The ambiguity surrounding the role played by the LOXs

The ambiguity surrounding the role played by the 15-LOXs in malignant biological processes stems also from the limitations of current animal models, and especially the usage of its 12/15-LOX murine homolog, which can also catalyze the production of 12-HETE. Indeed, the proinflammatory effect of 12-HETE on TNF-α production was partially reversed by creating transgenic mice expressing human 15-LOX-1, which does not produce high concentrations of 12-HETE, and thus produced more 13-HODE [69]. However, this expression was limited to epithelial cells, and may not reflect the full effect of 15-LOX expression and function in stromal Tenatoprazole mg and macrophages in the tumor bed. Moreover, the interplay between 15-LOX-1 and 15-LOX-2 is not reflected in such maneuvers. Part of the gap in our understanding of the role played by the different 15-LOX enzymes in cancerous tissue may stem from both incomplete methodology to measure their distinct activity, and restricted availability of instrumentation to that end, e.g., high-pressure liquid chromatography and liquid chromatography/mass spectrometry. Any attempt to create a solidifying concept regarding the role of the 15-LOXs in the neoplastic milieu is, therefore, premature. Presumably, much of the controversy stems from incomplete understanding of the molecular mechanisms and signaling cascades through which 15-LOX metabolites influence cell fates. Such understanding demands further research.
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Acknowledgements This work was supported by grants from the Israel Science Foundation (number 534/09), the Nutricia Research Foundation, and the Marc Rich Foundation (to A. Ariel). A. Ariel is a recipient of the young scientist award from Teva Pharmaceuticals Ltd.
Introduction Although anxiety disorders generally manifest early in life, the ones that evolve in late life represent a significant clinical problem with prevalence rates of 6%–10% in those aged 55 years or older (Schuurmans and van Balkom, 2011). Presently, it is not known whether, if at all, the pathophysiology and progression of anxiety disorders in the elderly group differs from younger age groups. For example, in both aged and young populations, anxiety disorders are associated with major depressive disorders. However, aged persons have additional medical comorbidities and lifetime exposure to various stressors, which could confer an increased biological vulnerability to the development of disorders characterized with clinical anxiety. The aged brain and young brain differ in several biochemical aspects, among which include the oxidation, metabolism, and signaling of bioactive lipids. Emerging work suggests that precise modulation of bioactive lipids in the brain is crucial for proper functioning, and that dysregulation of lipid oxidation could be involved in a number of neurologic and psychiatric diseases. The 12/15-lipoxygenase (12/15-LO) is a lipid-peroxidizing enzyme that is widely expressed in the central nervous system. It produces hydroxyperoxyeicosatetraenoic acid metabolites from arachidonic acid substrate and has been linked to aging-associated illnesses such as Alzheimer's disease (Chu et al., 2012). However, its role in anxiety has not yet been investigated. The goal of this study was to investigate whether overexpression of 12/15-lipoxygenase impacted anxiety-like behavior in mice. Here, we report that an anxiety phenotype developed in mice overexpressing the 12/15-LO (H12/15-LO) at the age of 15 months, which was absent at 12 months.
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Results
Discussion Aging-related changes in lipid metabolism and homeostasis have been relatively unexplored in the context of neurologic and psychiatric illness until recently. The aging brain is vulnerable to oxidative stress because it is a lipid-rich organ, and processes that oxidize brain lipids contribute to deterioration of neuronal functioning. Indeed, we have previously shown that 12/15-LO activity is associated with aging-associated brain oxidative damage and neuronal injury (Chinnici et al., 2005). Beyond direct neuronal damage through oxidation, lipid dysregulation has also been implicated in anxiogenesis following exposure to Gulf War agents and perinatal fatty acid depletion (Abdullah et al., 2012, Palsdottir et al., 2012). Thus, our current findings extend the importance of 12/15-LO as a molecular player in lipid-mediated anxiogenesis in addition to its known role as a brain pro-oxidant.