Retinal degenerative diseases result in retinal pigment epithelial (RPE) and photoreceptor cell loss. These cells are continuously exposed to the environment (light) and to potentially pro-oxidative conditions, as the retina's oxygen consumption is very high. There is also a high flux of docosahexaenoic acid (DHA), a PUFA that moves through the blood stream toward photoreceptors and between them and RPE cells. Photoreceptor outer segment shedding and phagocytosis intermittently renews photoreceptor membranes. DHA is converted through 15-lipoxygenase-1 into neuroprotectin D1 (NPD1), a potent mediator that evokes counteracting cell-protective, anti-inflammatory, pro-survival repair signaling, including the induction of anti-apoptotic proteins and inhibition of pro-apoptotic proteins. Thus, NPD1 triggers activation of signaling pathway/s that modulate/s pro-apoptotic signals, promoting cell survival. This review provides an overview of DHA in photoreceptors and describes the ability of RPE cells to synthesize NPD1 from DHA. It also describes the role of neurotrophins as agonists of NPD1 synthesis and how photoreceptor phagocytosis induces refractoriness to oxidative stress in RPE cells, with concomitant NPD1 synthesis.
"acute inflammatory responses) are programmed to be self-limited and tightly controlled   . Lipid mediators such as prostaglandins and leukotrienes play pivotal roles in the initiation of acute inflammation , whereas resolvins and protectins promote and stimulate active resolution   . In excess, prostaglandins and leukotrienes are generally pro-inflammatory  and involved in the classic initiation phase of the acute inflammatory response in humans. "
[Show abstract][Hide abstract] ABSTRACT: Acute inflammatory responses are protective, yet without timely resolution can lead to chronic inflammation and organ fibrosis. A systems approach to investigate self-limited (self-resolving) inflammatory exudates in mice and structural elucidation uncovered novel resolution phase mediators in vivo that stimulate endogenous resolution mechanisms in inflammation. Resolving inflammatory exudates and human leukocytes utilize DHA and other n-3 EFA to produce three structurally distinct families of potent di- and trihydroxy-containing products, with several stereospecific potent mediators in each family. Given their potent and stereoselective picogram actions, specific members of these new families of mediators from the DHA metabolome were named D-series resolvins (Resolvin D1 to Resolvin D6), protectins (including protectin D1- neuroprotectin D1), and maresins (MaR1 and MaR2). In this review, we focus on a) biosynthesis of protectins and maresins as anti-inflammatory - pro-resolving mediators; b) their complete stereochemical assignments and actions in vivo in disease models. Each pathway involves the biosynthesis of epoxide-containing intermediates produced from hydroperoxy-containing precursors from human leukocytes and within exudates. Also, aspirin triggers an endogenous DHA metabolome that biosynthesizes potent products in inflammatory exudates and human leukocytes, namely aspirin-triggered Neuroprotectin D1/Protectin D1 [AT-(NPD1/PD1)]. Identification and structural elucidation of these new families of bioactive mediators in resolution has opened the possibility of diverse patho-physiologic actions in several processes including infection, inflammatory pain, tissue regeneration, neuroprotection-neurodegenerative disorders, wound healing, and others. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 08/2014; 1851(4). DOI:10.1016/j.bbalip.2014.08.006 · 5.16 Impact Factor
"These data indicate tight regulation of DHA homeostasis in RPE cells. The DHA-derived compounds, protectin D1, neuroprotectin D1 and resolvin D1, have been identified as anti-inflammatory lipid mediators (Bazan et al., 2010; Mukherjee et al., 2004; Serhan et al., 2004). Therefore, the well-recognized role of CYP4 enzymes in fatty acid metabolism and the suspected abnormal lipid metabolism in BCD raises the possibility that a deficiency in the PUFAhydroxylase catalytic function of CYP4V2 might play a role in BCD (Kelly et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: Abstract Drug metabolism and transport processes in the liver, intestine and kidney that affect the pharmacokinetics and pharmacodynamics of therapeutic agents have been studied extensively. In contrast, comparatively little research has been conducted on these topics as they pertain to the eye. Recently, however, catalytic functions of ocular cytochrome P450 enzymes have gained increasing attention, in large part due to the roles of CYP1B1 and CYP4V2 variants in primary congenital glaucoma and Bietti's corneoretinal crystalline dystrophy, respectively. In this review, we discuss challenges to ophthalmic drug delivery, including Phase I drug metabolism and transport in the eye, and the role of three specific P450s, CYP4B1, CYP1B1 and CYP4V2 in ocular inflammation and genetically determined ocular disease.
Drug Metabolism Reviews 05/2014; 46(3):1-14. DOI:10.3109/03602532.2014.921190 · 5.36 Impact Factor
"To replace the damaged outer segments, photoreceptors shed the distal tips of the outer segments, which are phagocytosed by retinal pigment epithelial (RPE) cells. RPE cells respond to oxidative stress by synthesizing protectin D1 from DHA in the phagocytosed outer segment membranes (Bazan et al., 2010). Protectin D1 promotes the survival of RPE cells, and, as a consequence, photoreceptor cell integrity (Mukherjee et al., 2007). "
[Show abstract][Hide abstract] ABSTRACT: Fatty acids (FAs) are highly diverse in terms of carbon (C) chain-length and number of double bonds. FAs with C>20 are called very long-chain fatty acids (VLCFAs). VLCFAs are found not only as constituents of cellular lipids such as sphingolipids and glycerophospholipids but also as precursors of lipid mediators. Our understanding on the function of VLCFAs is growing in parallel with the identification of enzymes involved in VLCFA synthesis or degradation. A variety of inherited diseases, such as ichthyosis, macular degeneration, myopathy, mental retardation, and demyelination, are caused by mutations in the genes encoding VLCFA metabolizing enzymes. In this review, we describe mammalian VLCFAs by highlighting their tissue distribution and metabolic pathways, and we discuss responsible genes and enzymes with reference to their roles in pathophysiology.
Biomolecules and Therapeutics 02/2014; 22(2):83-92. DOI:10.4062/biomolther.2014.017 · 1.73 Impact Factor
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