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)

Cbln1, which belongs to the C1q/tumor necrosis factor superfamily, is released from cerebellar granule cells and plays a crucial role in forming and maintaining excitatory synapses between parallel fibers (PFs; axons of granule cells) and Purkinje cells not only during development but also in the adult cerebellum. Although neuronal activity is known to cause morphological changes at synapses, how Cbln1 signaling is affected by neuronal activity remains unclear. Here, we show that chronic stimulation of neuronal activity by elevating extracellular K(+) levels or by adding kainate decreased the expression of cbln1 mRNA within several hours in mature granule cells in a manner dependent on L-type voltage-dependent Ca(2+) channels and calcineurin. Chronic activity also reduced Cbln1 protein levels within a few days, during which time the number of excitatory synapses on Purkinje cell dendrites was reduced; this activity-induced reduction of synapses was prevented by the addition of exogenous Cbln1 to the culture medium. Therefore, the activity-dependent downregulation of cbln1 may serve as a new presynaptic mechanism by which PF-Purkinje cell synapses adapt to chronically elevated activity, thereby maintaining homeostasis. In addition, the expression of cbln1 mRNA was prevented when immature granule cells were maintained in high-K(+) medium. Since immature granule cells are chronically depolarized before migrating to the internal granule layer, this depolarization-dependent regulation of cbln1 mRNA expression may also serve as a developmental switch to facilitate PF synapse formation in mature granule cells in the internal granule layer.
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PMID:Activity-dependent repression of Cbln1 expression: mechanism for developmental and homeostatic regulation of synapses in the cerebellum. 1940 10

Pediatric non-infectious uveitis remains a rare but potentially sight-threatening group of diseases. However, early screening and treatment can improve outcomes. No single agent has proven to be efficacious in all cases. A wide variety of long-term immunomodulatory treatments are available; these agents differ in both their potency and side effect profiles. Corticosteroids remain an extremely valuable form of treatment in the short-term management of uveitis. Other major groups of immunomodulatory treatments include the calcineurin inhibitors and antimetabolites such as methotrexate, which is frequently used as the first-line agent. The biologics, including anti-tumor necrosis factor agents and interferons, are newer and potentially very useful therapies although side effects limit their use. Successful outcomes may be achieved with appropriate immunosuppressant therapy given early in the disease, although clinical trials are required to define the true efficacy of this strategy.
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PMID:Non-infectious pediatric uveitis: an update on immunomodulatory management. 1956 7

Adenosine is generated during tissue hypoxia and stress, which reduces inflammation by suppressing the activity of most immune cells. Among its various actions, adenosine suppresses the production of proinflammatory cytokines including tumor necrosis factor (TNF)-alpha, through the cAMP-elevating A(2A) adenosine receptor (AR) subtype. In this study, we examined the signaling mechanisms by which A(2A)AR activation inhibits TNF-alpha production in thioglycollate-elicited mouse peritoneal macrophages. Pretreating murine macrophages with the nonselective AR agonist adenosine-5'-N-ethylcarboxamide (NECA), the A(2A)AR agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680), or the cAMP-elevating agent forskolin reduced TNF-alpha production in response to lipopolysaccharide (LPS) by greater than 60%. All of these agents increased cAMP production in macrophages and activated protein kinase A (PKA). However, we were surprised to find that treating macrophages with three different PKA inhibitors or small interfering RNA-mediated knockdown of the exchange protein activated by cAMP (Epac-1) failed to block the suppressive actions of NECA or forskolin on LPS-induced TNF-alpha release. Instead, okadaic acid was effective at low concentrations that selectively inhibit protein serine/threonine phosphatases. Subsequent studies showed that NECA and forskolin decreased LPS-induced steady-state TNF-alpha mRNA levels; this effect was due to a decreased rate of transcription based on assays examining the rate of generation of primary TNF-alpha transcripts. Treatment with NECA or forskolin did not interfere with LPS-induced translocation or DNA binding of the RelA/p65 subunit of nuclear factor-kappaB or phosphorylation of inhibitor of nuclear factor-kappaB-alpha, extracellular signal-regulated kinase 1/2, c-Jun NH(2)-terminal kinase, or p38 kinase. Our results suggest that AR activation inhibits LPS-induced TNF-alpha production by murine macrophages at the level of gene transcription through a unique cAMP-dependent, but PKA- and Epac-independent, signaling pathway involving protein phosphatase activity.
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PMID:Adenosine suppresses lipopolysaccharide-induced tumor necrosis factor-alpha production by murine macrophages through a protein kinase A- and exchange protein activated by cAMP-independent signaling pathway. 1974 80

Cutaneous lupus erythematosus (LE) may present in a variety of clinical forms. Three recognized subtypes of cutaneous LE are acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), and chronic cutaneous LE (CCLE). ACLE may be localized (most often as a malar or 'butterfly' rash) or generalized. Multisystem involvement as a component of systemic LE (SLE) is common, with prominent musculoskeletal symptoms. SCLE is highly photosensitive, with predominant distribution on the upper back, shoulders, neck, and anterior chest. SCLE is frequently associated with positive anti-Ro antibodies and may be induced by a variety of medications. Classic discoid LE is the most common form of CCLE, with indurated scaly plaques on the scalp, face, and ears, with characteristic scarring and pigmentary change. Less common forms of CCLE include hyperkeratotic LE, lupus tumidus, lupus profundus, and chilblain lupus. Common cutaneous disease associated with, but not specific for, LE includes vasculitis, livedo reticularis, alopecia, digital manifestations such as periungual telangiectasia and Raynaud phenomenon, photosensitivity, and bullous lesions. The clinical presentation of each of these forms, their diagnosis, and the inter-relationships between cutaneous LE and SLE are discussed. Common systemic findings in SLE are reviewed, as are diagnostic strategies, including histopathology, immunopathology, serology, and other laboratory findings. Treatments for cutaneous LE initially include preventive (e.g. photoprotective) strategies and topical therapies (corticosteroids and topical calcineurin inhibitors). For skin disease not controlled with these interventions, oral antimalarial agents (most commonly hydroxychloroquine) are often beneficial. Additional systemic therapies may be subdivided into conventional treatments (including corticosteroids, methotrexate, thalidomide, retinoids, dapsone, and azathioprine) and newer immunomodulatory therapies (including efalizumab, anti-tumor necrosis factor agents, intravenous immunoglobulin, and rituximab). We review evidence for the use of these medications in the treatment of cutaneous LE.
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PMID:Cutaneous lupus erythematosus: issues in diagnosis and treatment. 1982 38

All human cells have a genetic program that upon activation will cause cell death, named apoptosis. Cancer cells can grow due to unbalances in proliferation, cell cycle regulation and their apoptosis machinery: genomic mutations resulting in non-functional pro-apoptosis proteins or over-expression of anti-apoptosis proteins form the basis of tumor formation. Surprisingly, lessons learned from viruses show that cancer cannot be regarded simply as the opposite of apoptosis. For instance, adenovirus can only transform cells when both its anti- and pro-apoptotic proteins are produced. Oncolytic viruses are known to replicate selectively in tumor cells resulting in cell death. Proteins derived from viruses, i.e. chicken anemia virus (CAV)-derived apoptosis-inducing protein (apoptin), adenovirus early region 4 open reading frame (E4orf4) and parvovirus-H1 derived non-structural protein 1 (NS1), the human alpha-lactalbumin made lethal to tumor cells (HAMLET), which is present in human milk or the human cytokines melanoma differentiation-associated gene-7 (mda-7) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have all the ability to induce tumor-selective apoptosis. The tumor-selective apoptosis-inducing proteins seem to interact with transforming survival processes, which can become redirected by these proteins into cell death. Transformation-related processes have been identified, which seem to be crucial for the tumor-selectively killing activity of these proteins. For instance, the transformation-related protein phosphatase 2A (PP2A) plays a role in the induction of tumor-selective apoptosis. The proteins mda-7, TRAIL and HAMLET are already successfully tested in first clinical trials. Proteins harboring tumor-selective apoptosis characteristics represent, therefore, a therapeutic potential and a tool for unraveling tumor-related processes. Fundamental molecular and (pre)clinical therapeutic studies of the various tumor-selective apoptosis-inducing proteins apoptin, E4orf4, HAMLET, mda-7, NS1, TRAIL and related proteins will be discussed.
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PMID:Proteins selectively killing tumor cells. 1983 76

Immunosuppressants are among the pharmacological agents with the greatest potential to cause adverse reactions, although induction of hepatotoxicity is paradoxical from the pathogenic point of view, since the response of the innate and acquired immune system is a key element in the chain of events leading to chemical liver damage. Hepatotoxicity induced by immunosuppressants is difficult to evaluate since these drugs are sometimes used to treat liver diseases, or in combination with other drugs that can also cause hepatotoxicity, or in the context of liver transplantation, in which rejection or biliary complications can act as confounding factors. In addition, immunosuppressant therapy can favor the development of infections, which by themselves can cause liver damage, or reactivate latent chronic viral hepatitis. Corticosteroids and calcineurin inhibitors only exceptionally cause hepatotoxicity. Methotrexate at high doses and in patients with risk factors can induce advanced fibrosis and cirrhosis. Thiopurine agents can cause a spectrum of hepatic lesions, including hepatocellular of cholestatic lesions, and hepatic vascular alterations. Leflunomide has high hepatotoxic potential, especially when combined with methotrexate. Anti-tumor necrosis factor-alpha agents have rarely been associated with hepatotoxicity, often with detectable autoantibodies, and most of the reactions - some severe - have been linked to infliximab, especially when used in patients with rheumatological diseases.
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PMID:[Hepatotoxicity induced by new immunosuppressants]. 1988 79

Vitamin B12 (cobalamin, Cbl) is indispensable for proper brain development and functioning, suggesting that it has neurotrophic effects beside its well-known importance in metabolism. The molecular basis of these effects remains hypothetical, one of the reasons being that no efficient cell model has been made available for investigating the consequences of B12 cellular deficiency in neuronal cells. Here, we designed an approach by stable transfection of NIE115 neuroblastoma cells to impose the anchorage of a chimeric B12-binding protein, transcobalamin-oleosin (TO) to the intracellular membrane. This model produced an intracellular sequestration of B12 evidenced by decreased methyl-Cbl and S-adenosylmethionine and increased homocysteine and methylmalonic acid concentrations. B12 deficiency affected the proliferation of NIE115 cells through an overall increase in catalytic protein phosphatase 2A (PP2A), despite its demethylation. It promoted cellular differentiation by improving initial outgrowth of neurites and, at the molecular level, by augmenting the levels of proNGF and p75(NTR). The up-regulation of PP2A and pro-nerve growth factor (NGF) triggered changes in ERK1/2 and Akt, two signaling pathways that influence the balance between proliferation and neurite outgrowth. Compared with control cells, a 2-fold increase of p75(NTR)-regulated intramembraneous proteolysis (RIP) was observed in proliferating TO cells (P < 0.0001) that was associated with an increased expression of two tumor necrosis factor (TNF)-alpha converting enzyme (TACE) secretase enzymes, Adam 10 and Adam 17. In conclusion, our data show that B12 cellular deficiency produces a slower proliferation and a speedier differentiation of neuroblastoma cells through interacting signaling pathways that are related with increased expression of PP2A, proNGF, and TACE.
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PMID:Vitamin B12 deficiency reduces proliferation and promotes differentiation of neuroblastoma cells and up-regulates PP2A, proNGF, and TACE. 1995 61

The effect of synthetic LVV-hemorphin-7 and hemorphin-7 on hypothalamo-pituitary-adrenocortical axis activity in response to endotoxin-induced stress was studied. The intraperitoneal (ip) endotoxin (lipopolysaccaride, LPS) (0.5 mg/kg) administration in combination with hemorphin (1 mg/kg) induce significant decrease in plasma corticosterone and modest decrease in plasma levels of tumor necrosis factor-alpha (TNFalpha) in compare with elevated levels of both corticosterone and TNFalpha in plasma of rats received LPS administration alone. Increased activity of calcineurin in both plasma and brain of rats received ip administration of LPS, was recovered under LPS + hemorphin treatment. In two independent proteome analysis, using 2-dimensional fluorescence difference gel electrophoresis and the isotope coded protein label technology, peptidyl-prolyl cis-trans-isomerase A (cyclophilin A) was identified as regulated by hemorphins protein in mouse brain. A therapeutic potential of hemorphins and mechanisms of their homeostatic action in response to endotoxin-induced stress are discussed.
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PMID:Hemorphins act as homeostatic agents in response to endotoxin-induced stress. 1996 45

Mitogen-activated protein kinase phosphatase (MKP)-1 is a protein phosphatase that regulates the activity of p38 mitogen-activated protein (MAP) kinase and c-Jun NH2-terminal kinase (JNK) and, to lesser extent, p42/44 extracellular signal-regulated kinase. Studies with MKP-1(-/-) mice show that MKP-1 is a regulating factor suppressing excessive cytokine production and inflammatory response. The data on the role of MKP-1 in the regulation of inflammatory gene expression in human cells are much more limited. In the present study, we investigated the effect of MKP-1 on the expression of interleukin (IL)-6, IL-8 and cyclooxygenase (COX)-2 in response to stimulation with cytokines (tumor necrosis factor, IL-1beta, and interferon-gamma; 10 ng/ml each) in A549 human lung epithelial cells. Cytokines enhanced p38 and JNK phosphorylation and MKP-1 expression. p38 MAP kinase inhibitors 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl] phenol (SB202190) and 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3(4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl)urea (BIRB 796) inhibited cytokine-induced phosphorylation of p38 substrate MAP kinase-activated protein kinase 2 and expression of IL-6, IL-8, and COX-2. An aminopyridine-based JNK inhibitor, N-(4-amino-5-cyano-6-ethoxypyridin-2-yl)-2-(2,5-dimethoxyphenyl)acetamide (JNK inhibitor VIII), inhibited phosphorylation of a JNK substrate c-Jun but did not have any effect on IL-6, IL-8, or COX-2 expression. Down-regulation of MKP-1 with small interfering RNA enhanced p38 and JNK phosphorylation and increased IL-6, IL-8, and COX-2 expression in A549 cells. In conclusion, cytokine-induced MKP-1 expression was found to negatively regulate p38 phosphorylation and the expression of IL-6, IL-8, and COX-2 in human pulmonary epithelial cells. Our results suggest that MKP-1 is an important negative regulator of inflammatory gene expression in human pulmonary epithelial cells, and compounds that enhance MKP-1 may have anti-inflammatory effects and control inflammatory response in the human lung.
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PMID:Mitogen-activated protein kinase phosphatase-1 negatively regulates the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in A549 human lung epithelial cells. 2008 8

Cantharidin is an active constituent of mylabris, a traditional Chinese medicine. It is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays an important role in control of cell cycle, apoptosis, and cell-fate determination. Owing to its antitumor activity, cantharidin has been frequently used in clinical practice. In the present study, we investigated the therapeutic potential of cantharidin in pancreatic cancer. Cantharidin efficiently inhibited the growth of pancreatic cancer cells, but presented a much lighter toxicity effect against normal pancreatic duct cells. It caused G2/M cell-cycle arrest that was accompanied by the down-regulation of cyclin-dependent kinase 1 (CDK1) and up-regulation of p21 expression. It induced apoptosis and elevated the expressions of pro-apoptotic factors tumor necrosis factor-alpha (TNF-alpha), TNF-related apoptosis inducing receptor 1 (TRAILR1), TRAILR2, Bad, Bak, and Bid, and decreased the expression of anti-apoptotic Bcl-2. Activation of caspase-8 and caspase-9 suggested that both extrinsic and intrinsic pathways are involved in the induction of apoptosis. Interestingly, unlike previous studies on other cancer cells, we found that the inhibitory role of cantharidin is independent of oxidative stress in pancreatic cancer cells. Mitogen-activated protein kinases (MAPKs), including ERK, JNK, and p38, were activated after treatment with cantharidin. Inhibition of JNK, but not ERK or p38, alleviated the cytotoxity effect of cantharidin, suggesting cantharidin exerted its anticancer effect through the JNK-dependent way. Hence, in addition to being an attractive candidate compound with therapeutic potential, cantharidin also highlighted the possibility of using PP2A as a therapeutic target for pancreatic cancer treatment.
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PMID:Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis. 2033 21


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