The ratio of ω-6 to ω-3 polyunsaturated fatty acids (PUFAs) appears to be critical in the regulation of various pathophysiological processes and to maintain cellular homeostasis. While a high proportion of dietary intake of ω-6 PUFAs is associated with various inflammatory disorders, higher intake of ω-3 PUFAs is known to offer protection. It is now well established that beneficial effects of ω-3 PUFAs are mediated in part by their oxygenated metabolites mainly via the lipoxygenase (LOX) and cyclooxygenase (COX) pathways. However, the down-stream signaling pathways that are involved in these anti-inflammatory effects of ω-3 PUFAs have not been elucidated. The present study evaluates the effects of 15-LOX metabolites of α-linolenic acid (ALA, ω-3 PUFA) on lipopolysaccharide (LPS) induced inflammation in RAW 264.7 cells and peritoneal macrophages. Further, the effect of these metabolites on the survival of BALB/c mice in LPS mediated septic shock and also polymicrobial sepsis in Cecal Ligation and Puncture (CLP) mouse model was studied. These studies reveal the anti-inflammatory effects of 13-(S)-hydroperoxyoctadecatrienoic acid [13-(S)-HPOTrE] and 13-(S)-hydroxyoctadecatrienoic acid [13-(S)-HOTrE] by inactivating NLRP3 inflammasome complex through the PPAR-γ pathway. Additionally, both metabolites also deactivated autophagy and induced apoptosis. In mediating all these effects 13-(S)-HPOTrE was more potent than 13-(S)-HOTrE.
Eicosanoids, a family of oxygenated metabolites of eicosapolyenoic fatty acids, such as arachidonic acid, formed via the lipoxygenase, cyclooxygenase (COX) and epoxygenase pathways, play an important role in the regulation of various pathophysiological processes, including inflammation and cancer. COX-2, the inducible isoform of COX, has emerged as the key enzyme regulating inflammation, and promises to play a considerable role in cancer. Although NSAIDs have been in use for centuries, the COX-2 selective inhibitors - coxibs - have emerged as potent anti-inflammatory drugs with fewer gastric side effects. As COX-2 plays a major role in neoplastic transformation and cancer growth, by downregulating apoptosis and promoting angiogenesis, invasion and metastasis, coxibs have a potential role in the prevention and treatment of cancer. Recent studies indicate their possible application in overcoming drug resistance by downregulating the expression of MDR-1. However, the cardiac side effects of some of the coxibs have limited their application in treating various inflammatory disorders and warrant the development of COX-2 inhibitors without side effects. This review will focus on the role of COX-2 in inflammation and cancer, with an emphasis on novel approaches to the development of COX-2 inhibitors without side effects.
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