Here, we describe the function and role of human 12-LOX, and mouse 12-LOX and 12/15-LOX, in the development of diabetes and diabetes-related complications, and describe promise in the development of strategies to limit pro-inflammatory metabolites, primarily via new small molecule 12-LOX inhibitors.
In addition, baicalein can protect rat cortical neurons from damage caused by diabetes via inhibiting the 12/15-LOX pathway and relieving inflammation and apoptosis of the central nervous system.
For in vivo studies, experimental diabetes was induced in wild-type (WT) mice and 12/15-Lo (also known as Alox15) knockout mice (12/15-Lo<sup>-/-</sup>); ER stress was then evaluated after 12-14 weeks of diabetes.
Isolated constituents were evaluated <i>in silico</i> and <i>in vitro</i> in assays related to the traditional use against diabetes (inhibition of α-glucosidase activity; inhibition of advanced glycation endproducts) and in inflammatory conditions (inhibition of AAPH induced linoleic acid peroxidation, inhibition of 15-LOX, antimicrobial activity).
Analysis of plasma bioactive lipids' heat map revealed that the activity of circulating 12/15-LO was not altered by diabetes as evident by no significant changes in the plasma levels of major metabolites derived from 12/15-lipoxygenation of different PUFAs, including linoleic acid (13-HODE), arachidonic acid (12- and 15- HETEs), eicosapentaenoic acid (12- and 15- HEPEs), or docosahexaenoic acid (17-HDoHE).
Increased expression and activity of 12/15-lipoxygenase (12/15-LO) in vascular smooth muscle cells (VSMCs) play a key role in the pathogenesis of diabetes and vascular complications.
Examination of knockout and transgenic animals revealed important roles for 12/15-LOX in inflammatory diseases, including atherosclerosis, cancer, osteoporosis, angiotension II-dependent hypertension and diabetes.