Upregulation of 8-Lipoxygenase in the Dermatitis of IκB-α-Deficient Mice

Schneider, Claus; Strayhorn, W. David; Brantley, Dana M.; Nanney, Lillian B.; Yull, Fiona E.; Brash, Alan R.

doi:10.1111/j.0022-202x.2004.22329.x

Cited by 20 publications

(16 citation statements)

References 41 publications

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“…15-LOX-2 that has an implication in psoriasis (Setsu et al 2006) is an ortholog of mouse 8-LOX (Brash et al 1999), which was found to be upregulated in the skin and blood samples of the psoriasis-like dermatitis-induced mice, contrary to the control group; however, its expression was lowered down after treatment with herbal extracts. This finding is in tune with the reports stating expression of 8-LOX in suprabasal murine keratinocytes (Heidt et al 2000) and upregulation in the psoriatic mice (Schneider et al 2004;Camp et al 1983).…”

Section: Discussionsupporting

confidence: 92%

“…15-LOX-2 has been implicated in IFN-γ-induced inflammatory processes in psoriatic skin (Setsu et al 2006). Human 15-LOX-2 is regarded as the ortholog of mouse 8(S)-LOX (Brash et al 1999), which is also reported to be expressed in suprabasal murine keratinocytes (Heidt et al 2000), and upregulated at transcriptional and translational levels in the psoriatic mice (Schneider et al 2004). Thus, inhibiting the gene expression of 15-LOX-2 in humans and 8-LOX in mice is consequential in checking the progression of these inflammatory disorders.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of imiquimod-induced psoriasis-like dermatitis in mice by herbal extracts from some Indian medicinal plants

2015

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Psoriasis is a chronic autoimmune human skin disorder that is characterized by excessive proliferation of keratinocytes, scaly plaques, severe inflammation and erythema. The pathophysiology of psoriasis involves interplay between epidermal keratinocytes, T lymphocytes, leukocytes and vascular endothelium. Increased leukocyte recruitment and elevated levels of cytokines, growth factors and genetic factors like interleukin (IL)-1β, IL-6, IL-17, IL-22, IL-23, tumour necrosis factor (TNF)-α, interferon (IFN)-γ, transforming growth factor (TGF)-β, toll-like receptor (TLR)-2, signal transducer and activator of transcription (STAT-3), 15-lipoxygenase (LOX)-2, coiled-coil alpha-helical rod protein 1 (CCHCR1), steroidogenic acute regulatory protein (StAR) and vitamin D receptor (VDR) are the most critical factors governing the exacerbation of psoriasis. In the present study, an attempt was made to elucidate the preventive role of herbal extracts of four dermo-protective Ayurvedic plants, Tinospora cordifolia (TC), Curcuma longa (CL), Celastrus paniculatus (CP) and Aloe vera (AV), against psoriasis-like dermatitis. Parkes (P) strain mice were initially induced with psoriasis-like dermatitis using topical application of imiquimod (IMQ, 5 %), followed by subsequent treatment with the herbal extracts to examine their curative effect on the psoriasis-like dermatitis-induced mice. The extracts were orally/topically administered to mice according to their ED/LD50 doses. Phenotypical observations, histological examinations, and semi-quantitative reverse transcription PCR (RT-PCR) analyses of the skin and blood samples of the control, IMQ-treated and herbal extract-treated psoriasis-like dermatitis-induced mice lead to the conclusion that the combination extract from all the plants was instrumental in downregulating the overexpressed cytokines, which was followed by the CL extract. Moreover, lesser yet positive response was evident from CP and TC extracts. The results suggest that these plants can prove to have tremendous preventive potential against the disease and can open the way to new therapeutic strategies for psoriasis treatment.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Inhibition of imiquimod-induced psoriasis-like dermatitis in mice by herbal extracts from some Indian medicinal plants

2015

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“…Although human 12R-LOX and mouse 8-LOX are not orthologous genes, there is other circumstantial evidence that they may act as functional homologs. For example, in a murine model of psoriasis there is upregulation of 8-LOX [23], while psoriasis in humans is characterized by accumulation of the 12R-LOX product, 12R-HETE [24,25]. Both enzymes, human 12R-LOX and mouse 8-LOX, were proposed to participate in the biosynthesis of lipid mediators that play a role in modulating the differentiation process of the rapidly proliferating keratinocytes [23].…”

Section: Discussionmentioning

confidence: 99%

“…For example, in a murine model of psoriasis there is upregulation of 8-LOX [23], while psoriasis in humans is characterized by accumulation of the 12R-LOX product, 12R-HETE [24,25]. Both enzymes, human 12R-LOX and mouse 8-LOX, were proposed to participate in the biosynthesis of lipid mediators that play a role in modulating the differentiation process of the rapidly proliferating keratinocytes [23]. If this biochemical catalytic activity is related to a functional role of eLOX3 in differentiation of the water impermeable barrier in skin (as implicated through the human genetic studies), then the mouse eLOX3 is best suited to utilize 8-HPETE as substrate for production of an epoxyalcohol product.…”

Section: Discussionmentioning

confidence: 99%

Human and mouse eLOX3 have distinct substrate specificities: Implications for their linkage with lipoxygenases in skin

Schneider

Boeglin

et al. 2006

Archives of Biochemistry and Biophysics

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Genetic and biochemical evidence suggests a functional link between human 12R-lipoxygenase (12R-LOX) and epidermal lipoxygenase-3 (eLOX3) in normal differentiation of the epidermis; LOXderived fatty acid hydroperoxide is isomerized by the atypical eLOX3 into a specific epoxyalcohol that is a potential mediator in the pathway. Mouse epidermis expresses a different complement of LOX enzymes, and therefore this metabolic linkage could differ. To test this concept, we compared the substrate specificities of recombinant mouse and human eLOX3 toward sixteen hydroperoxy stereoisomers of arachidonic and linoleic acids. Both enzymes metabolized R-hydroperoxides 2-3 times faster than the corresponding S enantiomers. Whereas 12R-hydroperoxyeicosatetraenoic acid (12R-HPETE) is the best substrate for human eLOX3 (2.4 sec −1 ; at 30 µM substrate), mouse eLOX3 shows the highest turnover with 8R-HPETE (2.9 sec −1 ) followed by 8S-HPETE (1.3 sec −1 ). Novel product structures were characterized from reactions of mouse eLOX3 with 5S-, 8R-, and 8S-HPETEs. 8S-HPETE is converted specifically to a single epoxyalcohol, identified as 10R-hydroxy-8S,9S-epoxyeicosa-5Z,11Z,14Z-trienoic acid. The substrate preference of mouse eLOX3 and the unique occurrence of an 8S-LOX enzyme in mouse skin point to a potential LOX pathway for the production of epoxyalcohol in murine epidermal differentiation.

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“…Therefore, it is theoretically possible to form hepoxilin analogs from 5-HPETE and 8-HPETE. The latter is upregulated in dermatitis of IkappaB-alpha-deficient mice [31]. Indeed, hepoxilins appear to play an important role in the skin [19] [see later section on 12R-LO in ichthyosis].…”

Section: Introductionmentioning

confidence: 99%

Hepoxilins in cancer and inflammation—use of hepoxilin antagonists

Pace-Asciak

2011

Cancer Metastasis Rev

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Cancer is often accompanied with inflammatory, thrombotic, and diabetic complications. Alternatively, chronic inflammation is believed to be a causative factor in several cancers. This review article brings together reported biological actions in these areas of the unstable naturally derived hepoxilins (HX), metabolites of arachidonic acid formed through the 12-LO pathway, and those of their synthetically derived stable HX antagonists (PBT; proprietary bioactive therapeutics). Although the HX pathway has been known for some three decades since its discovery by the author with much data originating from the author's laboratory, studies by others over the past few years have confirmed early findings of the actions of HX as potent pro-inflammatory chemoattractant mediators and further showed HX to be involved in bacterial infection (Salmonella-induced intestinal inflammation and in bone inflammation caused by infection with the Lyme bacterium). The HX pathway appears to be an important early signal leading to inflammation. This provides important therapeutic potential for the PBTs as the only available selective antagonists of this pathway. The PBTs have shown benefit and efficacy in animal models of cancer and inflammation, which together with their known actions as anti-thrombotic (thromboxane (TPα) receptor antagonists) and hypoglycemic agents in vivo appears to make the PBTs suitable as therapeutics to control these disorders. The PBT structure is both stable in vivo and is essentially devoid of side effects in the animal models tested. The PBT structure serves as an important platform for selective HX and TX antagonists.

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Upregulation of 8-Lipoxygenase in the Dermatitis of IκB-α-Deficient Mice

Cited by 20 publications

References 41 publications

Inhibition of imiquimod-induced psoriasis-like dermatitis in mice by herbal extracts from some Indian medicinal plants

Inhibition of imiquimod-induced psoriasis-like dermatitis in mice by herbal extracts from some Indian medicinal plants

Human and mouse eLOX3 have distinct substrate specificities: Implications for their linkage with lipoxygenases in skin

Hepoxilins in cancer and inflammation—use of hepoxilin antagonists

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