Dichloroacetate-induced metabolic reprogramming improves lifespan in a Drosophila model of surviving sepsis.

Sepsis is the leading cause of death in hospitalized patients and beyond the hospital stay and these long-term sequelae are due in part to unresolved inflammation. Metabolic shift from oxidative phosphorylation to aerobic glycolysis links metabolism to inflammation and such a shift is commonly observed in sepsis under normoxic conditions. By shifting the metabolic state from aerobic glycolysis to oxidative phosphorylation, we hypothesized it would reverse unresolved inflammation and subsequently improve outcome.

G Protein-Coupled Receptors in Asthma Therapy: Pharmacology and Drug Action.

Asthma is a heterogeneous inflammatory disease of the airways that is associated with airway hyperresponsiveness and airflow limitation. Although asthma was once simply categorized as atopic or nonatopic, emerging analyses over the last few decades have revealed a variety of asthma endotypes that are attributed to numerous pathophysiological mechanisms. The classification of asthma by endotype is primarily routed in different profiles of airway inflammation that contribute to bronchoconstriction.

Nitro-fatty acid formation and metabolism.

Nitro-fatty acids (NO-FA) are pleiotropic modulators of redox signaling pathways. Their effects on inflammatory signaling have been studied in great detail in cell, animal and clinical models primarily using exogenously administered nitro-oleic acid. While we know a considerable amount regarding NO-FA signaling, endogenous formation and metabolism is relatively unexplored.

Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions.

To fulfill bioenergetic demands of activation, T cells perform aerobic glycolysis, a process common to highly proliferative cells in which glucose is fermented into lactate rather than oxidized in mitochondria. However, the signaling events that initiate aerobic glycolysis in T cells remain unclear. We show T cell activation rapidly induces glycolysis independent of transcription, translation, CD28, and Akt and not involving increased glucose uptake or activity of glycolytic enzymes.

Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and Nitrate.

Dietary NO (nitrate) and NO (nitrite) support ˙NO (nitric oxide) generation and downstream vascular signaling responses. These nitrogen oxides also generate secondary nitrosating and nitrating species that react with low molecular weight thiols, heme centers, proteins, and unsaturated fatty acids. To explore the kinetics of NOand NOmetabolism and the impact of dietary lipid on nitrogen oxide metabolism and cardiovascular responses, the stable isotopes NaNO and NaNO were orally administered in the presence or absence of conjugated linoleic acid (cLA).

ERK1/2 Activation in Preexisting Oligodendrocytes of Adult Mice Drives New Myelin Synthesis and Enhanced CNS Function.

Unlabelled: Growing evidence shows that mechanisms controlling CNS plasticity extend beyond the synapse and that alterations in myelin can modify conduction velocity, leading to changes in neural circuitry. Although it is widely accepted that newly generated oligodendrocytes (OLs) produce myelin in the adult CNS, the contribution of preexisting OLs to functional myelin remodeling is not known. Here, we show that sustained activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in preexisting OLs of adult mice is sufficient to drive increased myelin thickness, faster conduction speeds, and enhanced hippocampal-dependent emotional learning.

Nitrite and nitrate-dependent generation of anti-inflammatory fatty acid nitroalkenes.

A gap in our understanding of the beneficial systemic responses to dietary constituents nitrate (NO3(-)), nitrite (NO2(-)) and conjugated linoleic acid (cLA) is the identification of the downstream metabolites that mediate their actions. To examine these reactions in a clinical context, investigational drug preparations of (15)N-labeled NO3(-) and NO2(-) were orally administered to healthy humans with and without cLA. Mass spectrometry analysis of plasma and urine indicated that the nitrating species nitrogen dioxide was formed and reacted with the olefinic carbons of unsaturated fatty acids to yield the electrophilic fatty acid, nitro-cLA (NO2-cLA).

15-Hydroxyprostaglandin dehydrogenase generation of electrophilic lipid signaling mediators from hydroxy ω-3 fatty acids.

15-Hydroxyprostaglandin dehydrogenase (15PGDH) is the primary enzyme catalyzing the conversion of hydroxylated arachidonic acid species to their corresponding oxidized metabolites. The oxidation of hydroxylated fatty acids, such as the conversion of prostaglandin (PG) E2 to 15-ketoPGE2, by 15PGDH is viewed to inactivate signaling responses. In contrast, the typically electrophilic products can also induce anti-inflammatory and anti-proliferative responses.

15-Oxoeicosatetraenoic acid is a 15-hydroxyprostaglandin dehydrogenase-derived electrophilic mediator of inflammatory signaling pathways.

Bioactive lipids govern cellular homeostasis and pathogenic inflammatory processes. Current dogma holds that bioactive lipids, such as prostaglandins and lipoxins, are inactivated by 15-hydroxyprostaglandin dehydrogenase (15PGDH). In contrast, the present results reveal that catabolic "inactivation" of hydroxylated polyunsaturated fatty acids (PUFAs) yields electrophilic α,β-unsaturated ketone derivatives.

Fatty acids, inflammation, and asthma.

Fatty acids and consequently diet play an essential role in the formation of inflammatory mediators involved in the pathogenesis of asthma. Because intake variations of omega-6 (n-6) and omega-3 (n-3) fatty acids ultimately determine cell membrane incorporation, changes in diet have the potential to modify downstream production of inflammatory mediators derived from these compounds. It has long been hypothesized that decreasing the n-6/n-3 ratio could reduce the production of more proinflammatory mediators while increasing the formation of downstream metabolites that can serve to limit or resolve inflammation.

Redox-dependent anti-inflammatory signaling actions of unsaturated fatty acids.

Unsaturated fatty acids are metabolized to reactive products that can act as pro- or anti-inflammatory signaling mediators. Electrophilic fatty acid species, including nitro- and oxo-containing fatty acids, display salutary anti-inflammatory and metabolic actions. Electrophilicity can be conferred by both enzymatic and oxidative reactions, via the homolytic addition of nitrogen dioxide to a double bond or via the formation of α,β-unsaturated carbonyl and epoxide substituents.