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Poly(ADP-ribose) polymerase (PARP) is involved in the pathogenesis of cell dysfunction, inflammation and organ failure during septic shock. The goal of the current study was to investigate the efficacy and safety of the clinically approved PARP inhibitor olaparib in experimental models of oxidative stress in vitro and in sepsis in vivo. ln mice subjected to cecal ligation a nd puncture (CLP) organ injury markers, circula ting and splenic immune cell distributions, circulating mediators, DNA integrity and survival was measured. ln U937 cells subjected to oxidative stress, cellular bioenergetics, viability and DNA integrity were measured. Olaparib was used to inhibit PARP. The results show that in adult male mice subjected to CLP, olaparib (1-10 mg/kg i.p.) improved multiorgan dysfonction. Olaparib treatrnent reduced the degree of bacterial CFUs. Olaparib attenuated the increases in the levels of several circulating mediators in the plasma. ln the spleen, the number of CD4 + and CDS + lymphocytes were reduced in response to CLP; this reduction was inhibited by olaparib treatrnent. Treg but not Thl 7 lymphocytes increased in response to CLP; these cell populations were reduced in sepsis when the animais received olaparib. The Thl 7 /Treg ratio was lower in CLP-olaparib group than in the CLP control group. Analysis of miRNA expression identifi ed a multitude of changes in spleen and circulating white blood cell miRNA levels after CLP; olaparib treatrnent selectively modulated these responses. Olaparib extended the survival rate of mice subjected to CLP. ln contrast to males, in female mice olaparib did not have significant protective effects in CLP. ln aged mice olaparib exerted beneficial effects that were Jess pronounced than the effects obtained in young adult males. ln in vitro experiments in U937 cells subjected to oxidative stress, olaparib (1-100 µM) inhibited PARP activity, protected against the Joss of cell viability, preserved NAD + levels and improved cellular bioenergetics. ln none of the in vivo or in vitro experiments did we observe any adverse effects of olaparib on

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The role of cathelicidin in a CLP model is investigated using cathelicidin-KO mice. Cathelicidin-KO mice show an enhanced immune response and improved survival rates. An anti-inflammatory effect of cathelicidin is likely to be detrimental for CLP. Cathelicidin-KO mice show upregulation of genes associated with increased plasma levels of pro-inflammatory Ils. Cathelicidins appear to have both pro- and anti-inflammatory properties.

The role of innate immunity in COVID-19 is not completely understood. Therefore, this study explored the impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection on the expression of Pattern Recognition Receptors (PRRs) in peripheral blood cells and their correlated cytokines. Seventy-nine patients with severe COVID-19 on admission, according to World Health Organization (WHO) classification, were divided into two groups: patients who needed mechanical ventilation and/or deceased (SEVERE, n = 50) and patients who used supplementary oxygen but not mechanical ventilation and survived (MILD, n = 29); a control group (CONTROL, n = 17) was also enrolled. In the peripheral blood, gene expression (mRNA) of Toll-like receptors (TLRs) 3, 4, 7, 8, and 9, retinoic-acid inducible gene I (RIGI), NOD-like receptor family pyrin domain containing 3 (NLRP3), interferon alpha (IFN-α), interferon beta (IFN-β), interferon gamma (IFN-γ), interferon lambda (IFN-λ), pro-interleukin(IL)-1β (pro-IL-1β), and IL-18 was determined on admission, between 5–9 days, and between 10–15 days. Circulating cytokines in plasma were also measured. When compared to the COVID-19 MILD group, the COVID-19 SEVERE group had lower expression of TLR3 and overexpression of TLR4.

High-fat diet induces liver inflammation by inhibiting PGC-1α expression and its suppressive effect in NFκB pathway.

The objective of this randomized animal study and laboratory investigation was to investigate whether lipopolysaccharide tolerance redirects neutrophil migration between organs. Male BALB/c mice received subcutaneous injections of lipopolysaccharide (1 mg/kg) for 5 days, followed by cecal ligation and puncture (CLP). Cytokines and adhesion molecules were measured after tolerance and CLP challenge. Increased numbers of neutrophils were observed in the peritoneal cavity of tolerant mice, which was associated with increased levels of adhesion molecules and chemokines. In contrast, nontolerant mice accumulated higher numbers of neutrophils in the lungs compared with those in the peritoneal cavity. Neutrophil function accessed by hydrogen peroxide production from neutrophils recovered from peritoneal cavity showed that tolerance increased the capacity to produce hydrogen peroxide. Mortality was reduced in tolerant animals. This study demonstrated that tolerance reduces leukocyte accumulation in the lung after CLP by redirecting neutrophils to the site of infection.