Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated serine/threonine protein phosphatase (PP) activity and the expression of PP2A during growth and differentiation of epidermal keratinocytes in culture. Keratinocyte PP activity was strongly inhibited by calyculin A and okadaic acid, indicating that the activity was mainly due to PP2A and PP1. The phosphatase activity decreased to about 20% of the initial (day 1) level by the time of confluence and to about 10% at day 7 postconfluence. In contrast to activity, the level of expression of the PP2A catalytic subunit protein and the mRNA for the two isoforms increased slightly over the period of growth. Keratinocyte differentiation was shown by a significant increase in profilaggrin expression after confluence. Keratinocytes were also cultured from individuals affected with harlequin ichthyosis. This severe hyperkeratotic skin disorder has abnormal lipid structures and is blocked in the PP2A-dependent conversion of phosphorylated profilggrin to the non-phosphorylated filaggrin. The PP activity in harlequin cultures was lower than in normal cultures (about 20% of the subconfluent normal control value) and decreased even further in confluent cultures. In contrast, the level of expression of the PP2A catalytic subunit protein and mRNA for the two isoforms was similar to that of normal keratinocytes and increased with confluence. These results suggest that PP activity in keratinocytes is regulated in a post-translational manner; they also support the possibility of impaired or reduced function of PPs in harlequin ichthyosis.
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PMID:Protein phosphatase activity in human keratinocytes cultured from normal epidermis and epidermis from patients with harlequin ichthyosis. 947 Sep 2

Atopic dermatitis is a chronic inflammatory skin disease characterized by severe pruritus, typical morphology and distribution of skin lesions, and personal and family history of atopy. The management of atopic dermatitis is directed at preventing the inflammation, itch, and secondary lesions. Therapy relies on general management measures, anti-inflammatory agents, antiprurites, antibiotics, and immunosuppressants. Treatment options for patients with severe or longstanding disease, extensive body surface area involvement of facial lesions are limited. Tacrolimus ointment is the first in the class of topical immunomodulators that has been formulated for the treatment of atopic dermatitis in children (2 to 15 years of age) and adult patients. The mechanism of action of tacrolimus in atopic dermatitis seems to involve T-cells, Langerhans cells, mast cells and basophiles. Experimental evidence suggests that tacrolimus inhibits T-lymphocytes activation by binding to an intracellular protein, FKBP-12. This binding phenomenon inhibits the ability of calcineurin to activate the promotor region of the gene for IL-2, IL-3, IL-4, IL-5, interferon gamma, tumor necrosis factor alpha, and granulocyte macrophage colony-stimulating factor, all of which participate in the early immune response and play a role in the pathogenesis of atopic dermatitis. Tacrolimus ointment is not atrophogenic, and is associated with minimal systemic absorption. There were no consistent changes in any laboratory variable during topical tacrolimus therapy. The most common adverse events associated with its use were transient skin burning and pruritus at the site of application. Tacrolimus ointment is safe and efficacious therapy for the treatment of pediatric and adult patients with atopic dermatitis on all skin regions including the face, neck and intertriginous areas. An overview is given of tacrolimus in atopic dermatitis.
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PMID:Tacrolimus ointment: a new therapy for atopic dermatitis--review of the literature. 1213 28

Atopic dermatitis is a common skin disease with a complex immunopathology that has a significant impact on the quality of life of patients and their families. Although topical corticosteroids have been the cornerstone of therapy, safety concerns, especially in children, with potent preparations or with chronic use have prompted treatment with various adjunctive therapies. Recently, topical calcineurin inhibitors, including tacrolimus and pimecrolimus, have been shown effective as monotherapy for this chronic relapsing disease.
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PMID:Combination therapy and new directions for managing atopic dermatitis. 1222 93

Controlled trials and clinical experience indicate that systemic cyclosporin A and tacrolimus are effective treatments for psoriasis, and that cyclosporin A also improves atopic eczema. A variety of other inflammatory and non-inflammatory skin diseases are probably also responsive to these drugs. However, the widespread and longer-term use of cyclosporin A and tacrolimus are limited by side effects. The molecular mechanisms of action of cyclosporin A, tacrolimus and a related drug, sirolimus, have been well defined in T cells and involve inhibition of critical signalling pathways that regulate T cell activation. For example cyclosporin and tacrolimus inhibit calcineurin phosphatase activity and thereby inhibit activation of the transcription factor NFAT. The therapeutic efficacy of topical calcineurin inhibitors in atopic eczema have restimulated interest in the mechanism of action of these drugs in skin disease. Recently the expression pattern of calcineurin and NFAT has been defined in non-immune tissues including the akin. The relevance of this to the mechanism of action of systemic and topical calcineurin inhibitors and sirolimus in skin disorders is discussed.
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PMID:Calcineurin inhibitors and sirolimus: mechanisms of action and applications in dermatology. 1246 50

Topical therapy of atopic dermatitis should incorporate an understanding of the underlying immune abnormalities of this complex chronic skin disease. Avoidance of irritants and proven allergens, skin hydration, and use of emollients and anti-inflammatory therapy help maintain a normal skin barrier. Topical calcineurin inhibitors have been added to the topical treatment armamentarium. Although the optimal treatment approach remains to be defined, several studies suggest the use of topical calcineurin inhibitors as early intervention therapy and topical corticosteroids as rescue therapy.
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PMID:Topical treatment of atopic dermatitis. 1547 63

For more than five decades, topical corticosteroids and emollients have been the mainstay of therapy for atopic dermatitis. However, the potential for side-effects limits the clinical utility of corticosteroids in providing long-term disease control. With a unique mode of action that differs from that of corticosteroids, the steroid-free topical calcineurin inhibitors (TCIs), tacrolimus ointment and pimecrolimus cream, provide skin-selective treatment that targets key factors involved in the pathogenesis of this chronic disease. An extensive series of clinical trials involving more than 16,000 patients with predominantly moderate to severe atopic dermatitis in tacrolimus studies and over 2000 patients with primarily mild to moderate disease in pimecrolimus studies has shown that both TCIs provide effective and well-tolerated treatment for atopic dermatitis. Randomized controlled trials have demonstrated that tacrolimus is superior to conventional hydrocortisone-based regimens and does not cause skin atrophy or other steroidal side-effects. Both tacrolimus and pimecrolimus prevent disease flares and provide progressive and sustained disease improvement with long-term therapy. These and other clinical benefits of TCIs are discussed, together with the safety profiles of tacrolimus and pimecrolimus and their use in clinical practice. In addition, this review summarizes findings from the many trials carried out with these agents and outlines how TCIs can provide long-term treatment and control of a chronic skin disease that may persist for years.
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PMID:The role of topical calcineurin inhibitors in atopic dermatitis. 1554 71

Atopic dermatitis (AD) is a highly pruritic, chronic, and relapsing inflammatory skin disorder affecting 10-20% of children worldwide. During the past year there have been significant advances in our understanding of the cellular and immunologic mechanisms underlying AD as well as the immunologic triggers involved in its pathogenesis. The introduction of a new class of topical anti-inflammatory medications, topical calcineurin inhibitors, has significantly increased our treatment options and led to the rethinking of potential management approaches in AD.
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PMID:Advances in atopic dermatitis. 1580 42

The prevalence of atopic dermatitis is increasing, and more than 50% of children with atopic dermatitis go on to develop asthma and allergies. A better understanding of the underlying immune abnormalities of this complex chronic relapsing skin disease is needed. Although the optimal treatment approach remains to be defined, several recent studies suggest a rationale for using topical calcineurin inhibitors as early intervention and adding topical corticosteroids as rescue therapy if needed.
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PMID:Atopic dermatitis: beyond the itch that rashes. 1587 59

Lichen sclerosus et atrophicus is a chronic inflammatory disease that mainly affects women in the 5th decade. Although lichen sclerosus most often affects the anogenital region, it may occur in other cutaneous or mucosal sites. Increased fibroblast activity causes cutaneous sclerosis. Recent studies have identified lichen sclerosus as an autoantibody-mediated chronic inflammatory dermatosis. Autoantibodies against the extracellular matrix protein-1 are present in up to 80% of affected patients. In addition to the well-accepted therapy with potent corticosteroids, promising results have been obtained using calcineurin antagonists in the treatment of lichen sclerosus. Interdisciplinary management with regular monitoring can improve the clinical manifestations and quality of life.
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PMID:[Lichen sclerosus. New aspects of pathogenesis and treatment]. 1588 30

This review highlights some of the research advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects that were reported primarily in the Journal in 2004. Clinical observations included that gastrointestinal symptoms during anaphylaxis are associated with an increased risk for hypotension; recurrence of peanut allergy can occur for about 8% of children who pass an oral food challenge and is associated with continued avoidance of the food after the challenge; seafood allergy is reported by 2.3% of the US population; and determination of the time to resolution of childhood egg and milk allergy might be predictable by means of serial determination of food-specific IgE levels. The comorbid effects of atopic dermatitis (AD) on asthma and the role of topical calcineurin inhibitors in the therapy of AD were also addressed. Basic and translational research observations indicate that improved diagnosis and therapy might become possible on the basis of reported identification or characterization of allergens such as: lipid transfer proteins and birch pollen-related cross-reactive allergens in plant foods; proteins in scorpion venom that cross-react with proteins from imported fire ant; mosquito saliva proteins responsible for systemic anaphylaxis; and IgE binding to quinolones detectable with an in vitro immunoassay. In addition, advances in understanding immune regulation associated with abrogation of oral tolerance in food allergy and of dendritic cell function, modulation of regulatory T cells, and chemokine expression in AD have elucidated possible targets for future intervention.
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PMID:Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects. 1599 Jul 89


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