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  • br Introduction Lipoxygenases LOXs are a heterogeneous


    Introduction Lipoxygenases (LOXs) are a heterogeneous family of enzymes that catalyze the peroxidation of polyunsaturated fatty acids (PUFAs). By oxidizing free PUFAs, they were shown to contribute to the generation of various bioactive lipid mediators. However, LOX-mediated oxidation of PUFAs esterified to phospholipids can also generate oxidized phospholipids that induce alternative signaling pathways and additionally affect the biophysical properties of cellular membranes. Different LOXs were shown to exert both pro- and anti-inflammatory effects, regulate phagocytosis and autophagy, control barrier function and modulate coagulation and hemostasis. Human 15-lipoxygenase (15-LOX) type 1 and it's murine orthologue 12/15-lipoxygenase (12/15-LOX) are encoded by the ALOX15 gene and represent evolutionary highly conserved members of this family of enzymes that are primarily expressed in myeloid Irsogladine synthesis such as reticulocytes, eosinophils and macrophages. Although the biological properties of 15-LOX and 12/15-LOX have been the focus of intense research, these efforts yielded conflicting results. The same is true for the various enzymatic products generated by 12/15-LOX, like hydroxyeicosatetraenoic acids (HETEs). 12/15-LOX and 15-LOX have been implicated in the pathogenesis of various inflammatory, metabolic, neurodegenerative and infectious disorders. The physiologic function of these two enzymes has remained still incompletely understood, though [1]. This review aims to give an overview about the biological properties of 12/15-LOX and 15-LOX and to give specific insights into their role during inflammation and immunity.
    Products and properties of 12/15-lipoxygenase
    12/15 Lipoxygenase during the resolution of inflammation and regulation of the innate and adaptive immune response
    12/15-LOX during the pathophysiology of disease
    Concluding remarks As an important regulator of inflammation, 12/15-LOX might be a relevant future target for clinical purposes. On the one hand, 12/15-LOX-inhibitors such as PD146176 [12] could provide potent therapeutics against a number of 12/15-LOX-triggered diseases, which include diabetes, hypertension and other disorders linked to chronic adipose tissue inflammation [10]. The emerging knowledge on the anti-inflammatory role of distinct 12/15-LOX-derived mediators such as lipoxins, on the other hand, suggests that lipoxin analogues and ALX agonists as well as 12/15-LOX activators could help to foster the resolution of inflammation and thus represent interesting molecules for the future therapy of chronic inflammatory diseases such as rheumatoid arthritis [167].
    Acknowledgments This work was supported by the Deutsche Forschungsgemeinschaft (CRC1181 to G.K.), the Else Kröner Fresenius Stiftung (2013_A274 to G.K.) and the European Union (ERC StG 640087 – SOS to G.K.).
    Introduction Diabetic retinopathy (DR) remains the leading cause of blindness among working-age populations worldwide, even though with the advent of many effective treatments [1]. It is characterized by breakdown of the blood retinal barrier (BRB) in the early stage of the disease, followed by capillary degeneration, and subsequent neovascularization (NV) at the late stages [2,3]. The current therapies are heavily relying on controlling systemic hyperglycemia. However, due to the Irsogladine synthesis metabolic memory effect, many diabetic patients develop retinopathy despite their tight glycemic control [4]. Furthermore, the existing therapeutic strategies; corticosteroids, anti-vascular endothelial growth factor (VEGF) agents, ranibizumab and aflibercept, as well as laser photocoagulation, are limited by their side effects [5]. Therefore, it is worthwhile to explore new therapeutic avenues to prevent DR via deeper understanding of its pathophysiology. Compelling evidence now indicates that DR is a multifactorial disease that involves chronic inflammation at every stage, from initiation to progression and eventually to ischemia and NV [6,7]. Data from animal studies suggest that leukocyte-endothelial cell adhesion and entrapment (leukostasis) are rate-limiting steps for initiation of retinal inflammatory response prior to any clinical sign of DR [8,9]. Further studies using human tissues demonstrated an increase in leukocyte density in human eyes with DR and strong relationship between leukocyte-endothelial cell adhesion and retinal capillary damage in diabetes [10]. Once leukocytes have attached to the endothelial cells, pro-inflammatory cytokines and chemokines are released. These mediators are known to alter endothelial cell junctional proteins, allowing leukocytic infiltration into the retina, with concomitant compromise of the BRB [11]. Attachment and extravasation of these leukocytes are mediated by adhesive interactions between molecules present on leukocytes and their counter receptors expressed on activated endothelial cells such as the E- and P-selectins and intercellular cell adhesion molecule (ICAM)-1 [12,13]. ICAM-1 is directly up-regulated by diabetes [10] in the retinal vasculature where its blockade has highlighted it as a potential target for DR therapies, both clinically [14] and experimentally [15]. Yet, the exact underlying mechanisms of how hyperglycemia mediates ICAM-1 upregulation and hence leukocyte-endothelial cell adhesion need to be further elucidated.