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)

Okadaic acid, a phosphatase inhibitor from a marine organism, mimics tumor necrosis factor/interleukin-1 (TNF/IL-1) in inducing changes in early cellular protein phosphorylation. A total of approximately 116 proteins exhibit significant and concordant changes in phosphorylation or dephosphorylation within 15 min in human fibroblasts activated by either okadaic acid, TNF, or IL-1. The fidelity of this mimicry by okadaic acid extends to the phosphorylation of the 27 hsp complex, stathmin, eIF-4E, myosin light chain, nucleolin, epidermal growth factor receptor, and other cdc2-kinase substrates (c-abl, RB, and p53). The okadaic acid-induced pattern of protein phosphorylation is distinct from that observed in cells treated with phorbol 12-myristate 13-acetate or with ligands like epidermal growth factor, cyclic AMP agonists, bradykinin, or interferons. Like TNF, okadaic acid also induces the transcription of immediate early response genes like c-jun and Egr-1 as well as the interleukin-6 genes. The overall early effects of okadaic acid uniquely parallel those of TNF/IL-1 and not those of other cytokines or ligands. Regulation of protein phosphatase inhibition is discussed as a mechanism for TNF/IL-1 signal transduction.
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PMID:Okadaic acid mimics multiple changes in early protein phosphorylation and gene expression induced by tumor necrosis factor or interleukin-1. 137 Apr 82

Several disciplines, including chemical ecology, seek to understand the molecular basis of information transfer in biological systems, and general molecular strategies are beginning to emerge. Often these strategies are discovered by a careful analysis of natural products and their biological effects. Cyclosporin A, FK506, and rapamycin are produced by soil microorganisms and are being used or considered as clinical immunosuppressive agents. They interrupt the cytoplasmic portion of T-cell signaling by forming a complex with a binding protein--FKBP12 in the case of FK506 and rapamycin and cyclophilin A (CyPA) in the case of cyclosporin A (CsA). This complex in turn inhibits a protein target, and the best understood target is calcineurin, which is inhibited by FK506-FKBP12 and CyPA-CsA. Mutational and structural studies help define how FK506-FKBP12 interacts with calcineurin, and the results of these studies are summarized. The existence of strong FK506-FKBP12 binding suggests that FK506 is mimicking some natural ligand for FKBP12. Synthetic and structural studies to probe this mimicry are also described.
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PMID:The chemistry of signal transduction. 752 14

The increasing prevalence and severity of atopic dermatitis during recent decades has prompted the development of safe and more highly effective drugs. Although topical corticosteroids have been used for more than 50 years as first line therapy for atopic dermatitis, their potential side effects limits their clinical uses. In light of this, steroid-free topical calcineurin inhibitors were developed and have been used in patients with moderate to severe atopic dermatitis. In the present study, we examined if hirsutenone suppressed the profiles of atopic dermatitis development in vitro via mimicry of calcineurin inhibitor actions in mouse splenocytes and RBL-2H3 mast cells. Our results showed that hirsutenone effectively inhibited T cell activation by blocking dephosphorylation of nuclear factor of activated T cells (NFAT). This inhibition was confirmed by inactivation of mitogen-activated protein kinases (MAPKs), which subsequently inhibited production of cytokine mRNAs (interleukin-2, -4, -5, -13 and interferon-gamma) after T cell receptor stimulation. We also showed that the early T cell activation marker, CD25, was suppressed in the presence of hirsutenone after T cell receptor stimulation with anti-CD3. Moreover, degranulation of mast cells was remarkably suppressed, comparable to that by cyclosporine A. This indicates that hirsutenone may specifically inhibit calcium-activated processes in both T cells and mast cells. Therefore, our results suggest that hirsutenone may be a new topical drug candidate, which probably acts by mimicking calcineurin inhibitor mechanisms.
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PMID:Suppression of T cell activation by hirsutenone, isolated from the bark of Alnus japonica, and its therapeutic advantages for atopic dermatitis. 1940 88

Autoimmune hepatitis (AIH) is an immune-mediated liver disorder characterised by female preponderance, elevated transaminase and immunoglobulin G levels, seropositivity for autoantibodies and interface hepatitis. Presentation is highly variable, therefore AIH should be considered during the diagnostic workup of any increase in liver enzyme levels. Overlap/variant forms of the disease, presenting with concomitant features of primary biliary cirrhosis or primary sclerosing cholangitis are increasingly recognised. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival. Difficult-to-treat or non-responsive patients should be treated with mycophenolate mofetil or, failing that, calcineurin inhibitors. Persistent failure to respond or lack of adherence to treatment result in end-stage liver disease. These patients, and those with fulminant liver failure (encephalopathy grade II-IV) at diagnosis, will require liver transplantation. The pathogenesis of AIH is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4(pos) T-cells, although recent studies support the involvement of diverse populations, including Th17 cells. Animal models faithfully representing the human condition are needed to unravel the contribution of innate and adaptive, effector and regulatory immune responses. A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigen-specific regulatory T-cells, which ultimately aim to restore tolerance to liver-derived antigens.
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PMID:Autoimmune hepatitis: a comprehensive review. 2321 32

Hepatocellular carcinoma (HCC) is one of the most common and therapeutically challenging malignancies worldwide. For patients ineligible for "curative resection" or liver transplantation, chemotherapy is an important minimally effective option. Strategies for chemosensitization are urgently needed. Here, we report that LB-100, a serine/threonine protein phosphatase 2A (PP2A) inhibitor, enhances the cytotoxicity of chemotherapy for HCC in vitro and in vivo. We found that LB-100 significantly enhanced inhibition of HCC by doxorubicin and cisplatin in vitro and in vivo in a PP2A-dependent way, while having little inhibitory activity when used alone. LB-100 promoted vascular endothelial growth factor secretion and vasculogenic mimicry, associated with increased microvessel density and blood perfusion of tumor cell xenografts. LB-100 also enhanced paracellular endothelial permeability to Evans Blue dye and doxorubicin in vivo and in vitro, presumably by altering vascular endothelial-cadherin contact between cells. Changes in permeability and perfusion were accompanied by increased accumulation of doxorubicin in HCC xenografts but not in normal liver tissue. In conclusion, LB-100 enhances chemotherapy by interfering with DNA damage-induced defense mechanisms and by increasing angiogenesis and drug penetration into tumor cells. The induction of angiogenesis and vascular permeability of tumor xenografts by inhibition of PP2A may be a novel approach for enhancing the cytotoxic treatment of HCC and potentially other cancers.
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PMID:Inhibition of protein phosphatase 2A enhances cytotoxicity and accessibility of chemotherapeutic drugs to hepatocellular carcinomas. 2486 49

Autoimmune hepatitis (AIH), a liver disorder affecting both children and adults, is characterized by inflammatory liver histology, elevated transaminase levels, circulating nonorganspecific autoantibodies, and increased levels of immunoglobulin G, in the absence of a known etiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody define AIH type 1 and antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a paediatric disease, though it does occasionally affects young adults. AIH should be considered during the diagnostic workup of any patient with increased liver enzyme levels. AIH is exquisitely responsive to immunosuppressive treatment with prednisolone with or without azathioprine, with symptom free long-term survival for the majority of patients. For those who do not respond to standard treatment, or who are difficult-to-treat, mycophenolate mofetil and, in the absence of a response, calcineurin inhibitors should be tried in addition to steroids. The pathogenesis of AIH is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4 T-cells, although recent studies support the involvement of diverse populations, including Th17 cells. A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigenspecific regulatory T-cells, which ultimately aim at restoring tolerance to liver-derived antigens.
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PMID:Update on Autoimmune Hepatitis. 2635 34

Autoimmune Hepatitis (AIH) is a chronic progressive inflammatory disease of the liver that responds to immunosuppressive therapy. In patients with AIH who have an acute liver failure presentation or those who develop end stage liver disease despite medical therapy, liver transplantation (LT) may become necessary. Despite good outcomes after LT, AIH can develop/recur in the allograft with an estimated incidence of recurrence between 8 and 12% at 1 year and 36-68% at 5 years. The presence of non-organ specific autoantibodies, elevated serum aminotransferases and immunoglobulin G as well as the characteristic histologic features of interface hepatitis (peri-portal plasma cell infiltration) characterize recurrence of disease. De novo AIH is the development of features of classical AIH in the allograft of patients who have not been transplanted for AIH. There are several reports in the pediatric transplant population, where administering immunosuppressive therapy in the regimen used to treat AIH has stabilized graft function in de novo AIH. In adults, hepatitis C (HCV) is the most common indication for LT and HCV often recurs after LT, requiring treatment with Interferon and Ribavirin. Labeling the graft dysfunction 'de novo AIH' can be problematic in this context, particularly if HCV RNA is positive at that time. Some have chosen to give other names like 'graft dysfunction mimicking AIH' and 'plasma cell hepatitis'. Regardless of the nomenclature, autoimmune liver graft dysfunction, if managed appropriately with the treatment regimen used to treat AIH, can save grafts and patients. The mechanism causing recurrent or de novo AIH after LT remains unknown. Several mechanisms have been implicated in this loss of self-tolerance including impaired thymic regulation, impaired activity of T regulatory cells, molecular mimicry, calcineurin inhibitors, glutathione-s transferase and genetic polymorphisms. While the phenotype of de novo AIH in pediatrics has been uniform, it has been more variable in adults, highlighting the need for uniform diagnostic criteria or scoring system post LT. Better understanding of the development of autoimmunity and its difference from classical rejection after LT will allow better therapeutic strategies and improved outcome.
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PMID:'De novo' and 'recurrent' autoimmune hepatitis after liver transplantation: A comprehensive review. 2637 32

In paediatrics, there are 2 liver disorders in which liver damage most likely stems from an autoimmune attack: 'classical' autoimmune hepatitis (AIH) and the AIH/sclerosing cholangitis overlap syndrome (also known as autoimmune sclerosing cholangitis, ASC). The presentation of childhood autoimmune liver disease (AILD) is non-specific and can mimic most other liver disorders. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival. Difficult-to-treat or non-responsive patients should be treated with mycophenolate mofetil; if this fails then calcineurin inhibitors can be tried. Persistent failure to respond or lack of adherence to treatment result in end-stage liver disease. These patients, and those with fulminant liver failure at diagnosis, will require liver transplantation. ASC responds to the same immunosuppressive treatment used for AIH when treatment is initiated early. Abnormal liver function tests often resolve within a few months of treatment, although medium- to long-term prognosis is worse than that of AIH because bile duct disease continues to progress despite treatment in approximately 50% of patients. Ursodeoxycholic acid is usually added to conventional treatment regimen in ASC, but whether this actually helps arrest the progression of bile duct disease remains to be established. The pathogenesis of paediatric-onset AILD is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4pos T-cells. While Th1 effector cells are associated with hepatocyte damage in both AIH and ASC, Th17 immune responses predominate in the latter where they correlate with biochemical indices of cholestasis, indicating that IL-17 is involved in the bile duct damage characteristic of this condition. Since a substantial difference between these 2 pathologies is the frequent association of ASC with inflammatory bowel disease, it can be speculated that lymphocytes of intestinal origin are present in patients with a diagnosis of ASC rather than in those with AIH. Animal models faithfully representing the human conditions are needed to unravel the contribution of innate and adaptive, effector and regulatory immune responses. A deeper understanding of the pathogenesis of AILD is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigen-specific regulatory T-cells, which ultimately aim at restoring tolerance to liver-derived antigens.
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PMID:Paediatric Autoimmune Liver Disease. 2664 70

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