mezerein and Disease-Models--Animal

Topics: Alkynes; Animals; Anthralin; Arachidonic Acid; Cantharidin; Capsaicin; Carrageenan; Croton Oil; Dermatitis; Disease Models, Animal; Diterpenes; Edema; Foot; Inflammation; Irritants; Male; Mice; Models, Animal; Mustard Plant; Otitis Externa; Plant Extracts; Plant Oils; Rats; Reproducibility of Results; Terpenes; Tetradecanoylphorbol Acetate; Zymosan

Nurr1 is an orphan nuclear receptor that is essential for the differentiation and maintenance of dopaminergic neurons in the brain, and it is a therapeutic target for Parkinson's disease (PD). During the screening for Nurr1 activators from natural sources using cell-based assay systems, a methanol extract of the combined stems and roots of Daphne genkwa was found to activate the transcriptional function of Nurr1 at a concentration of 3 μg/mL. The active components were isolated and identified as genkwanine N (1) and yuanhuacin (2). Both compounds 1 and 2 significantly enhanced the function of Nurr1 at 0.3 μM. Nurr1-specific siRNA abolished the activity of 1 and 2, strongly suggesting that transcriptional activation by 1 and 2 occurred through the modulation of Nurr1 function. Additionally, treatment with 1 and 2 inhibited 6-hydroxydopamine (6-OHDA)-induced neuronal cell death and lipopolysaccharide (LPS)-induced neuroinflammation. Moreover, in a 6-OHDA-lesioned rat model of PD, intraperitoneal administration of 2 (0.5 mg/kg/day) for 2 weeks significantly improved behavioral deficits and reduced tyrosine hydroxylase (TH)-positive dopaminergic neuron death induced by 6-OHDA injection and had a beneficial effect on the inflammatory response in the brain. Accordingly, compounds 1 and 2, the first reported Nurr1 activators of natural origin, are potential lead compounds for the treatment of PD.

Topics: Animals; Daphne; Disease Models, Animal; Diterpenes; Dopamine; Dopaminergic Neurons; Molecular Structure; Neuroprotective Agents; Nuclear Receptor Subfamily 4, Group A, Member 2; Oxidopamine; Parkinson Disease; Plant Roots; Rats; Rats, Sprague-Dawley; Republic of Korea; Tyrosine 3-Monooxygenase

The mechanisms by which lipoxin A(4) (LXA(4)) inhibit skin inflammation remain unclear. In the present studies, the ear inflammatory model was induced by topical application of mezerein. Treatment of the mouse ear with LXA(4) exhibited the inhibitory effects on oedema, neutrophil infiltration, vascular permeability, expressions of interleukin (IL)-1, IL-6 and IL-8 mRNA, DNA-binding activity of nuclear factor-kappaB (NF-kappaB), and on dermal hyperplasia. NF-kappaB reporter activities and nuclear translocations of NF-kappaB p65 in cultured keratinocytes stimulated by mezerein were inhibited by pretreatment of the cells with LXA(4). LXA(4) reduced degradation, but not phosphorylation of IkappaBalpha in cultured keratinocytes stimulated by mezerein, suggesting that LXA(4)-attenuated IkappaBalpha degradation may restore the mezerein-blocked inhibitory effects of IkappaB on nuclear translocation and DNA-binding activity of NF-kappaB. Our results demonstrated that LXA(4) displays the anti-inflammatory and anti-proliferative role on ear inflammatory model induced by mezerein and these effects were related with downregulation of DNA-binding activity of NF-kappaB.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carcinogens; Cell Line; Cytokines; Dermis; Disease Models, Animal; Diterpenes; Female; Humans; Hyperplasia; Inflammation; Keratinocytes; Lipoxins; Mice; Mice, Inbred Strains; NF-kappa B

Lipoxins and 15-epi-lipoxins are counter-regulatory lipid mediators that modulate leukocyte trafficking and promote the resolution of inflammation. To assess the potential of lipoxins as novel anti-inflammatory agents, a stable 15-epi-lipoxin A(4) analog, 15-epi-16-p-fluorophenoxy-lipoxin A(4) methyl ester (ATLa), was synthesized by total organic synthesis and examined for efficacy relative to a potent leukotriene B(4) (LTB(4)) receptor antagonist (LTB(4)R-Ant) and the clinically used topical glucocorticoid methylprednisolone aceponate. In vitro, ATLa was 100-fold more potent than LTB(4)R-Ant for inhibiting neutrophil chemotaxis and trans-epithelial cell migration induced by fMLP, but was approximately 10-fold less potent than the LTB(4)R-Ant in blocking responses to LTB(4). A broad panel of cutaneous inflammation models that display pathological aspects of psoriasis, atopic dermatitis, and allergic contact dermatitis was used to directly compare the topical efficacy of ATLa with that of LTB(4)R-Ant and methylprednisolone aceponate. ATLa was efficacious in all models tested: LTB(4)/Iloprost-, calcium ionophore-, croton oil-, and mezerein-induced inflammation and trimellitic anhydride-induced allergic delayed-type hypersensitivity. ATLa was efficacious in mouse and guinea pig skin inflammation models, exhibiting dose-dependent effects on edema, neutrophil or eosinophil infiltration, and epidermal hyperproliferation. We conclude that the LXA(4) and aspirin-triggered LXA(4) pathways play key anti-inflammatory roles in vivo. Moreover, these results suggest that ATLa and related LXA(4) analogs may have broad therapeutic potential in inflammatory disorders and could provide an alternative to corticosteroids in certain clinical settings.

Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Calcimycin; Cell Movement; Chemotaxis, Leukocyte; Croton Oil; Disease Models, Animal; Diterpenes; Female; Guinea Pigs; Humans; Hydroxyeicosatetraenoic Acids; Hypersensitivity, Delayed; Iloprost; Inflammation; Leukotriene B4; Lipoxins; Mice; Phthalic Anhydrides; Skin; Terpenes

Topics: Animals; Carcinogens; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Female; Mice; Papilloma; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate