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evolution
gene ALOX15 encodes for human 15-LOX type 1 and murine 12/15-LOX. Although the encoded enzymes display slightly different specificities (15- versus 12-lipoxygenating activity), these proteins represent evolutionary and functionally closely-related enzymes that share a high degree of sequence similarity. Of note, these 12/15LOXs that are encoded by the ALOX15 genes have separated from other LOXs early during evolution, although they share close biochemical properties with other LOXs such as ALOX12 or ALOX15B
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
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mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
H2QBX9
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
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mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
evolution
-
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
malfunction
macrophages that lack 12/15LO have enhanced transporter expression, reduced ATP-binding cassette G1 phosphorylation, and increased cholesterol efflux
malfunction
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12-LOX inhibition attenuates platelet aggregation
malfunction
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12-LOX-overexpressing PC-3 cells show an enhanced invasive ability which results from an increase in MMP9 expression and secretion
malfunction
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cells with RNAi silenced 12/15-LO and stimulated with PDGF show an impaired STAT3 phosphorylation compared to cells transfected with the scrambled control
malfunction
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the time to cessation of bleeding in 12-LOX-/- mice is significantly prolonged. Mice deficient in 12-LOX show a significant attenuation of alphaIIbeta3 activation for both agonists compared to wild-type mice
malfunction
ALOX12 expression and its metabolite 12(S)-hydroxyeicosatetraenoic acid are significantly increased in the visceral adipose tissue of type 2 diabetes subjects with body mass index of 21
malfunction
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deletion of 12/15-LOX in mice leads to increased cytochrome P450-derived bioactive lipid mediator epoxyeicosatrienoic acids, i.e. 11,12-EpETrE and 14,15-EpETrE, which are further enhanced by acute PUFA intake post-MI. Macrophage density is decreased in wild-type + PUFA and 12/15-LOX-/- mice compared with their respective standard diet-fed wild-type controls at day 5 post-MI. 12/15-LOX-/- + PUFA mice display an increased expression of chemokine (C-C motif) ligand 2 and reparative macrophages markers (Ym-1, Mrc-1, and Arg-1) in the infarcted area. Furthermore, 12/15-LOX-/- mice, with or without PUFA, show reduced collagen deposition at day 5 post-MI compared with wild-type mice. In conclusion, deletion of 12/15-LOX and short-term exposure of PUFA promote leukocyte clearance, thereby limiting cardiac remodeling and promoting an effective resolution of inflammation
malfunction
disruption of normal 12- and 15-LO function by the inflammatory obese condition promotes adipocyte dysfunction and overall metabolic disease including insulin resistance and diabetes
malfunction
pharmacologic inhibition of 12-LOX in human platelets results in significant attenuation of FcgammaRIIa-mediated aggregation. Activation of the FcgammaRIIa receptor leads to immune-mediated thrombosis, which is often life threatening in patients undergoing heparin-induced thrombocytopenia or sepsis. Inhibiting FcgammaRIIa-mediated activation, e.g. by inhibiting the enzyme 12-LOX, in platelets limits thrombosis and is the principal target for prevention of immune-mediated platelet activation
malfunction
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platelets from transgenic mice expressing human FcgammaRIIa but deficient in platelet 12-LOX, fail to form normal platelet aggregates and exhibit deficiencies in Rap1 and aIIbbeta3 activation
malfunction
streptozotocin (STZ)-induced diabetic mice show upregulated expression of 12/15-LOX and inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and nuclear factor (NF)-kappaB in diabetic hearts. Disruption of 12/15-LOX significantly improves STZ-induced cardiac dysfunction and fibrosis. Deletion of 12/15-LOX inhibits the increases of TNF-alpha and NF-kappaB as well as the production of STZ-induced reactive oxygen species in the heart. Administration of N-acetylcysteine in diabetic mice prevents STZ-induced cardiac fibrosis. Neonatal cultured cardiomyocytes exposed to high glucose conditions induce the expression of 12/15-LOX as well as TNF-alpha, NF-kappaB, and collagen markers. These increases are inhibited by treatment of the 12/15-LOX inhibitor. Disruption of 12/15-LOX reduces inflammation, oxidative stress, and fibrosis in the diabetic heart, thereby improving systolic dysfunction. Disruption of 12/15-LOX decreases cardiac inflammation induced by hyperglycemia
malfunction
the 12LO inhibitor induces a 2-2.5fold increase in cell death, which appears to result from apoptosis, as indicated by DNA fragmentation, activation of procaspase 3 to caspase 3 and cytochrome c release from the mitochondria to the cytosol. Human platelet-type 12LO-antisense knockdown, by either plasmid transfection or adeno-associated virus (AAV) infection also induces substantial VSMC death over controls, which can also be prevented by treatment with 12HETE, but not 5HETE. Hence, biochemical 12LO inhibition or 12LO-antisense knockdown in VSMC can induce programmed cell death
malfunction
the cytokine expression profile of Alox15-/- dendritic cells show multiple alterations in comparison to that for wild-type dendritic cells. Alox15/ dendritic cells display a shift in the mRNA and protein expression of different IL-12/IL-23 subunits and increased expression of the IL-23-specific subunit p19, whereas expression of the subunit p40 (shared by IL-12 and IL-23) is unaltered and the IL-12-specific subunit p35 is decreased. Alox15-deficient mice display an increased differentiation of Th17 cells and an aggravation of T celldependent autoimmune responses, Alox15-/- mice reveal significant increase in the expression of the IL-23 subunit p19, whereas expression levels of the IL-12/IL-23 subunits p35 and p40 are not significantly changed
malfunction
the cytokine expression profile of Alox15-/- dendritic cells show multiple alterations in comparison to that for wild-type dendritic cells. Alox15/ dendritic cells display a shift in the mRNA and protein expression of different IL-12/IL-23 subunits and increased expression of the IL-23-specific subunit p19, whereas expression of the subunit p40 (shared by IL-12 and IL-23) is unaltered and the IL-12-specific subunit p35 isdecreased
malfunction
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streptozotocin (STZ)-induced diabetic mice show upregulated expression of 12/15-LOX and inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and nuclear factor (NF)-kappaB in diabetic hearts. Disruption of 12/15-LOX significantly improves STZ-induced cardiac dysfunction and fibrosis. Deletion of 12/15-LOX inhibits the increases of TNF-alpha and NF-kappaB as well as the production of STZ-induced reactive oxygen species in the heart. Administration of N-acetylcysteine in diabetic mice prevents STZ-induced cardiac fibrosis. Neonatal cultured cardiomyocytes exposed to high glucose conditions induce the expression of 12/15-LOX as well as TNF-alpha, NF-kappaB, and collagen markers. These increases are inhibited by treatment of the 12/15-LOX inhibitor. Disruption of 12/15-LOX reduces inflammation, oxidative stress, and fibrosis in the diabetic heart, thereby improving systolic dysfunction. Disruption of 12/15-LOX decreases cardiac inflammation induced by hyperglycemia
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malfunction
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the cytokine expression profile of Alox15-/- dendritic cells show multiple alterations in comparison to that for wild-type dendritic cells. Alox15/ dendritic cells display a shift in the mRNA and protein expression of different IL-12/IL-23 subunits and increased expression of the IL-23-specific subunit p19, whereas expression of the subunit p40 (shared by IL-12 and IL-23) is unaltered and the IL-12-specific subunit p35 is decreased. Alox15-deficient mice display an increased differentiation of Th17 cells and an aggravation of T celldependent autoimmune responses, Alox15-/- mice reveal significant increase in the expression of the IL-23 subunit p19, whereas expression levels of the IL-12/IL-23 subunits p35 and p40 are not significantly changed
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malfunction
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deletion of 12/15-LOX in mice leads to increased cytochrome P450-derived bioactive lipid mediator epoxyeicosatrienoic acids, i.e. 11,12-EpETrE and 14,15-EpETrE, which are further enhanced by acute PUFA intake post-MI. Macrophage density is decreased in wild-type + PUFA and 12/15-LOX-/- mice compared with their respective standard diet-fed wild-type controls at day 5 post-MI. 12/15-LOX-/- + PUFA mice display an increased expression of chemokine (C-C motif) ligand 2 and reparative macrophages markers (Ym-1, Mrc-1, and Arg-1) in the infarcted area. Furthermore, 12/15-LOX-/- mice, with or without PUFA, show reduced collagen deposition at day 5 post-MI compared with wild-type mice. In conclusion, deletion of 12/15-LOX and short-term exposure of PUFA promote leukocyte clearance, thereby limiting cardiac remodeling and promoting an effective resolution of inflammation
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metabolism
cardiac 12/15-LOX pathway induced by high glucose condition increases the expression of cardiac inflammation in vitro
metabolism
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cardiac 12/15-LOX pathway induced by high glucose condition increases the expression of cardiac inflammation in vitro
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physiological function
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12/15-LOX is a critical mediator of the chronic type 1 inflammatory response. Evolution of the immune response to Toxoplasma gondii is accompanied by an increasing requirement for 12/15-LOX mediated signaling. Although 12/15-LOX deficient mice are resistant to acute Toxoplasma gondii infection, 80% of 12/15-LOX-deficient mice die during chronic toxoplasmosis, compared to no deaths in wild-type controls. The enhanced susceptibility of 12/15-LOX-deficient mice to chronic toxoplasmosis is associated with reduced production of IL-12 and gamma interferon (IFN-gamma) that is not evident during acute infection. Ex vivo IFN-gamma production by 12/15-LOX-deficient splenocytes can be rescued by the addition of recombinant IL-12. 12/15-LOX does not play a role in macrophage killing of Toxoplasma gondii in vitro
physiological function
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12/15-LOX is the central executioner in an oxidative stress-related neuronal death program. In neuronal HT22 cells subjected to glutamate-induced oxidative stress, 12/15-LOX damages mitochondria, which represents the committed step that condemns the cell to die. Mitochondria incubated with 12/15-LOX generate reactive oxygen species
physiological function
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12/15LO activity in the vessel wall contributes to atherogenesis by impairing the macrophage ATP-binding cassette transporter G1 cholesterol efflux pathway. 12/15LO activity reduces high density lipoprotein-mediated cholesterol efflux, ATP-binding cassette transporter G1 cellular expression. 12/15LO activity does not affect ATP-binding cassette transporter G1 mRNA expression
physiological function
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12/15LO expression increases chemokine production. 2/15LO mediates early stages of adipose tissue inflammation and whole body insulin resistance induced by high fat feeding. Adipose tissue from high fat diet-fed 12/15LO KO mice is not infiltrated by macrophages and does not display any increase in the inflammatory markers compared to adipose tissue from normal chow-fed mice. 12/15LO KO mice exhibit no high fat diet-induced change in insulin-stimulated glucose disposal rate or hepatic glucose output. Insulin-stimulated Akt phosphorylation in muscle tissue from high fat diet-fed mice is significantly greater in 12/15LO KO mice than in wild-type mice
physiological function
12/15LO plays a key role in activating the mitogen-activated protein kinase pathway. 12/15LO regulates ATP-binding cassette G1 expression and function through p38- and c-Jun N-terminal kinase 2-dependent mechanisms
physiological function
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anti-inflammatory and tissue-protective role of 12/15-LO and its eicosanoidic products during chronic inflammatory disorders such as arthritis. 12/15-LO-deficient mice show enhanced inflammatory gene expression and decreased levels of the eicosanoid lipoxin A(4) within their inflamed synovia. 12/15-LO-deficient macrophages display significantly reduced levels of lipoxin A(4), which correlate with increased activation of p38MAPK and an enhanced inflammatory gene expression after stimulation with TNF-alpha
physiological function
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endogenous 12/15-LOX defines the resident peritoneal macrophage population and regulates both the recruitment of monocytes/peritoneal macrophage and cytokine response to bacterial products in vivo
physiological function
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increased expression of 2/15-LOX causes heart failure. 2/15-LOX induces cardiac inflammation. Alox15 transgenic mice develop systolic dysfunction. Cardiac fibrosis increases in Alox15 transgenic mice with advancing age and is associated with the infiltration of macrophages. Cardiac expression of monocyte chemoattractant protein 1 is up-regulated in Alox15 transgenic mice compared with wild-type mice. Disruption of 12/15-LOX significantly reduces cardiac monocyte chemoattractant protein-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload
physiological function
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p12-LOX plays an important role in tumor development, is required for tumor promotion of epidermal cells. The enzyme is involved in activation of NF-kappaB in the tumor necrosis factor-alpha-stimulated JB6 P+ cells
physiological function
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possibility of 12-LOX involvement in ceramide-mediated generation of reactive oxygen species and cellular oxidative stress
physiological function
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the 12/15-LO pathway participates in the regulation of monocyte chemoattractant protein-1 expression in mouse macrophages
physiological function
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the 12/15-LO pathway participates in the regulation of monocyte chemoattractant protein-1 expression in mouse macrophages
physiological function
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12-LOX mediates the MMP9 secretion via activation of PI3K/Akt/NF-kappaB
physiological function
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12/15-lipoxygenase contributes to PDGF-induced activation of STAT3
physiological function
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ALOX15B might play a major role in human atherosclerosis
physiological function
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inhibition of 12-LOX activity inhibits platelet aggregation, which is coupled to a significant shift in the ability of the platelet to induce normal integrin activation, dense granule secretion, and platelet adhesion under venous shear
physiological function
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PDGF-induced STAT3 phosphorylation in primary human aortic smooth muscle cells requires the activity of 15-LO
physiological function
12-lipoxygenase (12LO) is a dioxygenase enzyme that incorporates molecular oxygen into unsaturated fatty acids such as arachidonic acid at carbon position 12. Arachidonate LOs and their products play an important role in mediating growth factor induced tumor cell proliferation and appear to enhance the growth and migration of vascular smooth muscle cells, VSMC. VSMC proliferation is essential in vascular wall function as well as plaque formation and the inhibition of the renin angiotensin system can induce VSMC apoptosis
physiological function
12/15-lipoxygenase derived metabolites, hydroxyeicosatetraenoic acids (HETEs), contribute to diabetic retinopathy via NADPH oxidase (NOX) and disruption of the balance in retinal levels of the vascular endothelial growth factor and pigment epithelium-derived factor. Pigment epithelium-derived factor inhibits retinal microvascular dysfunction induced by 12/15-lipoxygenase-derived eicosanoids, i.e. (5Z,8Z,10E,14Z)-(12S)-12-hydroperoxyicosa-5,8,10,14-tetraenoate, mechanism, overview. 12-HETE stimulates inflammatory cytokine production such as interleukin IL-6 and TNF-alpha from retinal Müller cells (rMCs)
physiological function
12/15-lipoxygenase metabolites of arachidonic acid activate PPARgamma, involvement of 12(S)- and 15(S)-hydroperoxyicosatetraenoate in the regulation of PPARgamma following cerebral ischemia and effects on ischemia-induced inflammatory response. 12(S)-HETE and 15(S)-HETE elicit neuroprotection in rats exposed to focal ischemia. PPARgamma is a member of the nuclear hormone receptorfamily of ligand-dependent transcription factors. PPARgamma regulates genes that are implicated in adipocyte differentiation, lipid and glucose metabolism, and insulin sensitivity
physiological function
12/15-lipoxygenase-meditated (12/15-LO-mediated) enzymatic lipid oxidation regulates dendritic cell activation and fine-tunes consecutive T cell responses. 12/15-LO activity determines the dendritic cell activation threshold via generation of phospholipid oxidation products that induce an antioxidative response dependent on the transcription factor NRF2. Dendritic cells comprise a heterogenic group of antigen-presenting cells, which share the ability to prime naive T cells. 12/15-LO regulates the maturation process of human dendritic cell (DC). DC-intrinsic 12/15-LO activity attenuates Th17 T cell differentiation. NRF2 mediates the immune-modulatory effects of 12/15-LO-derived oxidized phospholipids
physiological function
12/15-lipoxygenase-meditated (12/15-LO-mediated) enzymatic lipid oxidation regulates dendritic cell activation and fine-tunes consecutive T cell responses. 12/15-LO activity determines the dendritic cell activation threshold via generation of phospholipid oxidation products that induce an antioxidative response dependent on the transcription factor NRF2. Dendritic cells comprise a heterogenic group of antigen-presenting cells, which share the ability to prime naive T cells. 12/15-LO regulates the maturation process of human dendritic cell (DC). DC-intrinsic 12/15-LO activity attenuates Th17 T cell differentiation. NRF2 mediates the immune-modulatory effects of 12/15-LO-derived oxidized phospholipids
physiological function
12/15-LOX is implicated in the pathogenesis of multiple chronic inflammatory diseases, and its physiologic functions seem to include potent immune modulatory properties that physiologically contribute to the resolution of inflammation and the clearance of inflammation-associated tissue damage. 12/15-LOXs are also involved in the synthesis of lipoxins, which likewise act as anti-inflammatory, pro-resolving mediators. Inflammatory eicosanoids are produced by eosinophils in a 12/15-LOX dependent manner. Docosahexaenoic acid (DHA) is a further substrate of 12/15-LOX. The oxidation of DHA leads to the production of 17S-hydroxy-DHA, an anti-inflammatory mediator, which can be further metabolized into highly active and potent anti-inflammatory resolvins and protectins. 12/15-LOX can metabolize not only free PUFAs, but also PUFAs esterified to membrane-bound phospholipids as well as PUFAs within cholesterol esters. 12/15-LOX-derived mediators as regulators of inflammation, role of 12/15-LOX during inflammation, detailed overview. 12/15-LOX activity in resident macrophages interferes with theMFG-E8-dependent uptake of apoptotic cells (ACs) by inflammatory, immune-competent phagocytes and thereby fosters the non-immunogenic clearance of ACs, whereas 12/15-LOX-derived lipoxins directly increase the non-inflammatory uptake of dying cells. Possible role of 12/15-LOX in atherosclerosis
physiological function
ALOX12 may have a critical role in regulation of inflammation in visceral adipose tissue in obesity and type 2 diabetes. Visceral adipose tissue (VAT) is a key contributor to chronic inflammation in obesity. The 12/15-lipoxygenase pathway (ALOX) is present in adipose tissue (AT) and leads to inflammatory cascades that are causal for the onset of insulin resistance in rodent models of obesity
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
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ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
H2QBX9
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
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ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
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ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
cardiac 12/15-LOX-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy. 12/15-LOX induces cardiac oxidative stress in the diabetic heart
physiological function
enzyme 12-lipoxygenase is involved in adipose tissue inflammation. The lipoxygenases (LOs) are principal enzymes involved in the oxidative metabolism of polyunsaturated fatty acids, including arachidonic acid. 12- and 15-LO and their lipid metabolites are implicated in the development of insulin resistance and diabetes. Adipose tissue, and in particular visceral adipose tissue, plays a primary role in the development of the inflammation seen in these conditions. 12- and 15-LO and their lipid metabolites act as upstream regulators of many of the cytokines involved in the inflammatory response in adipose tissue. Significant role for 12- and 15-LO function in white adipose tissue adipogenesis and adipocyte health. 12- and 15-LO function in adipogenesis and has anti-inflammatory roles in adipose tissue, detailed overview. Leukocyte-type 12-LO, or 12/15-LO appears to be a key player in the progression of adipocyte dysfunction and resultant systemic decline. 12/15-LO is upregulated in white adipose tissue in the obese state. Increased expression of all of the 12- and 15-LO enzyme isoforms in omental vs. subcutaneous white adipose tissue suggests that the pathways may contribute to the proinflammatory milieu prominently associated with visceral fat in obesity. The potent vasoconstricting and pro-inflammatory hormone angiotensin II (Ang II) led to increases in leukocyte-type 12-LO mRNA and protein levels, as well as increased enzyme activity
physiological function
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murine platelets require 12-LOX for normal FcgammaRIIa-induced platelet aggregation
physiological function
platelet 12(S)-lipoxygenase (12-LOX), a highly expressed oxylipin-producing enzyme in the human platelet, is an essential component of FcgammaRIIa-mediated thrombosis. Platelet enzyme 12-LOX modulates FcgammaRIIa signaling and is essential for FcgammaRIIa-mediated platelet activation. 12-LOX is essential for FcgammaRIIa-induced phospholipase Cgamma2 activity leading to activation of calcium mobilization, Rap1 and protein kinase C activation, and subsequent activation of the integrin aIIbbeta3. 12-LOX regulates dense and a granule secretion in FcgammaRIIa-activated platelets
physiological function
the 5-LO-derived leukotriene A4, LTA4, can be converted by the action of platelet 12-lipoxygenase (12-LO) to lipoxin A4 (LXA4), which exerts potent anti-inflammatory activities and vascular bed-dependent vasodilatory actions. Dietary plant sterols, beta-sitosterol, campesterol, and stigmasterol, in the combination used, can alleviate lipid peroxidation and inflammatory events in vivo. These effects are possibly exerted via the modulation of myeloperoxidase, 5-lipoxygenase, and 12-lipoxygenase activities
physiological function
the enzyme is required for normal embryonic development in the fish
physiological function
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the metabolic transformation of fatty acids to form oxylipids using 12/15-lipoxygenase (LOX) can promote either resolving or nonresolving inflammation. 12/15-LOX interacts with polyunsaturated fatty acids (PUFA) in postmyocardial infarction (post-MI) healing, mechanism, overview
physiological function
12/15-LOX-deficient mice display augmented IL-33-induced lung inflammation, characterized by an increased number of infiltrated eosinophils and group 2 innate lymphoid cells in the airway. The levels of a series of 12/15-LOX-derived metabolites are significantly decreased, and application of 14(S)-hydroxy docosahexaenoic acid suppresses IL-33-mediated eosinophilic inflammation in 12/15-LOX-deficient mice. 14(S)-hydroxy docosahexaenoic acid and 10(S),17(S)-dihydroxy docosahexaenoic acid markedly attenuate ILC2 proliferation and cytokine production at micromolar concentration in vitro
physiological function
15 lipoxygenase 1 is abundant in asthmatic human airway epithelial cells and binds phosphatidylethanolamine-binding protein 1 (PEBP1), leading to generation of hydroperoxy-phospholipids, which drive ferroptotic cell death. 15LO1, PEBP1, and glutathione peroxidase 4 GPX4 activity drives abnormal asthmatic redox biology, to enhance type 2 inflammatory responses. In vitro, type 2 inflammatory cytokine IL-13 induces 15LO1 generation of hydroperoxy-phospholipids, which lowers intracellular GSH and increased extracellular GSSG levels. Lowering GSH further by inhibiting cystine transporter SLC7A11 enhances type 2 inflammatory protein expression and ferroptosis. Ex vivo, redox imbalances correspond to 15LO1 and SLC7A11 expression, type 2 inflammatory biomarkers, and worsen clinical outcomes
physiological function
a sharp increase in protein expression of 12/15 lipoxygenase is found in the pancreatic islets of 10-week old db-/- obese diabetic mice compared to 8-week old counterparts. The increase in islet 12/15 lipoxygenase parallels a decline in islet number. A 2- to 3fold increase especially in 12(S)-hydroperoxytetraeicosanoid acid mirrors the increase in 12/15 lipoxygenase expression in islets. A significant increase of platelet 12/15 lipoxygenase gene expression is found along with 12-hydroperoxytetraeicosanoid acids and 15-hydroperoxytetraeicosanoid acids
physiological function
activity of 12S-lipoxygenase is hardly observed in liver cytosol of normal chow-fed mice but is clearly detectable in that of nonalcoholic steatohepatitis model mice prepared. The expression levels of mRNA and protein of platelet-type 12S-lipoxygenase in the liver of methionine- and choline-deficient diet-fed mice are significantly increased compared with those of normal chow-fed mice. Platelet-type 12S-lipoxygenase colocalizes with alpha-smooth muscle actin as well as vitamin A in the cells distributing along liver sinusoids
physiological function
cold and beta3-adrenergic stimulation can promote the biosynthesis and release of 12-LOX metabolites from brown adipose tissue. 12-LOX ablation in brown adipocytes impaires glucose uptake and metabolism, resulting in blunted adaptation to the cold in vivo. The cold-induced 12-LOX product 12-hydroxyeicosapentaenoic acid is a batokine that improves glucose metabolism by promoting glucose uptake into adipocytes and skeletal muscle through activation of an insulin-like intracellular signaling pathway
physiological function
eosinophils are the major cell type expressing 12/15-LOX during the corneal wound healing process. Eosinophils are recruited into the conjunctiva after corneal epithelium wounding, and eosinophil-deficient and/or eosinophil-specific 12/15-LOX knockout mice show delayed corneal wound healing compared with wild-type mice. A series of 12/15-LOX-derived mediators are significantly decreased in eosinophil-deficient mice and topical application of 17-hydroxydocosahexaenoic acid restores the phenotype
physiological function
eosinophils express the 15-lipoxygenase-1 but not the 15-lipoxygenase-2. The synthesis of 15-lipoxygenase metabolites by neutrophils does not involve the 15-lipoxygenase-1
physiological function
lipoxin B4 is the primary product of 12-LOX and 15-LOX-1 catalysis, if 5S,15S-dihydroperoxyeicosatetraenoic acid is the substrate, with 15-LOX-1 being 20fold more efficient than 12-LOX
physiological function
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Lox1 converts arachidonic acid and other polyunsaturated fatty acids enantioselectively to the corresponding n-9 hydroperoxy derivatives. The enzyme prefers C20- and C22-polyenoic fatty acids but does not exhibit significant membrane oxygenase activity
physiological function
male Balb/c mice subjected to simulated hypobaric hypoxia for three consecutive days show a robust increase in intra-hippocampal (5Z,8Z,10E,14Z)-(12S)-12-hydroperoxyeicosa-5,8,10,14-tetraenoate level, which is significantly reduced following baicalein treatment. The elevated level of (5Z,8Z,10E,14Z)-(12S)-12-hydroperoxyeicosa-5,8,10,14-tetraenoate correlates with simultaneous increase in expression of 12/15 LOX in neurons and microglia lining the hippocampal CA3 region. 12/15 LOX gets embedded onto the periphery of mitochondria following hypobaric hypoxia and a strong correlation is observed with loss of mitochondrial integrity
physiological function
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12/15-lipoxygenase metabolites of arachidonic acid activate PPARgamma, involvement of 12(S)- and 15(S)-hydroperoxyicosatetraenoate in the regulation of PPARgamma following cerebral ischemia and effects on ischemia-induced inflammatory response. 12(S)-HETE and 15(S)-HETE elicit neuroprotection in rats exposed to focal ischemia. PPARgamma is a member of the nuclear hormone receptorfamily of ligand-dependent transcription factors. PPARgamma regulates genes that are implicated in adipocyte differentiation, lipid and glucose metabolism, and insulin sensitivity
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physiological function
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12/15-LOX is a critical mediator of the chronic type 1 inflammatory response. Evolution of the immune response to Toxoplasma gondii is accompanied by an increasing requirement for 12/15-LOX mediated signaling. Although 12/15-LOX deficient mice are resistant to acute Toxoplasma gondii infection, 80% of 12/15-LOX-deficient mice die during chronic toxoplasmosis, compared to no deaths in wild-type controls. The enhanced susceptibility of 12/15-LOX-deficient mice to chronic toxoplasmosis is associated with reduced production of IL-12 and gamma interferon (IFN-gamma) that is not evident during acute infection. Ex vivo IFN-gamma production by 12/15-LOX-deficient splenocytes can be rescued by the addition of recombinant IL-12. 12/15-LOX does not play a role in macrophage killing of Toxoplasma gondii in vitro
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physiological function
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endogenous 12/15-LOX defines the resident peritoneal macrophage population and regulates both the recruitment of monocytes/peritoneal macrophage and cytokine response to bacterial products in vivo
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physiological function
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the 12/15-LO pathway participates in the regulation of monocyte chemoattractant protein-1 expression in mouse macrophages
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physiological function
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cardiac 12/15-LOX-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy. 12/15-LOX induces cardiac oxidative stress in the diabetic heart
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physiological function
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12/15-lipoxygenase-meditated (12/15-LO-mediated) enzymatic lipid oxidation regulates dendritic cell activation and fine-tunes consecutive T cell responses. 12/15-LO activity determines the dendritic cell activation threshold via generation of phospholipid oxidation products that induce an antioxidative response dependent on the transcription factor NRF2. Dendritic cells comprise a heterogenic group of antigen-presenting cells, which share the ability to prime naive T cells. 12/15-LO regulates the maturation process of human dendritic cell (DC). DC-intrinsic 12/15-LO activity attenuates Th17 T cell differentiation. NRF2 mediates the immune-modulatory effects of 12/15-LO-derived oxidized phospholipids
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physiological function
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12/15LO expression increases chemokine production. 2/15LO mediates early stages of adipose tissue inflammation and whole body insulin resistance induced by high fat feeding. Adipose tissue from high fat diet-fed 12/15LO KO mice is not infiltrated by macrophages and does not display any increase in the inflammatory markers compared to adipose tissue from normal chow-fed mice. 12/15LO KO mice exhibit no high fat diet-induced change in insulin-stimulated glucose disposal rate or hepatic glucose output. Insulin-stimulated Akt phosphorylation in muscle tissue from high fat diet-fed mice is significantly greater in 12/15LO KO mice than in wild-type mice
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physiological function
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the metabolic transformation of fatty acids to form oxylipids using 12/15-lipoxygenase (LOX) can promote either resolving or nonresolving inflammation. 12/15-LOX interacts with polyunsaturated fatty acids (PUFA) in postmyocardial infarction (post-MI) healing, mechanism, overview
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physiological function
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12/15-lipoxygenase derived metabolites, hydroxyeicosatetraenoic acids (HETEs), contribute to diabetic retinopathy via NADPH oxidase (NOX) and disruption of the balance in retinal levels of the vascular endothelial growth factor and pigment epithelium-derived factor. Pigment epithelium-derived factor inhibits retinal microvascular dysfunction induced by 12/15-lipoxygenase-derived eicosanoids, i.e. (5Z,8Z,10E,14Z)-(12S)-12-hydroperoxyicosa-5,8,10,14-tetraenoate, mechanism, overview. 12-HETE stimulates inflammatory cytokine production such as interleukin IL-6 and TNF-alpha from retinal Müller cells (rMCs)
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additional information
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
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molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
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molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
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molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
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molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
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H2QBX9
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
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molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
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molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
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molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
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molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
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molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
platelets from transgenic mice expressing human FcgammaRIIa but deficient in platelet 12-LOX, fail to form normal platelet aggregates and exhibit deficiencies in Rap1 and aIIbbeta3 activation
additional information
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platelets from transgenic mice expressing human FcgammaRIIa but deficient in platelet 12-LOX, fail to form normal platelet aggregates and exhibit deficiencies in Rap1 and aIIbbeta3 activation
additional information
structure-function analysis
additional information
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structure-function analysis