Bioactive lipid mediators

Conversely, arachidonic acid is also metabolized by various enzymes of the LOX pathway (Fig. 6.IB), to produce bioactive lipid mediators. The chief enzymes of the LOX pathway are the 5-LOX, 12-LOX, and the 15-LOX enzymes, whose names are derived from the position in which molecular oxygen is inserted by the enzyme species into the arachidonic acid backbone. The major bioactive products of the 5-LOX pathway are the leukotrienes (LT). Leuko-trienes are formed from arachidonic acid presented to the 5-LOX enzyme by the... 

The involvement of platelets in assisting hematogenous spread of metastatic tumor cells and the interactions between platelets, cancer cells, and the blood vessel wall were proposed decades ago. This was confirmed in experimental model systems of thrombocytopenia which showed inhibition of metastasis (Gasic et al., 1973 Kimoto et al., 1993). Honn et al, proposed the first hypothesis on the involvement of bioactive lipid mediators, specifically TXA2... 

Kendall, A. C. and A. Nicolaou 2013. Bioactive lipid mediators in skin inflammation and immunity. 52(1) 141-164. 

Several enveloped viruses, and some physical gene transfer techniques such as electroporation, deliver the nucleic acid into the cell by direct crossing of the cell membrane. Lipid-based, enveloped systems can do this by a physiological, selfsealing membrane fusion process, avoiding physical damage of the cell membrane. For cationic lipid-mediated delivery of siRNA, most material is taken up by endo-cytotic processes. Recently, direct transfer into the cytosol has been demonstrated to be the bioactive delivery principle for certain siRNA lipid formulations [151]. 

This chapter surveys the neurochemistry of lipid messengers, as well as the mechanisms by which bioactive lipids accumulate upon stimulation in response to injury, cerebral ischemia, seizures, neurotrauma or neurodegen-erative diseases, and their significance in pathophysiology. Emphasis is placed on three groups of bioactive lipids AA and its metabolites, known collectively as eicosanoids PAF, a highly potent ether phospholipid and the newly identified DHA-derived mediator, neuroprotectin Dl. 

The lipid mediators derived from ARA, EPA, and DHA discussed above (i.e., lipox-ins, resolvins, protectins, and maresins) have different biosynthetic origins and variable overall bioactivity profiles. These molecules have been collectively termed specialized pro-resolving lipid mediators (SPM), due to their conunon biological role, namely their ability to reduce the inflanunatory response, and to promote the resolution of inflammation and return to homeostasis. 

Vickers, P.J., DeLuca, C., Wong, E. and Abramovitz, M. J. Lipid Mediators, (1998) in Eicosanoids and other Bioactive Lipids in Cancer, Inflammation and Radiation Injury, 2, Part A (Honn, K.V., ed.), pp. 145-151, Plenum Press, New York... 

This section will address the most commonly used experimental approaches and tools that are available to probe ceramide-mediated functions. It should be noted at the outset that the interconnected metabolism of sphingolipids complicates the study of ceramide bioactivity, since ceramide participates in a network of metabolic pathways that connect several bioactive lipids, including sphingosine, sphingosine-1-phosphate, diacylglycerol and others. 

Lipid phosphate phosphohydrolases (LPPs), formerly called type 2 phosphatidate phosphohydrolases (PAP-2), catalyse the dephosphorylation of bioactive phospholipids (phosphatidic acid, ceramide-1-phosphate) and lysophospholipids (lysophosphatidic acid, sphingosine-1-phosphate). The substrate selectivity of individual LPPs is broad in contrast to the related sphingosine-1-phosphate phosphatase. LPPs are characterized by a lack of requirement for Mg2+ and insensitivity to N-ethylmaleimide. Three subtypes (LPP-1, LPP-2, LPP-3) have been identified in mammals. These enzymes have six putative transmembrane domains and three highly conserved domains that are characteristic of a phosphatase superfamily. Whether LPPs cleave extracellular mediators or rather have an influence on intracellular lipid phosphate concentrations is still a matter of debate. 

Other systems like electroporation have no lipids that might help in membrane sealing or fusion for direct transfer of the nucleic acid across membranes they have to generate transient pores, a process where efficiency is usually directly correlated with membrane destruction and cytotoxicity. Alternatively, like for the majority of polymer-based polyplexes, cellular uptake proceeds by clathrin- or caveolin-dependent and related endocytic pathways [152-156]. The polyplexes end up inside endosomes, and the membrane disruption happens in intracellular vesicles. It is noteworthy that several observed uptake processes may not be functional in delivery of bioactive material. Subsequent intracellular obstacles may render a specific pathway into a dead end [151, 154, 156]. With time, endosomal vesicles become slightly acidic (pH 5-6) and finally fuse with and mature into lysosomes. Therefore, polyplexes have to escape into the cytosol to avoid the nucleic acid-degrading lysosomal environment, and to deliver the therapeutic nucleic acid to the active site. Either the carrier polymer or a conjugated endosomolytic domain has to mediate this process [157], which involves local lipid membrane perturbation. Such a lipid membrane interaction could be a toxic event if occurring at the cell surface or mitochondrial membrane. Thus, polymers that show an endosome-specific membrane activity are favorable. 

LOX-catalyzed oxidation of LDL has been studied in subsequent studies [26,27]. Belkner et al. [27] showed that LOX-catalyzed LDL oxidation was not restricted to the oxidation of lipids but also resulted in the cooxidative modification of apoproteins. It is known that LOX-catalyzed LDL oxidation is regio- and enantio-specific as opposed to free radical-mediated lipid peroxidation. In accord with this proposal Yamashita et al. [28] showed that LDL oxidation by 15-LOX from rabbit reticulocytes formed hydroperoxides of phosphatidylcholine and cholesteryl esters regio-, stereo-, and enantio-specifically. Sigari et al. [29] demonstrated that fibroblasts with overexpressed 15-LOX produced bioactive minimally modified LDL, which is probably responsible for LDL atherogenic effect in vivo. Ezaki et al. [30] found that the incubation of LDL with 15-LOX-overexpressed fibroblasts resulted in a sharp increase in the cholesteryl ester hydroperoxide level and a lesser increase in free fatty acid hydroperoxides. 

---