MCTR3 reprograms arthritic monocytes to upregulate Arginase-1 and exert pro-resolving and tissue-protective functions in experimental arthritis.

Background: Rheumatoid arthritis (RA) is a progressive degenerative disorder that leads to joint destruction. Available treatments only target the inflammatory component with minimal impact on joint repair. We recently uncovered a previously unappreciated family of pro-resolving mediators, the maresin conjugate in tissue regeneration (MCTR), that display both immunoregulatory and tissue-protective activities.

Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway.

Background & Aims: Infection is a major problem in advanced liver disease secondary to monocyte dysfunction. Elevated prostaglandin (PG)E is a mediator of monocyte dysfunction in cirrhosis; thus, we examined PGE signalling in outpatients with ascites and in patients hospitalised with acute decompensation to identify potential therapeutic targets aimed at improving monocyte dysfunction.

Methods: Using samples from 11 outpatients with ascites and 28 patients hospitalised with decompensated cirrhosis, we assayed plasma levels of PGE and lipopolysaccharide (LPS); performed quantitative real-time PCR on monocytes; and examined peripheral blood monocyte function.

Disrupted Resolution Mechanisms Favor Altered Phagocyte Responses in COVID-19.

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Changes in brown adipose tissue lipid mediator signatures with aging, obesity, and DHA supplementation in female mice.

Brown adipose tissue (BAT) dysfunction in aging and obesity has been related to chronic unresolved inflammation, which could be mediated by an impaired production of specialized proresolving lipid mediators (SPMs), such as Lipoxins-LXs, Resolvins-Rvs, Protectins-PDs, and Maresins-MaRs. Our aim was to characterize the changes in BAT SPMs signatures and their association with BAT dysfunction during aging, especially under obesogenic conditions, and their modulation by a docosahexaenoic acid (DHA)-rich diet. Lipidomic, functional, and molecular studies were performed in BAT of 2- and 18-month-old lean (CT) female mice and in 18-month-old diet-induced obese (DIO) mice fed with a high-fat diet (HFD), or a DHA-enriched HFD.

Proresolving mediator profiles in cerebrospinal fluid are linked with disease severity and outcome in adults with tuberculous meningitis.

Tuberculous meningitis (TBM) is the most lethal form of tuberculosis infection, characterized by a dysregulated immune response that frequently leads to neurologic injury and death despite the best available treatment. The mechanisms driving the inflammatory response in TBM are not well understood. To gain insights into these mechanisms, we used a lipid mediator-profiling approach to investigate the regulation of a novel group of host protective mediators, termed specialized proresolving mediators (SPMs), in the cerebrospinal fluid (CSF) of adults with TBM.

A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults.

Adjunctive dexamethasone reduces mortality from tuberculous meningitis (TBM) but not disability, which is associated with brain infarction. We hypothesised that aspirin prevents TBM-related brain infarction through its anti-thrombotic, anti-inflammatory, and pro-resolution properties. We conducted a randomised controlled trial in HIV-uninfected adults with TBM of daily aspirin 81 mg or 1000 mg, or placebo, added to the first 60 days of anti-tuberculosis drugs and dexamethasone (NCT02237365).

Increased 15-PGDH expression leads to dysregulated resolution responses in stromal cells from patients with chronic tendinopathy.

The mechanisms underpinning the failure of inflammation to resolve in diseased musculoskeletal soft tissues are unknown. Herein, we studied bioactive lipid mediator (LM) profiles of tendon-derived stromal cells isolated from healthy donors and patients with chronic tendinopathy. Interleukin(IL)-1β treatment markedly induced prostaglandin biosynthesis in diseased compared to healthy tendon cells, and up regulated the formation of several pro-resolving mediators including 15-epi-LXA and MaR1.

Albumin Counteracts Immune-Suppressive Effects of Lipid Mediators in Patients With Advanced Liver Disease.

Background & Aims: Patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF) have immune dysfunction, which increases their risk for infections; however, there are no effective treatments to restore their immune function. We investigated whether the potentially immune-restorative effects of albumin are mediated by its effects on prostaglandin E (PGE) and other lipids.

Methods: We analyzed bloods samples from 45 of 79 patients with AD/ACLF and serum levels of albumin less than 30 g/L for whom infusion of 20% human albumin solution (HAS) increased serum levels of albumin 30 g/L or more in a feasibility study of effects of 20% HAS.

Resolving inflammation by using nutrition therapy: roles for specialized proresolving mediators.

Purpose Of Review: Inflammation is a unifying component of many of the diseases that afflict Western civilizations. Nutrition therapy and, in particular, essential fatty acid supplementation is one of the approaches that is currently in use for the treatment and management of many inflammatory conditions. The purpose of the present review is to discuss the recent literature in light of the discovery that essential fatty acids are converted by the body to a novel genus of lipid mediators, termed specialized proresolving mediators (SPMs).

Adaptation to HIF-1 deficiency by upregulation of the AMP/ATP ratio and phosphofructokinase activation in hepatomas.

Background: HIF-1 deficiency has marked effects on tumour glycolysis and growth. We therefore investigated the consequences of HIF-1 deficiency in mice, using the well established Hepa-1 wild-type (WT) and HIF-1β-deficient (c4) model. These mechanisms could be clinically relevant, since HIF-1 is now a therapeutic target.

Proteomic and metabolomic analyses of atherosclerotic vessels from apolipoprotein E-deficient mice reveal alterations in inflammation, oxidative stress, and energy metabolism.

Objective: Proteomics and metabolomics are emerging technologies to study molecular mechanisms of diseases. We applied these techniques to identify protein and metabolite changes in vessels of apolipoprotein E(-/-) mice on normal chow diet.

Methods And Results: Using 2-dimensional gel electrophoresis and mass spectrometry, we identified 79 protein species that were altered during various stages of atherogenesis.