Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion.

Sulfide-releasing compounds reduce reperfusion injury by decreasing mitochondria-derived reactive oxygen species production. We previously characterised ammonium tetrathiomolybdate (ATTM), a clinically used copper chelator, as a sulfide donor in rodents. Here we assessed translation to large mammals prior to clinical testing.

Antibiotics, Sedatives, and Catecholamines Further Compromise Sepsis-Induced Immune Suppression in Peripheral Blood Mononuclear Cells.

Objectives: We hypothesized that the immunosuppressive effects associated with antibiotics, sedatives, and catecholamines amplify sepsis-associated immune suppression through mitochondrial dysfunction, and there is a cumulative effect when used in combination. We thus sought to determine the impact of the exemplar drugs ciprofloxacin, propofol, and norepinephrine, used alone and in combination, at clinically relevant concentrations, on the ex vivo functionality of peripheral blood mononuclear cells (PBMCs) drawn from healthy, infected, and septic individuals.

Design: In vitro/ex vivo investigation.

Association Between Hypocholesterolemia and Mortality in Critically Ill Patients With Sepsis: A Systematic Review and Meta-Analysis.

Unlabelled: To ascertain the association between cholesterol and triglyceride levels on ICU admission and mortality in patients with sepsis.

Data Sources: Systematic review and meta-analysis of published studies on PubMed and Embase.

Study Selection: All observational studies reporting ICU admission cholesterol and triglyceride levels in critically ill patients with sepsis were included.

The Many Roles of Cholesterol in Sepsis: A Review.

The biological functions of cholesterol are diverse, ranging from cell membrane integrity, cell membrane signaling, and immunity to the synthesis of steroid and sex hormones, vitamin D, bile acids, and oxysterols. Multiple studies have demonstrated hypocholesterolemia in sepsis, the degree of which is an excellent prognosticator of poor outcomes. However, the clinical significance of hypocholesterolemia has been largely unrecognized.

The Pharmacology and Therapeutic Utility of Sodium Hydroselenide.

Metabolically active gasotransmitters (nitric oxide, carbon monoxide and hydrogen sulfide) are important signalling molecules that show therapeutic utility in oxidative pathologies. The reduced form of selenium, hydrogen selenide (HSe/HSe), shares some characteristics with these molecules. The simple selenide salt, sodium hydroselenide (NaHSe) showed significant metabolic activity, dose-dependently decreasing ex vivo O consumption (rat soleus muscle, liver) and transiently inhibiting mitochondrial cytochrome C oxidase (liver, heart).

Lipid metabolic signatures deviate in sepsis survivors compared to non-survivors.

Sepsis remains a major cause of death despite advances in medical care. Metabolic deregulation is an important component of the survival process. Metabolomic analysis allows profiling of critical metabolic functions with the potential to classify patient outcome.

Protein recycling and limb muscle recovery after critical illness in slow- and fast-twitch limb muscle.

An impaired capacity of muscle to regenerate after critical illness results in long-term functional disability. We previously described in a long-term rat peritonitis model that gastrocnemius displays near-normal histology whereas soleus demonstrates a necrotizing phenotype. We thus investigated the link between the necrotizing phenotype of critical illness myopathy and proteasome activity in these two limb muscles.

Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation.

Glucocorticoids acting through the glucocorticoid receptor (GR) inhibit TNF-induced lethal inflammation. Here, we demonstrate that GR dimerization plays a role in reducing TNF sensitivity. In mutant mice unable to dimerize GR, we found that TNF failed to induce MAPK phosphatase 1 (MKP1).

Molecular control of systemic bile acid homeostasis by the liver glucocorticoid receptor.

Systemic bile acid (BA) homeostasis is a critical determinant of dietary fat digestion, enterohepatic function, and postprandial thermogenesis. However, major checkpoints for the dynamics and the molecular regulation of BA homeostasis remain unknown. Here we show that hypothalamic-pituitary-adrenal (HPA) axis impairment in humans and liver-specific deficiency of the glucocorticoid receptor (GR) in mice disrupts the normal changes in systemic BA distribution during the fasted-to-fed transition.

Tumor necrosis factor inhibits glucocorticoid receptor function in mice: a strong signal toward lethal shock.

As glucocorticoid resistance (GCR) and the concomitant burden pose a worldwide problem, there is an urgent need for a more effective glucocorticoid therapy, for which insights into the molecular mechanisms of GCR are essential. In this study, we addressed the hypothesis that TNFα, a strong pro-inflammatory mediator in numerous inflammatory diseases, compromises the protective function of the glucocorticoid receptor (GR) against TNFα-induced lethal inflammation. Indeed, protection of mice by dexamethasone against TNFα lethality was completely abolished when it was administered after TNFα stimulation, indicating compromised GR function upon TNFα challenge.