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Purpose Asymptomatic or minimally symptomatic infection with COVID-19 can result in silent transmission to large numbers of individuals, resulting in expansion of the pandemic with a global increase in morbidity and mortality. New ways of screening the general population for COVID-19 are urgently needed along with novel effective prevention and treatment strategies. Hypothesis A hypothetical three-part prevention, diagnostic, and treatment approach based on an up-to-date scientific literature review for COVID- 19 is proposed. Regarding diagnosis, a validated screening questionnaire and digital app for COVID-19 could help identify individuals who are at risk of transmitting the disease, as well as those at highest risk for poor clinical outcomes. Global implementation and online tracking of vital signs and scored questionnaires that are statistically validated would help health authorities properly allocate essential health care resources to test and isolate those at highest risk for transmission and poor outcomes. Second, regarding prevention, no validated protocols except for physical distancing, hand washing, and isolation exist, and recently ivermectin and the antimalarial drugs chloroquine and hydroxychloroquine has been published to have anti-viral properties against COVID-19. A randomized trial of ivermectin or hydroxychloroquine alone, and/or nutraceuticals that have been published to support immune function including Vitamin C, zinc, and immunomodulatory supplements (3,6 Beta glucan) could be beneficial in preventing transmission or lessening symptomatology but requires statistical validation. Third, concerning treatment, COVID-19 induced inflammation and “cytokine storm syndrome” with hemophagocytic lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) have resulted in extreme morbidity and mortality in those with certain comorbidities, secondary to “acute respiratory distress syndrome” (ARDS) and multiorgan dysfunction with disseminated intravascular coagulation (DIC). Deficiency in red blood cell, serum and alveolar glutathione has been published in the medical literature for ARDS, as well as viral and bacterial pneumonias, resulting from increased levels of free radical/oxidative stress. A randomized controlled trial of blocking NFKappa B and cytokine formation using glutathione precursors (N-acetyl-cysteine [NAC] and alpha lipoic acid) and PO/IV glutathione should be performed, along with an evaluation of Nrf2 activators (curcumin, sulforaphane glucosinolate) which have been scientifically proven to lower inflammation. Since high mortality rates from sepsis induced DIC due to COVID 19 infection has also been associated with thrombotic events and elevated levels of D-dimer, randomized controlled trials of using anticoagulant therapy with heparin is urgently required. This is especially important in patients on ventilators who have met certain sepsis induced coagulopathy (SIC) criteria. The use of acetazolamide with or without sildenafil also needs to be explored with or without heparin, since increased oxygen delivery to vital organs through prevention of thrombosis/pulmonary emboli along with carbonic anhydrase inhibition may help increase oxygenation and prevent adverse clinical outcomes. Conclusion and Implications a three-part prevention, diagnostic, and treatment plan is proposed for addressing the severe complications of COVID-19. Digital monitoring of symptoms to clinically diagnose early exposure and response to treatment; prevention with hydroxychloroquine and/or ivermetin as well as nutritional therapies that support a healthy immune response; treatment with anti-inflammatory therapies that block NFKappaB and activate Nrf2 pathways, as well as novel therapies that address COVID-19 pneumonia and ARDS with DIC including anticoagulation and/ or novel respiratory therapies with or without acetazolamide and sildenafil. These three broad-based interventions urgently need to be subjected to randomized, controlled trials.

Intestinal ischemia-reperfusion (I/R) injury is a life-threatening vascular emergency and has long been a disturbing problem for surgeons. Oxidative stress is considered a vital factor in I/R injury. Metformin has anti-oxidative properties and protects against I/R injury. The present study aimed to investigate whether Metformin protects against intestinal I/R injury and reveal the protective mechanism of Metformin. I/R injury was induced in mice by temporary superior mesenteric artery occlusion, and Caco-2 cells were subjected to OGD/R to establish an in vitro model. Different doses of Metformin were administered in vivo and in vitro. We found that I/R injury led to intestinal barrier disruption and cell death by examining histopathological results and the intestinal barrier index, including TER, tight junction proteins and serum biomarkers. We confirmed the existence of pyroptosis in intestinal I/R injury. Moreover, we confirmed the role of pyroptosis in intestinal I/R injury by silencing the gasdermin D (GSDMD). Then, we confirmed that Metformin treatment protected barrier function against intestinal I/R injury and reduced oxidative stress and the inflammatory response. Importantly, Metformin reduced pyroptosis-related proteins, including NLRP3, cleaved caspase-1, and the N-terminus of GSDMD. Knocking down the GSDMD could reversed the protective effects of Metformin, which showed pyroptosis was one of the major cell death pathways controlled by Metformin treatment in setting of intestinal I/R injury. We also discovered that Metformin suppressed the expression of TXNIP and the interaction between TXNIP and NLRP3. We performed siRNA knockdown and found that the protective effects were abolished, which further confirmed our findings. In conclusion, we believe that Metformin protects against intestinal I/R injury in a TXNIP-NLRP3-GSDMD-dependent manner., Highlights • Pyroptosis plays an important role in intestinal I/R injury. • Metformin protects against intestinal I/R injury in mice. • Metformin protects Caco-2 cells subjected to OGD/R. • Metformin inhibits pyroptosis, inflammation and oxidative stress during I/R injury. • Metformin exerts protective effect through TXNIP-NLRP3-GSDMD pathway.

Background Several immune mediators (IM) including cytokines, chemokines, and their receptors have been suggested to play a role in COVID-19 pathophysiology and severity. Aim To determine if early IM profiles are predictive of clinical outcome and which of the IMs tested possess the most clinical utility. Methods A custom bead-based multiplex assay was used to measure IM concentrations in a cohort of SARS-CoV-2 PCR positive patients (n = 326) with varying disease severities as determined by hospitalization status, length of hospital stay, and survival. Patient groups were compared, and clinical utility was assessed. Correlation plots were constructed to determine if significant relationships exist between the IMs in the setting of COVID-19. Results In PCR positive SARS-CoV-2 patients, IL-6 was the best predictor of the need for hospitalization and length of stay. Additionally, MCP-1 and sIL-2Rα were moderate predictors of the need for hospitalization. Hospitalized PCR positive SARS-CoV-2 patients displayed a notable correlation between sIL-2Rα and IL-18 (Spearman’s ρ = 0.48, P=

Inflammasomes are macromolecular complexes involved in the host response to external and endogenous danger signals. Inflammasome-mediated sterile inflammation plays a central role in several human conditions such as autoimmune diseases, type-2 diabetes, and neurodegenerative disorders, indicating inflammasomes could be appealing therapeutic targets. Previous work has demonstrated that inhibiting the ATPase activity of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3), disrupts inflammasome assembly and function. However, there is a necessity to find new potent compounds with therapeutic potential. Here we combine computational modeling of the target and virtual screening to discover a group of novel compounds predicted to inhibit NLRP3. We characterized the best compounds and determined their potency, specificity, and ability to inhibit processes downstream from NLRP3 activation. Moreover, we analyzed in mice the competence of a lead candidate to reduce lipopolysaccharide-induced inflammation. We also validated the active pharmacophore shared among all the NLRP3 inhibitors, and through computational docking, we clarify key structural features for compound positioning within the inflammasome ATP-binding site. Our study sets the basis for rational design and optimization of inflammasome-targeting probes and drugs.

BACKGROUND AND AIMS: IL-18 expression is up-regulated in atherosclerotic plaques, and higher levels are seen in obese and Type 2 Diabetic individuals. More recently, a possible role for IL-18 in glucose and energy homeostasis has been suggested.METHODS AND RESULTS: We investigated variation within the IL18 gene and its association with measures of obesity and the metabolic syndrome. Five IL18 tagging single nucleotide polymorphisms (rs1946519, rs2043055, rs549908, rs360729, rs3882891) were selected and genotyped in the Gene-Diet Attica Investigation on childhood obesity (GENDAI) (age range 10-14 yrs); in young European men in the second European Atherosclerosis Research offspring Study (EARSII), an offspring study (age range 18-28 yrs) and in a group of healthy women from the Greek Obese Women study (GrOW) (age range 18-74 yrs). Six common haplotypes were observed. In GrOW, Hap6 (Frequency-2.6%) was associated with higher insulin levels (pCONCLUSION: Association of IL18 variation with insulin levels and estimates of insulin resistance were only observed in our adult study, suggesting that the effects of IL-18 are only associated with increasing age. Taken together with the association of IL18 variants with post-prandial measures, this provides support for IL-18 as a metabolic factor.

The goal of the present study was to identify novel protein biomarkers from the target genes of six serum miRNAs that we identified previously in patients with sepsis. The target genes were predicted by bioinformatics analysis; the levels of the respective proteins in the sera of patients with sepsis were detected by ELISA. ACVR2A (activin A receptor, type IIA), FOXO1 (forkhead box O1), IHH (Indian hedgehog), STK4 (serine/threonine kinase 4) and DUSP3 (dual specificity phosphatase 3) were predicted to be the targets of the six miRNAs, and their encoded proteins were used for biomarker identification. Levels of ACVR2A (P, Four novel protein biomarkers encoded by the miRNA target genes were identified for patients with sepsis. The combined analysis of the four proteins indicated that their predictive value for sepsis prognosis was better than the values for the SOFA score and APACHE II score.