Resolvins: A Family of Bioactive Products of Omega-3 Fatty Acid Transformation Circuits Initiated by Aspirin Treatment that Counter Proinflammation Signals

Aspirin (ASA) is unique among current therapies because it acetylates cyclooxygenase (COX)-2 enabling the biosynthesis of R-containing precursors of endogenous antiinflammatory mediators. Here, we report that lipidomic analysis of exudates obtained in the resolution phase from mice treated with ASA and docosahexaenoic acid (DHA) (C22:6) produce a novel family of bioactive 17R-hydroxy-containing di- and tri-hydroxy-docosanoids termed resolvins. Murine brain treated with aspirin produced endogenous 17R-hydroxydocosahexaenoic acid as did human microglial cells. Human COX-2 converted DHA to 13-hydroxy-DHA that switched with ASA to 17R-HDHA that also proved a major route in hypoxic endothelial cells. Human neutrophils transformed COX-2-ASA–derived 17R-hydroxy-DHA into two sets of novel di- and trihydroxy products; one initiated via oxygenation at carbon 7 and the other at carbon 4. These compounds inhibited (IC50 ∼50 pM) microglial cell cytokine expression and in vivo dermal inflammation and peritonitis at ng doses, reducing 40–80% leukocytic exudates. These results indicate that exudates, vascular, leukocytes and neural cells treated with aspirin convert DHA to novel 17R-hydroxy series of docosanoids that are potent regulators. These biosynthetic pathways utilize omega-3 DHA and EPA during multicellular events in resolution to produce a family of protective compounds, i.e., resolvins, that enhance proresolution status

Profound Chemopreventative Effects of a Hydrogen Sulfide-Releasing NSAID in the APC(Min/+) Mouse Model of Intestinal Tumorigenesis

Canadian Institutes of Health Research grant to JL

Well. From Artificial Intelligence to Empathy?

There is no abstract for this article

It is Personal – or not!

There is no abstract for this article

Lipoxin agonists: turn right! to path of resolving neutrophil

An impressive array of cellular and molecular adaptive responses achieves homeostasis. The inflammatory reaction is an adaptive response triggered by an insult to culminate into the overt cardinal signs of inflammation, eventually leading to resolution and returning the organism back to its original centered state. This article focuses on some aspects of the lipoxin A4 signaling pathway during the resolution phase, to better understand molecular mechanisms by which a neutrophil directs an inflammatory reaction to switch off and resume homeostasis. Defining the resolution state of a neutrophil at the molecular level will aid in treatments of diseases that are associated with an exaggerated and uncontrolled inflammation

The Peroxisome Proliferator-Activated Receptor-γ Agonist Pioglitazone Represses Inflammation in a Peroxisome Proliferator-Activated Receptor-α–Dependent Manner In Vitro and In Vivo in Mice

ObjectivesOur aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)-γ agonist pioglitazone modulates inflammation through PPARα mechanisms.BackgroundThe thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPARγ agonists used to treat type 2 diabetes (T2DM). Despite evidence for TZDs limiting inflammation and atherosclerosis, questions exist regarding differential responses to TZDs. In a double-blinded, placebo-controlled 16-week trial among recently diagnosed T2DM subjects (n = 34), pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group. Previously we reported PPARα but not PPARγ agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPARα activation, we studied pioglitazone's effects via PPARα.MethodsPioglitazone effects on known PPARα responses—ligand binding domain activation and PPARα target gene expression—were tested in vitro and in vivo, including in wild-type and PPARα-deficient cells and mice, and compared with the effects of other PPARγ (rosiglitazone) and PPARα (WY14643) agonists.ResultsPioglitazone repressed endothelial TNFα-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic IκBα in a manner dependent on both pioglitazone exposure and PPARα expression. Pioglitazone also activated the PPARα ligand binding domain and induced PPARα target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and IκBα expression in wild-type but not PPARα-deficient mice.ConclusionsPioglitazone regulates inflammatory target genes in hepatic (IκBα) and endothelial (VCAM-1) settings in a PPARα-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses

Characterization of Peroxisomal Regulation Networks.

Peroxisome proliferation involves signal recognition and computation by molecular networks that direct molecular events of gene expression, metabolism, membrane biogenesis, organelle proliferation, protein import, and organelle inheritance. Peroxisome biogenesis in yeast has served as a model system for exploring the regulatory networks controlling this process. Yeast is an outstanding model system to develop tools and approaches to study molecular networks and cellular responses and because the mechanisms of peroxisome biogenesis and key aspects of the transcriptional regulatory networks are remarkably conserved from yeast to humans. In this chapter, we focus on the complex regulatory networks that respond to environmental cues leading to peroxisome assembly and the molecular events of organelle assembly. Ultimately, understanding the mechanisms of the entire peroxisome biogenesis program holds promise for predictive modeling approaches and for guiding rational intervention strategies that could treat human conditions associated with peroxisome function