Enzymatically oxidized phospholipids assume center stage as essential regulators of innate immunity and cell death.

Enzymatically oxidized phospholipids (eoxPLs) are formed through regulated processes by which eicosanoids or prostaglandins are attached to phospholipids (PLs) in immune cells. These eoxPLs comprise structurally diverse families of biomolecules with potent bioactivities, and they have important immunoregulatory roles in both health and disease. The formation of oxPLs through enzymatic pathways and their signaling capabilities are emerging concepts. This paradigm is changing our understanding of eicosanoid, prostaglandin, and PL biology in health and disease. eoxPLs have roles in cellular events such as ferroptosis, apoptosis, and blood clotting and diseases such as arthritis, diabetes, and cardiovascular disease. They are increasingly recognized as endogenous bioactive mediators and potential targets for drug development. This review will describe recent evidence that places eoxPLs and their biosynthetic pathways center stage in immunoregulation.

Genome-wide identification of tomato (Solanum lycopersicum L.) lipoxygenases coupled with expression profiles during plant development and in response to methyl-jasmonate and wounding.

Lipoxygenases (LOXs) (EC 1.13.11.12) catalyze the oxygenation of fatty acids and produce oxylipins including the plant hormone jasmonate (jasmonic acid/methyl jasmonate; MeJA). Little is known about the tomato LOX gene family members that impact tomato growth and development, and less so about their feed-back regulation in response to MeJA. We present genome wide identification of 14 LOX gene family members in tomato which map unevenly on 12 chromosomes. The characteristic structural features of 9-LOX and 13-LOX tomato gene family, their protein domains/features, and divergence are presented. Quantification of the expression patterns of all the 14 SlLOX gene members segregated the members based on differential association with growth, development, or fruit ripening. We also identified those SlLOX genes whose transcription responds to exogenous MeJA and/or wounding stress. MeJA-based feedback regulation that involves activation of specific members of LOX genes is defined. Specific nature of SlLOX gene regulation in tomato is defined. The novel data on dynamics of SlLOX gene expression should help catalyze future strategies to elucidate role(s) of each gene member in planta and for crop biotechnological intervention.

Oxidized PLs and vascular inflammation.

Oxidized PLs (OxPLs) generated in health and disease are now recognized as important mediators of cellular signalling. There is an increasing body of evidence showing that PL peroxidation is not only increased in vascular disorders, but is also a physiological event of relevance to coagulation, innate immunity, and self-tolerance. Nonenzymatically formed OxPLs generated during chronic inflammation is an uncontrolled event, generating hundreds of diverse structures, and prone to more deleterious bioactivities. In contrast, enzymatic formation of OxPLs is tightly regulated, involving receptors and intracellular signaling, acting as part of the normal physiological response to injury in order to restore homeostasis. In the present review, the major nonenzymatic OxPLs structures found during vascular inflammation are summarized, along with a brief description of their known biological activities. Also, we review what is currently known about enzymatic formation of OxPLs by acutely activated immune cells and their signaling actions under homeostatic and pathological conditions.

[Pharmaceutical aspects of animal lipoxygenases]. / Farmaceutické aspekty zivocísnej lipoxygenázy.

Lipoxygenases (LOX, plant LOX [EC 1.13.11.12], linoleate: oxygen oxidoreductase, animal LOXs [5-LOX, EC 1.13.11.34; 8-LOX, EC 1.13.11.40; 12-LOX, EC 1.13.11.31; 15-LOX, EC 1.13.11.33], arachidonate: oxygen oxidoreductase) belong to the family of structurally related dioxygenases containing non-heme and non-sulfide iron in the active site. LOX catalyzes the regiospecific and stereospecific insertion of molecular oxygen into the molecule of unsaturated fatty acid with the (1Z,4Z)-penta-1,4-diene structural unit in its aliphatic chain. The result of this reaction is the production of conjugated optically active (S)- or (R)-hydroperoxides of polyunsaturated fatty acids. The occurrence of LOX was determined in plants, in animals, and also in lower organisms such as mushrooms, corals and bacteria. The dominant substrate of animal LOX is arachidonic acid which is released from membrane phospholipids by phospholipase A2 or enters the cell from the extracellular space. Products of the arachidonic acid cascade can play an important role in the pathogenesis of different diseases such as asthma bronchiale, psoriasis and inflammatory diseases, cancer diseases, atherosclerosis, diabetes mellitus and renal diseases.

Eicosanoids in prevention and management of diseases.

Eicosanoids, which originate from polyunsaturated fatty acids (PUFAs), have a major impact on homeostasis maintenance as secondary signal transducers. Signal cascade, which includes reception, processing and signal transduction coming from the environment into the cell, determines the type of response evoked. Signal distortion may take place on every level of this cascade and this in consequence could lead to the development of many diseases. Any intervention into PUFAs metabolism leads to quantitative and qualitative changes of synthesized eicosanoids. Some of them promote, whereas others inhibit carcinogenesis, some are pro- or anti-inflammatory and the overall result depends on the outcome of these contradictory effects. The type and amount of produced eicosanoids depends on substrates' availability and activity of enzymes catalyzing different stages of their transformation. A particularly negative role was assigned to the over expression of phospholipase A2, cyclooxygenase-2, 5- and 12-lipoxygenases, while the contribution of other oxygenases and their metabolites is considerably less clear. The information about their interplay is extremely sparse and inadequate to understand intricacies of the mechanisms involved. There are indications that utilization of selected eicosanoids (their analogs, agonists or antagonists) could be a better way of disease prevention and treatment, more effective than excessive dietary supplementation of fatty acids. This review presents a more global picture of oxygenases and their PUFA metabolites giving a brief summary of our current understanding of perspectives and pitfalls of their regulation and mediatory action in human diseases.

Regulation of endothelial cell functions by basement membrane- and arachidonic acid-derived products.

Angiogenesis, the formation of new blood vessels from preexisting vasculature, is required for normal physiological as well as pathological events. The angiogenic process requires endothelial cells to proliferate, migrate, and undergo tubulogenesis. These multistep processes necessitate secretion of pro-angiogenic growth factors, activation of specific intracellular signaling, and interaction of endothelial cells with basement membrane (BM) extracellular matrix components. The generation and release of angiogenic molecules are highly regulated and are influenced by numerous factors, including BM-derived fragments, proteolytic enzymes, as well as metabolites of arachidonic acid (AA). The interactions between these key modulators of angiogenesis is extremely complex, as AA metabolites can regulate the synthesis of soluble angiogenic factors, BM components, as well as enzymes capable of cleaving BM components, which result in the generation of pro- and/or anti-angiogenic products. Furthermore, some BM-derived fragments can alter the expression of AA-converting enzymes and consequently the synthesis of angiogenic factors. In this review we describe the relationship between BM components and AA metabolites with respect to the regulation of endothelial cell functions in health and disease.