional level. Only solTNFR1 was higher in the severe group as compared to the mildly ill (p < 0.01), and the level was higher in COVID-19 patients who died than those that survived (p < 0.0001). The solTNFR1 level had a discrete negative correlation with C-reactive protein (p = 0.006, Rho = −0.33). The solADAM17 level was higher in severe as compared to mild disease conditions (p < 0.01), as well as in COVID-19 patients who died as compared to those that survived (p < 0.001). Additionally, a potential association between polymorphism TNFRSF1A:rs767455 and a severe degree of disease was suggested. These data suggest that solTNFR1 and solADAM17 are increased in severe conditions. solTNFR1 should be considered a potential target in the development of new therapeutic options. [ABSTRACT FROM AUTHOR]