Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Canine atopic dermatitis (AD) is a chronic allergic skin disorder with an immunopathogenesis comparable to that in humans with AD. The high frequency of recurrent infections with Staphylococcus pseudo intermedius and Malassezia pachydermatis may indicate a defective innate immune response in the skin of atopic dogs. Production of beta-defensins constitutes an important role in skin defense but information on canine beta-defensin localization and regulation is scarce. We conducted a gene-expression study of 16 canine beta-defensins (cBDs) in 11 tissues of healthy dogs, which revealed a variable expression of cBDs in different organ systems of the dog. In skin, three beta-defensins, cBD1, cBD103 and cBD107, were extensively expressed, while inconsistent expression of five other beta-defensins was detected. Using immunohistochemistry abundant expression of cBD103 peptide was detected in the epidermis, hair follicles and sebaceous glands, comparable to hBD3 expression in human skin. To examine the gene-expression of beta-defensins in atopic dogs, full thickness skin biopsy specimens (non-lesional and lesional) of 10 atopic dogs and 7 healthy dogs were examined with real-time PCR. A significant 12-fold increased expression of cBD1 was detected in lesional atopic skin compared to healthy skin, while non-lesional skin showed a 5-fold increase. Contrary to cBD1, expression of cBD103 was slightly (2-fold) downregulated in skin of atopic dogs. Gene-expression levels of S100A8, a marker for atopic dermatitis, were also highly upregulated in skin of atopic dogs, confirming the diagnostics of the skin biopsies. Taken together these results provide new evidence for a possible defect in the innate immune response of dogs with atopic dermatitis, and indicate the potential of the dog as a model for human AD.
Mol Immunol 2009 Aug
PMID:Altered cutaneous expression of beta-defensins in dogs with atopic dermatitis. 1957 34

Infiltration of T cells is a key step in the pathogenesis of the inflammatory skin diseases atopic dermatitis, allergic contact dermatitis and psoriasis. Understanding the mechanisms of T cell recruitment to the skin is therefore of fundamental importance for the discovery and application of novel therapies for these conditions. Studies of both clinical samples and experimental models of skin inflammation have implicated specific adhesion molecules and chemokines in lymphocyte recruitment. In particular, recent studies using advanced in vivo imaging techniques have greatly increased our understanding of the kinetics and molecular basis of this process. In this review, we summarise the current understanding of the cellular immunology of antigen-driven dermal inflammation and the roles of adhesion molecules and chemokines. We focus on results obtained using intravital microscopy to examine the dermal microvasculature and interstitium to determine the mechanisms of T cell recruitment and migration in experimental models of T-cell-mediated skin inflammation.
Expert Rev Mol Med 2009 Aug 20
PMID:Molecular mechanisms of leukocyte trafficking in T-cell-mediated skin inflammation: insights from intravital imaging. 1969 14

Transglutaminase II (TGase II) is a protein cross-linking enzyme with diverse biological functions. Here we report the role of TGase II in allergic inflammation. Antigen stimulation induced expression and activity of TGase II by activation of NF-kappaB in rat basophilic leukemia (RBL2H3) cells. This induction of TGase II was dependent on FcepsilonRI and EGFR. Interaction between TGase II and rac1 was induced following antigen stimulation. TGase II was responsible for the increased production of reactive oxygen species, expression of prostaglandin E2 synthase (PGE2 synthase) and was responsible for increased secretion of prostaglandin E2. ChIP assay showed that TGase II, through interaction with NF-kappaB, was responsible for the induction of histone deacetylase-3 (HDAC3) and snail by direct binding to promoter sequences. HDAC3 and snail induced by TGase II, exerted transcriptional repression on E-cadherin. Snail exerted negative effect on expression of MMP-2, and secretion of Th2 cytokines. Inhibition of matrix metalloproteinase-2 (MMP-2) inhibited secretion of Th2 cytokines. In vivo induction of TGase II was observed in Balb/c mouse model of IgE antibody-induced passive cutaneous anaphylaxis. Chemical inhibition of TGase II exerted negative effect on IgE-dependent passive cutaneous anaphylaxis. Chemical inhibition of TGase II by cystamine exerted negative effect on Balb/c mouse model of phorbol myristate acetate (PMA)-induced atopic dermatitis. These results suggest novel role of TGase II in allergic inflammation and TGase II can be developed as target for the development of allergy therapeutics.
Mol Immunol 2010 Feb
PMID:Transglutaminase II interacts with rac1, regulates production of reactive oxygen species, expression of snail, secretion of Th2 cytokines and mediates in vitro and in vivo allergic inflammation. 2000 74

Two common inflammatory skin disorders with impaired barrier, atopic dermatitis (AD) and psoriasis, share distinct genetic linkage to the Epidermal Differentiation Complex (EDC) locus on 1q21. The EDC is comprised of tandemly arrayed gene families encoding proteins involved in skin cell differentiation. Discovery of semi-dominant mutations in filaggrin (FLG) associated with AD and a copy number variation within the LCE genes associated with psoriasis provide compelling evidence for the role of EDC genes in the pathogenesis of these diseases. To date, little is known about the potentially complex regulatory landscape within the EDC. Here, we report a computational approach to identify conserved non-coding elements (CNEs) in the EDC queried for regulatory function. Coordinate expression of EDC genes during mouse embryonic skin development and a striking degree of synteny and linearity in the EDC locus across a wide range of mammalian (placental and marsupial) genomes suggests an evolutionary conserved regulatory milieu in the EDC. CNEs identified by comparative genomics exhibit dynamic regulatory activity (enhancer or repressor) in differentiating or proliferating conditions. We further demonstrate epidermal-specific, developmental in vivo enhancer activities (DNaseI and transgenic mouse assays) in CNEs, including one within the psoriasis-associated deletion, LCE3C_LCE3B-del. Together, our multidisciplinary study features a network of regulatory elements coordinating developmental EDC gene expression as an unexplored resource for genetic variants in skin diseases.
Hum Mol Genet 2010 Apr 15
PMID:A milieu of regulatory elements in the epidermal differentiation complex syntenic block: implications for atopic dermatitis and psoriasis. 2008 30

It is widely accepted that cationic antimicrobial peptides possess potent microbicidal properties. Recent studies show that in addition to their antimicrobial action, these peptides can exhibit anti-inflammatory activity. The purpose of this chapter is to describe in vivo ear inflammation models that can be used for evaluating the anti-inflammatory activity of antimicrobial peptides. The models are based on different mechanisms of inflammation development and include irritant dermatitis (a model induced by a single application of 12-o-tetradecanoylphorbol acetate [TPA]) and allergic dermatitis, or delayed type hypersensitivity reaction (a model induced by repetitive application of oxazolone).
Methods Mol Biol 2010
PMID:Assay systems for measurement of anti-inflammatory activity. 2009 74

Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine that requires a heterodimeric receptor complex composed of the interleukin-7 receptor alpha chain and the TSLP receptor, which is related to the common gamma chain. TSLP has been shown to play an important role in the development of allergic inflammation, such as asthma and atopic dermatitis. Chimeric receptors composed of the cytoplasmic region of the TSLP receptor fused to the extracellular regions of homodimeric receptors, such as erythropoietin (Epo) receptor and thrombopoietin receptor have been used to dissect signaling events induced by the TSLP receptor. Intriguingly, studies using such chimeric TSLP receptors revealed that the human, but not mouse, TSLP receptor cytoplasmic domain can support proliferation of growth factor-dependent cells after homodimerization. Here, we used a systematic approach to investigate the mechanistic basis of this difference. Our studies revealed that induced homodimerization of receptor chimeras containing the transmembrane and cytoplasmic domains of both human and mouse TSLP receptors is not sufficient for driving cell proliferation. However, chimeric receptors with the transmembrane and juxtamembrane domains of Epo receptor fused to the cytoplasmic domain of human TSLP receptor signal like the Epo receptor and induce the activation of Jak2. Site-directed mutagenesis showed that the lone tyrosine residue in human TSLP receptor is not required for transmitting proliferative signals in receptor chimeras, which is consistent with the observation that none of the tyrosine residues are required for Epo receptor to support proliferation. Our data suggests that in the chimeric receptor context, the transmembrane and juxtamembrane domains of mouse Epo receptor are essential for the cytoplasmic domain of human TSLPR to achieve the strong proliferative ability and can modulate signaling pathway transmitted by the cytoplasmic domains of these chimeras.
Mol Immunol 2010 Mar
PMID:Effects of transmembrane and juxtamembrane domains on proliferative ability of TSLP receptor. 2009 61

Anti-allergic effects of galactooligosaccharide (GOS), which is found in breast milk and frequently added to food for promoting health, were evaluated in a human-like mouse model of atopic dermatitis (AD). NC/Nga mice were fed 5.5% GOS for 8 weeks, and we examined whether this treatment suppressed the development of AD-like skin lesions in these mice. Mice fed GOS exhibited significantly less symptoms of dermatitis, reduced scratching frequency, and lower levels of serum total immunoglobulin E compared to control. At the end of the 8-week-experimental period, spleens were removed, and the splenocytes were stimulated with phorbol 12-myristate 13-acetate and ionomycin, following which production of cytokines and a chemokine was analyzed. Elevated levels of Th1 cytokines such as interferon-gamma were observed in splenocytes from GOS-fed mice. However, the levels of Th2 cytokines such as interleukin (IL)-13 were unchanged. Furthermore, GOS inhibited the production of inflammatory cytokines such as IL-1beta, IL-6, IL-17, and tumor necrosis factor-alpha but enhanced production of immunomodulatory IL-10. The results indicate that GOS effectively blocked AD-like skin lesions in the mice by at least partly inducing production of IL-10 and suppressing the production of cytokines such as IL-17, which are involved in skin inflammation.
Int J Mol Med 2010 Mar
PMID:Oral administration of a galactooligosaccharide preparation inhibits development of atopic dermatitis-like skin lesions in NC/Nga mice. 2012 36

RNA interference is a promising method for silencing specific genes and has great potential for therapeutic applications. However, the major hurdle for therapeutic application is the limited stability of double-strand RNA (dsRNA) and the absence of a reliable delivery method to target cells. Skin appears to be a favorable target for small interfering RNA (siRNA) therapy. Dendritic cells (DCs) exist in the skin and mucosae on the front lines of defense; these cells capture antigens and play a crucial role in inducing immunity and tolerance.In our recent work, we have shown a successful treatment using CD86 siRNA targeting cutaneous DCs. A costimulatory molecule, CD86, is induced on DCs in situ after antigen uptake, and CD86-expressing DCs migrate to the regional lymph nodes to present antigens to T cells. Topical application of cream-emulsified CD86 siRNA ameliorated the clinical manifestations in murine contact hypersensitivity (CH) and atopic dermatitis (AD)-like disease. Our method may be advantageous for the treatment of allergic skin diseases.
Methods Mol Biol 2010
PMID:Topical application of siRNA targeting cutaneous dendritic cells in allergic skin disease. 2021 64

Hempseed, a rich source of polyunsaturated fatty acids (PUFAs) and phytosterols, has been recognized as a potential therapeutic food used for cardioprotection, preventing platelet aggregation, and improving atopic dermatitis. Although several studies have revealed the physiological benefits of hempseed on a variety of animals, the effects of dietary hempseed intake on animal development are currently unknown. In this study, we evaluated the developmental effects of the addition of hempseed meal (HSM) to the diet of Drosophila. Interestingly, dietary HSM intake was shown to increase the body size of flies by increasing cell numbers, and also truncated the larval period without affecting survival rate or longevity. The oviposition of female flies was also increased by dietary HSM supplementation. Interestingly, the levels of sterols, which are precursors of ecdysone, a molting hormone, were found to be elevated in the larvae fed on HSM. Additionally, the hexane extracts of hempseed mimicked the effects of HSM on growth, developmental timing, and reproduction. Moreover, among the major nonpolar components of HSM, feeding on cholesterol but not PUFA mix or campesterol accelerated pupariation and increased body size. These results indicate that the dietary intake of HSM accelerates both body growth and developmental rates in Drosophila via the stimulation of cell growth and ecdysone synthesis. Additionally, nonpolar components of hempseed, such as cholesterol, might be responsible for the effects of HSM on development and reproduction.
Mol Cells 2010 Jul
PMID:Dietary hempseed meal intake increases body growth and shortens the larval stage via the upregulation of cell growth and sterol levels in Drosophila melanogaster. 2065 93

The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2) is a G protein-coupled receptor that has been reported to modulate inflammatory responses in various rodent models of asthma, allergic rhinitis and atopic dermatitis. In this study, we describe the biological and pharmacological properties of {(7R)-7-[[(4-fluorophenyl)sulfonyl](methyl)amino]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetic acid (MK-7246), a novel synthetic CRTH2 antagonist. We show that MK-7246 1) has high affinity for the human, monkey, dog, rat, and mouse CRTH2, 2) interacts with CRTH2 in a reversible manner, 3) exhibits high selectivity over all prostanoid receptors as well as 157 other receptors and enzymes, 4) acts as a full antagonist on recombinant and endogenously expressed CRTH2, 5) demonstrates good oral bioavailability and metabolic stability in various animal species, 6) yields ex vivo blockade of CRTH2 on eosinophils in monkeys and sheep, and 7) significantly blocks antigen-induced late-phase bronchoconstriction and airway hyper-responsiveness in sheep. MK-7246 represents a potent and selective tool to further investigate the in vivo function of CRTH2.
Mol Pharmacol 2011 Jan
PMID:Pharmacological characterization of MK-7246, a potent and selective CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) antagonist. 2094 73


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