Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth suppression of normal human keratinocytes by high Ca2+ or TGFbeta was shown to be mediated by p21WAF1/CIP1 and Sp1 [Pardali, K., et al. (2000) J. Biol. Chem. 275, 29244-29256; Santini, M. P., Talora, C., Seki, T., Bolgan, L. & Dotto, G. P. (2001) Proc. Nat. Acad. Sci. USA 98, 9575-9580; Al-Daraji, W. I., Grant, K. R., Ryan, K., Saxton, A., & Reynolds, N. J. (2002) J. Invest. Dermatol. 118, 779-788]. We previously demonstrated that S100C/A11 is a key mediator for growth inhibition of normal human epidermal keratinocytes (NHK) triggered by high Ca2+ or TGFbeta [Sakaguchi, M., et al. (2003) J. Cell Biol. 163, 825-835; Sakaguchi, M., et al. (2004) 164, 979-984]. On exposure of NHK cells to either agent, S100C/A11 is transferred to nuclei, where it induces p21WAF1/CIP1 through activation of Sp1/Sp3. In the present study, we found that high Ca2+ activated NFAT1 through calcineurin-dependent dephosphorylation. In growing NHK cells, Krueppel-like factor (KLF)16, a member of the Sp/KLF family, bound to the p21WAF1/CIP1 promoter and, thereby, inhibited the transcription of p21(WAF1/CIP1). Sp1 complexed with NFAT1 in high Ca2+-treated cells or with Smad3 in TGFbeta1-treated cells, but not Sp1 alone, replaced KLF16 from the p21WAF1/CIP1 promoter and transcriptionally activated the p21WAF1/CIP1 gene. Thus, high Ca2+ and TGFbeta1 have a common S100C/A11-mediated pathway in addition to a unique pathway (NFAT1-mediated pathway for high Ca2+ and Smad-mediated pathway for TGFbeta1) for exhibiting a growth inhibitory effect on NHK cells, and both pathways were shown to be indispensable for growth inhibition.
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PMID:Bifurcated converging pathways for high Ca2+- and TGFbeta-induced inhibition of growth of normal human keratinocytes. 1617 1

Frontal fibrosing alopecia (FFA) is an uncommon, slowly progressive, cicatricial alopecia which mainly affects postmenopausal women. It is considered to be a variant of lichen planopilaris. We describe two postmenopausal women who developed over 11 and 24 months an asymptomatic atrophic alopecia, restricted to the frontal hairline. The diagnosis of FFA was confirmed by biopsy showing a perifollicular lymphocytic infiltrate with fibrosis. Topical corticosteroids, in one case combined with minoxidil, administered for 3 months arrested the hair loss. The treatment of FFA is often difficult. In most cases, the disease resolves spontaneously after several years. Immunomodulators such as corticosteroids and calcineurin antagonists should be tried in the early stage of FFA (frontal effluvium with perifollicular erythema) in order to arrest the disease in its inflammatory phase.
J Dtsch Dermatol Ges 2004 Aug
PMID:[Two cases of frontal fibrosing alopecia in postmenopausal women]. 1627 32

The use of calcineurin inhibitors in solid organ transplantation results in an increased risk of skin cancer. We examined the effect of these drugs on DNA repair in normal human keratinocytes after ultraviolet B (UVB) irradiation. We found that both cyclosporine A (CsA) and ascomycin inhibited removal of cyclobutane pyrimidine dimers, and that they also inhibited UVB-induced apoptosis. We also observed that UVB induced nuclear localization of the transcription factor nuclear factor of activated T-cells (NFAT), and that this was blocked by CsA and ascomycin. These data suggest that the increased risk of skin cancer observed in organ-transplant patients may be as a result of not only systemic immune suppression but also the local inhibition of DNA repair and apoptosis in skin by calcineurin inhibitors. These findings may have implications for the use of topical calcineurin inhibitors in sun-exposed skin and eyes.
J Invest Dermatol 2005 Nov
PMID:Calcineurin inhibitors decrease DNA repair and apoptosis in human keratinocytes following ultraviolet B irradiation. 1802 38

Pimecrolimus (SDZ ASM981) is a non-steroid member of calcineurin inhibitors recently developed for the treatment of inflammatory skin diseases. In this study, we compared the effect of pimecrolimus and corticosteroids on the differentiation, maturation and function of murine bone marrow-derived dendritic cells (BM-DC). We added pimecrolimus at concentrations of 5-500 ng/ml or 0.5 ng/ml mometasone furoate at different timepoints to the BM-DC culture and checked (i) the number of matured cells, (ii) the expression of activation markers, (iii) the release of cytokines and (iv) the stimulatory capacity of the resulting BM-DC in vivo. Even at the highest concentration, pimecrolimus treatment resulted in only modest effects. In the pimecrolimus-treated culture, we observed a decrease in the numbers of matured cells but no significant effects on the expression of activation markers. The release of some inflammatory cytokines was reduced, but the stimulatory capacity in vivo was not affected. In contrast, mometasone furoate has pronounced effects on BM-DC at a concentration ten to 1000 times lower than those used with pimecrolimus. Furthermore, topical treatment of mice with clobetasole cream 0.05% resulted in almost complete depletion of splenic DC and a severe hyposplenia, while high-dose oral pimecrolimus treatment did not show any effects on the spleen or on splenic DC. These results support that pimecrolimus, unlike corticosteroids, has little effects on dendritic cells. To the best of our knowledge, this is the first study of this type with use of BM-DC.
Exp Dermatol 2006 Jan
PMID:Effect of pimecrolimus vs. corticosteroids on murine bone marrow-derived dendritic cell differentiation, maturation and function. 1636 30

Bullous pemphigoid (BP) is a cutaneous autoimmune disease predominantly affecting older patients which can cause death either due to severe clinical manifestations or due to the side effects of systemic immunosuppressive treatment. Topical treatment with corticosteroids is an established alternative to systemic treatment. However, prolonged application is accompanied by side effects such as skin atrophy. Recently, the immunomodulatory calcineurin antagonists tacrolimus and pimecrolimus have been introduced for topical treatment of skin diseases. Tacrolimus has been reported to be effective in several inflammatory skin disorders such as atopic dermatitis, psoriasis, lichen planus, lupus erythematosus and pyoderma gangraenosum. Efficacy has also been described in the topical treatment of BP in some cases. Here we present the case of a 89 year old patient with BP. He was treated with 0.1% tacrolimus ointment, which was able to control the disease. We briefly review the literature and discuss the potential role of tacrolimus as a novel option for the topical treatment of BP.
J Dtsch Dermatol Ges 2005 Mar
PMID:[Topical treatment of bullous pemphigoid with tacrolimus. Case report with brief literature review]. 1637 15

Therapeutic options for rosacea include topical agents, oral therapies, laser and light treatments, and surgical procedures. Topical therapies play a critical role in the treatment of patients with papulopustular rosacea and erythematotelangiectatic rosacea, and have the ability to effectively minimize certain manifestations of the disease, including papules, pustules, and erythema. The 3 primary agents for the topical treatment of rosacea are metronidazole, azelaic acid, and sodium sulfacetamide-sulfur. Each of these therapies is approved for the treatment of rosacea and has been validated by multiple studies. Additional topical therapies including benzoyl peroxide, clindamycin, retinoids, topical steroids, calcineurin inhibitors, and permethrin are not approved for the treatment of rosacea and play variable roles in the management of this condition.
J Drugs Dermatol 2006 Jan
PMID:Topical therapies for rosacea. 1646 88

Autoimmunity results from loss of mechanisms controlling self-reactivity. Autoimmune disorders play an increasingly important role and CD40-CD40 ligand (CD40L) interaction on immunocompentent cells is able to break established immunotolerance. To study the effects of the calcineurin-inhibitor FK506 on CD40L-induced systemic autoimmunity, CD40L transgenic (tg) mice, which spontaneously develop a mixed connective tissue-like disease, were treated with FK506 after onset of overt autoimmunity. Interestingly, FK506-treated CD40L tg mice showed significantly reduced autoimmune dermatitis scores and markedly decreased numbers of lesional infiltrating leukocytes. This finding was associated with diminished lymphadenopathy induced by FK506 treatment. Furthermore, FK506 suppressed the development of cytotoxic/autoreactive CD8(+) T cells as evidenced by the reduced expression of T cell activation markers in treated CD40L tg mice. Importantly, FK506 induced a significant reduction in autoantibody titers in the serum of CD40L tg animals. As CD40L tg mice develop nephritis leading to loss of renal function proteinuria was determined after FK506 injections. Notably, FK506 treatment re-established renal function as indicated by significantly reduced uric protein concentrations of treated CD40L tg mice. Together, these findings show the beneficial therapeutic effects of FK506 for the treatment of CD40L-induced autoimmunity. Additionally, these results demonstrate that FK506 is able to suppress ongoing severe autoimmune responses.
J Invest Dermatol 2006 Jun
PMID:FK506 controls CD40L-induced systemic autoimmunity in mice. 1670 68

Atopic dermatitis is a common inflammatory skin condition with increasing incidence in recent decades. The mainstay of treatment has been the combination of emollients and topical corticosteroids, with the addition of systemic therapies in severe cases. New drugs such as the topical calcineurin inhibitors have shown promise in treating mild-to-severe atopic dermatitis. Other novel therapies that have been reported in the literature include leukotriene antagonists, monoclonal antibodies such as infliximab, leflunomide, recombinant interferon gamma and intravenous immunoglobulin. This review will focus on the treatment of adult atopic dermatitis.
Australas J Dermatol 2006 May
PMID:Recent developments in the treatment of adult atopic dermatitis. 1663

Atopic dermatitis is a common chronically relapsing disease affecting about 10 percent of children and 3 percent of adults. Currently, no standard management exists for long-term treatment. Topical corticosteroids and recently calcineurin-inhibitors are effective in most patients. In severe cases, however, systemic agents have to be employed. Their use may be limited by unwanted effects or insufficient long-term efficiency. Leflunomide is an immunomodulating and disease-modifying antirheumatic drug with anti-inflammatory and immunosuppressive activity, exhibiting an extremely long in vivo half life. Because T cells and eosinophils play an important role in the pathophysiology of atopic dermatitis, and long-term treatment is often required, leflunomide seems to be ideally suited for treatment of severe atopic eczema. We present a case highlighting the application regimen of leflunomide, and discuss the pathophysiological mechanism of action in atopic dermatitis. Because treatment benefit differs between patients, we propose the design of a proof-of-principle study for leflunomide in atopic dermatitis encompassing an evaluation of predictive markers for successful application.
Dermatol Online J 2006 Mar 30
PMID:Severe atopic dermatitis and leflunomide: first clinical experience and highlights of pertinent experimental data. 1663 20

Atopic dermatitis (AD) is a common, chronic, relapsing, severely pruritic, eczematous skin disease. Topical steroids are the mainstay of treatment. However, the adverse effects of steroids on hormonal function are the major obstacle for their use as long-term topical therapy. Topical calcineurin inhibitors, such as tacrolimus, not only complement existing treatment options but also overcome some of the drawbacks of topical steroid therapy and fulfill the long-term needs of patients in preventing disease progression. Short- and long-term efficacy and safety of topical tacrolimus has been widely recognized and it is also accepted as a first-line treatment for the inflammation of AD. In order to reduce the possible long-term adverse effects, it is important to monitor the clinical dose in daily clinics.
Dermatol Ther
PMID:Topical tacrolimus in the management of atopic dermatitis in Japan. 1666 95


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