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:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the induction of macrophage pro-inflammatory responses by transferrin-derived synthetic peptide originally identified following digestion of transferrin from different species (murine, bovine, human N-lobe and goldfish) using elastase. The mass spectrometry analysis of elastase-digested murine transferrin identified a 31 amino acid peptide located in the N2 sub-domain of the transferrin N-lobe, that we named TMAP. TMAP was synthetically produced and shown to induce a number of pro-inflammatory genes by quantitative PCR. TMAP induced chemotaxis, a potent nitric oxide response, and TNF-alpha secretion in different macrophage populations; P338D1 macrophage-like cells, mouse peritoneal macrophages, mouse bone marrow-derived macrophages (BMDM) and goldfish macrophages. The treatment of BMDM cultures with TMAP stimulated the production of nine cytokines and chemokines (IL-6, MCP-5, MIP-1 alpha, MIP-1 gamma, MIP-2, GCSF, KC, VEGF, and RANTES) that was measured using cytokine antibody array and confirmed by Western blot. Our results indicate that transferrin-derived peptide, TMAP, is an immunomodulating molecule capable of inducing pro-inflammatory responses in lower and higher vertebrates.
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PMID:Transferrin-derived synthetic peptide induces highly conserved pro-inflammatory responses of macrophages. 1895 94

Monocyte chemotactic protein-1 and interleukin-6 are important inflammatory cytokines, which have close relationships with atherosclerosis. Visfatin is a novel adipokine involved in regulation of inflammatory cytokines, however, associations of visfatin with cytokines (MCP-1, IL-6) in human umbilical vein endothelial cells are unclear. The aim of this study was to determine whether visfatin has effects on the expression of MCP-1 and IL-6 in human umbilical vein endothelial cells. Enzyme-linked immunosorbent assay were used for measuring MCP-1 and IL-6 production in human umbilical vein endothelial cells. Real-time quantitative reverse-transcription polymerase chain reaction was used for determining MCP-1 and IL-6 mRNA expression. For the pathway determination following inhibitors were used: wortmannin [phosphatiylinositol 3-kinase (PI3K)], SB203580 [p38 mitogen-activated protein kinase (MAPK)], PD98059 [extracellular signal-regulated kinase (ERK) 1/2)], JNK inhibitor II [c-Jun NH 2-terminal kinase (JNK)]. We demonstrated that visfatin could obviously upregulate secretion of MCP-1and IL-6 in a dose- and time-dependent manner in human umbilical vein endothelial cells. Visfatin-induced effects were diminished by SB203580, wortmannin, and PD98059. In summary, these results suggest that visfatin-induced MCP-1 and IL-6 production involve p38 MAPK, PI3K, and ERK 1/2 pathways in human umbilical vein endothelial cells as determined by inhibition with specific inhibitors.
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PMID:Visfatin stimulates production of monocyte chemotactic protein-1 and interleukin-6 in human vein umbilical endothelial cells. 1900 99

Cachexia is a term used to describe the poor status of a patient suffering from a benign disease (Crohn's disease, chronic heart and kidney failure) as well as from a malignant disease. Cachexia has an important impact on the survival and morbidity in patients with cancer. The aim of this study is to elucidate the pathophysiology in cancer cachexia with a special emphasis on pancreatic cancer. The dramatic weight loss in malignant diseases is due to anorexia resulting in malnutrition and is characterised by a progressive loss of muscle and fat tissue. Different cytokines like TNF-alpha, IFN-gamma, IL-1, IL-6 are involved in this process. Via the ubiquitin-proteasome pathway, in which also the proteolysis inducing factor (PIF) is involved, the majority of protein is degraded. In patients with cancer cachexia we find an elevated level of lipases, which indicates that rather fat catabolism and not reduced fat synthesis is the main factor in fat metabolism. The development of an effective (pharmacological) treatment is still the main challenge. As yet, none of the used therapies show a long-lasting effect on weight stabilisation and survial. Cachexia is an important issue, especially in pancreatic cancer; it influences the qualitiy of life and has an important impact on survival. Today, there are only a few different pharmacological therapies used in the treatment of cancer cachexia, but each and every single treatment has failed to show a persistent effect on survival. The aim of research and treatment is to interrupt the natural clinical course of cachexia.
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PMID:[Molecular mechanisms and its clinical impact in cancer cachexia]. 1905 8

Despite their common ability to activate intracellular signaling through CD80/CD86 molecules, cytotoxic T lymphocyte antigen 4 (CTLA-4)-Ig and CD28-Ig bias the downstream response in opposite directions, the latter promoting immunity, and CTLA-4-Ig tolerance, in dendritic cells (DCs) with opposite but flexible programs of antigen presentation. Nevertheless, in the absence of suppressor of cytokine signaling 3 (SOCS3), CD28-Ig-and the associated, dominant IL-6 response-become immunosuppressive and mimic the effect of CTLA-4-Ig, including a high functional expression of the tolerogenic enzyme indoleamine 2,3-dioxygenase (IDO). Here we show that forced SOCS3 expression antagonized CTLA-4-Ig activity in a proteasome-dependent fashion. Unrecognized by previous studies, IDO appeared to possess two tyrosine residues within two distinct putative immunoreceptor tyrosine-based inhibitory motifs, VPY(115)CEL and LLY(253)EGV. We found that SOCS3-known to interact with phosphotyrosine-containing peptides and be selectively induced by CD28-Ig/IL-6-would bind IDO and target the IDO/SOCS3 complex for ubiquitination and subsequent proteasomal degradation. This event accounted for the ability of CD28-Ig and IL-6 to convert otherwise tolerogenic, IDO-competent DCs into immunogenic cells. Thus onset of immunity in response to antigen within an early inflammatory context requires that IDO be degraded in tolerogenic DCs. In addition to identifying SOCS3 as a candidate signature for mouse DC subsets programmed to direct immunity, this study demonstrates that IDO undergoes regulatory proteolysis in response to immunogenic stimuli.
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PMID:SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis. 1908 99

Whereas many cytochrome P450 enzymes are transcriptionally suppressed by inflammatory stimuli, down-regulation of CYP2B protein by the inflammatory cytokine interleukin (IL)-1beta is nitric oxide (NO)-dependent and occurs via polyubiquitination and proteasomal degradation. Here, we used iTRAQ proteomic analysis to search for other proteins that are potentially down-regulated by cellular NO in cultured rat hepatocytes, and we identified CYP3A1 as one such protein. Therefore, we examined whether CYP3A proteins, like CYP2B, undergo NO- and proteasome-dependent degradation in response to cytokine treatment of rat hepatocytes. In cultured rat hepatocytes treated with phenobarbital, IL-1beta stimulation failed to down-regulate CYP3A1 mRNA within 24 h of treatment, whereas CYP3A protein was down-regulated to 40% of control within 6 h, showing the post-transcriptional down-regulation of CYP3A1 protein. The down-regulation of CYP3A after 9 h of stimulation by IL-1beta was attenuated by inhibitors of NO synthase (NOS) and of the proteasome, showing NO- and proteasome-dependent down-regulation at earlier time points. However, the down-regulation of CYP3A evoked by IL-1beta measured 24 h after stimulation was not affected by the inhibition of NOS or by proteasomal inhibitors, showing that CYP3A1 down-regulation at later time points is NO- and proteasome-independent. IL-6, which did not evoke NO production nor affect CYP3A1 mRNA within 24 h, produced a delayed proteasome-independent down-regulation as well. Taken together, these observations show a novel dual mode of post-transcriptional CYP3A down-regulation by cytokines: NO- and proteasome-dependent at earlier time points and NO- and proteasome-independent at later times.
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PMID:Dual mechanisms of CYP3A protein regulation by proinflammatory cytokine stimulation in primary hepatocyte cultures. 1917 75

Sequestosome 1/p62 (p62) is a scaffold/adaptor protein with multiple functions implicated for neuronal and bone diseases. It carries a ubiquitin binding domain through which it mediates proteasome-dependent proteolysis. In addition, p62 is reported to regulate NF-kappaB activity in some cells. To date, however, the role of p62 in innate immunity has not been fully elucidated. In this study, we report that IFN-gamma plus TLR signaling stimulates late expression of p62 in murine macrophages. Overexpression of p62 inhibited expression of multiple cytokines, IL-12p40, TNF-alpha, IL-1beta, IL-6, and IFN-beta, whereas p62 underexpression by small hairpin RNA markedly elevated their expression, indicating that p62 is a broad negative regulator of cytokine expression in stimulated macrophages. We show that p62 interacts with IFN regulatory factor 8 and Ro52, the transcription factor and ubiquitin E3 ligase that are important for IL-12p40 expression. This interaction, detectable at a late stage in stimulated macrophages, led to increased polyubiquitination and destabilization of IFN regulatory factor 8. We also show that upon macrophage stimulation, p62 binds to TNFR-associated factor 6, another E3 ligase important for NF-kappaB activation, but later this interaction was replaced by the recruitment of the deubiquitinating enzyme, cylindromatosis, an inhibitor of NF-kappaB activity. Recruitment of cylindromatosis coincided with reduced TNFR-associated factor 6 autoubiquitination and lower NF-kappaB activation. Our results indicate that p62 orchestrates orderly regulation of ubiquitin modification processes in macrophages to ensure attenuation of cytokine transcription postactivation. Together, p62 may provide a mechanism by which to control excessive inflammatory responses after macrophage activation.
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PMID:The sequestosome 1/p62 attenuates cytokine gene expression in activated macrophages by inhibiting IFN regulatory factor 8 and TNF receptor-associated factor 6/NF-kappaB activity. 1920 66

D-Serine, an endogenous amino acid, is involved in many physiological processes through its interaction with the glycine binding site of the N-methyl-D-aspartate (NMDA) receptor. It has important roles in development, learning, and cell death signaling. Recent evidence suggests that decreased function of the NMDA receptor is related to the etiology of schizophrenia, and the use of D-serine as add-on therapy is beneficial in alleviating the symptoms of treatment-refractory schizophrenia. The NMDA receptor also plays a major role in neuronal cell death and neurodegeneration mediated by excitatory amino acid toxicity in ischemia, epilepsy, and trauma. Due to its co-activator function, D-serine can markedly potentiate NMDA-mediated excitotoxicity. To investigate potential adverse effects of D-serine treatment, we investigated gene expression changes in the forebrain of male F-344 rats treated with a single intraperitoneal injection of D-serine (5, 20, 50, 200, or 500 mg/kg) at 96 h post-treatment. Gene expression profiling using Affymetrix Rat Genome 230 2.0 arrays revealed that D-serine treatment resulted in up- and down-regulation of 134 and 52 genes, respectively, based on the common genes identified using three statistical methods, i.e. t test (p < 0.01 over two consecutive doses), ANOVA (with adjusted Bonferonni correction for multiple testing) and significance analysis of microarray (SAM). Self organized map (SOM) clustering analysis of the differentially expressed genes showed two clusters, one with all 134 up-regulated probe sets and the other with all 52 down-regulated probe sets. The dose-response pattern of the down-regulated cluster showed nearly a perfect mirror image of that of the up-regulated one. Gene ontology analysis revealed that pathways implicated in neuronal functions and/or neurodegenerative disorders are over-represented among the differentially expressed genes. Specifically, genes involved in vesicle-mediated transport, endocytosis, ubiquitin conjugation pathway, regulation of actin filament polymerization/depolymerization, focal adhesion, Wnt signaling, and insulin signaling were up-regulated, while genes involved in RNA metabolism/splicing/processing and Notch signaling were down-regulated. Consistent with this finding, pathway analysis using GenMAPP showed a significant number of differentially expressed genes in these pathways. In addition, the GenMAPP result also showed activation of the signaling pathways of several proinflammatory cytokines (including IL-2, IL-3, IL-5, IL-6 and TNF-alpha), which might suggest the onset of neuroinflammation. Biological association network analysis showed that several nuclear factors implicated in transcription regulation (including Taf1, Max, Myc, and Hnf4a) are highly connected to a large number of up-regulated genes. While the transcript levels of these transcription factors were not changed, their connections to Ddx3x, a gene involved in mRNA processing and translation initiation, raise the possibility that they may be up-regulated at the post-transcriptional level. The observation that Ubqln1 and Ube2d, two differentially expressed genes involved in ubiquitin-mediated proteolysis and implicated in neurodegenerative disorders, are highly connected in this network suggests a role of ubiquitination proteasome pathway in response to D-serine exposure. This finding is consistent with the result of gene ontology analysis and suggests that D-serine treatment might result in damage to cellular proteins and subsequent up-regulation of ubiquitination proteasome pathway to clear these damaged proteins. In summary, D-serine exposure resulted in perturbation of a number of pathways implicated in neuronal functions and neurodegenerative disorders. However, activation of cellular response to counter the toxic effects of D-serine might be hindered due to the down-regulation of such important cellular machinery like RNA metabolism, splicing and processing. Consequently, cell damage might be further exacerbated. Taken together, these findings highlight the potential impacts of D-serine exposure on neuronal functions.
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PMID:D-Serine exposure resulted in gene expression changes implicated in neurodegenerative disorders and neuronal dysfunction in male Fischer 344 rats. 1921 59

Brief virologic news included the discovery of the virophage, a unique parasite of the giant mimivirus and the association of HHV-8 infection with a peculiar form of African diabetes. Secondly, this news focused on risk factors for arterial or venous thrombosis and therapy for auto-immune disorders. Only oral estrogen therapy increases the risk of venous thromboembolism in postmenopausal women. Despite significant homocysteine lowering, vitamin supplementation with folic acid, vitamins B6 and B12 did not reduce total cardiovascular events among high-risk patients. Patients with venous thromboembolism have a substantially increased long-term risk of subsequent cardiovascular events while obesity, systemic arterial hypertension, and diabetes are common risk factors for arterial and venous thrombosis. The non fasting ApoB/ApoA1 ratio was superior to any of the cholesterol ratios for estimation of the risk of acute myocardial infection in all ethnic groups. Preventive anticoagulation of in-patients with risk of venous thromboembolism was inadequately prescribed in many hospitals of the world. Subcutaneous administration of methotrexate was more effective than the oral administration at the same dosage in patients suffering from active rheumatoid arthritis. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-beta2-glycoprotein I complexes to phospholipid bilayers. Anti-IL-5 and anti-IL-6 antibodies were effective for the treatment of respectively hypereosinophilic syndrome and rheumatoid arthritis. The efficacy of proteasome inhibitors and mesenchymal stems cells have been demonstrated in respectively two mouse strains with lupus-like disease and steroid-resistant severe acute graft-versus-host disease. These treatments may be useful for auto-immune disorders if their long term toxicity is acceptable. In conclusion, subcutaneous injections of physiological saline, used as placebo in two different trials, enhanced in vitro activation of immunocompetent cells in healthy individuals.
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PMID:[What's new in internal medicine?]. 1926 9

Titanium dioxide nanoparticles (TNP) are nanomaterials which have various applications including photocatalysts, cosmetics, and pharmaceuticals because of their high stability, anticorrosiveness, and photocatalytic properties. Induction of cytokines and potential chronic inflammation were investigated in mice treated with TNP (5 mg/kg, 20 mg/kg, and 50 mg/kg) by a single intratracheal instillation. Pro-inflammatory cytokines such as IL-1, TNF-a, and IL-6 were significantly induced in a dose-dependent manner at day 1 after instillation. The levels of Th1-type cytokines (IL-12 and IFN-gamma) and Th2-type cytokines (IL4, IL-5 and IL-10) were also elevated dose-dependently at day 1 and the inflammatory responses were sustained until the remainder of experimental period for 14 days. By the induction of Th2-type cytokines, the increased B cell distributions both in spleen and in blood, and increased IgE production in BAL fluid and serum were observed. In lung tissue, increase of inflammatory proteins (MIP and MCP) and granuloma formation were observed. Furthermore, the expressions of genes related with antigen presentation (H2-T23, H2-T17, H2-K1, and H2-Eb1) and genes related with the induction of chemotaxis of immune cells (Ccl7, Ccl3, Cxcl1, Ccl4, Ccl2) were markedly increased using microarray analysis. From these data, it could be suggested that TNP possibly cause chronic inflammatory diseases through Th2-mediated pathway in mice.
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PMID:Induction of chronic inflammation in mice treated with titanium dioxide nanoparticles by intratracheal instillation. 1946 67

The multi-protein beta-catenin destruction complex tightly regulates beta-catenin protein levels by shuttling beta-catenin to the proteasome. Glycogen synthase kinase 3beta (GSK3beta), a key serine/threonine kinase in the destruction complex, is responsible for several phosphorylation events that mark beta-catenin for ubiquitination and subsequent degradation. Because modulation of both beta-catenin and GSK3beta activity may have important implications for treating disease, a complete understanding of the mechanisms that regulate the beta-catenin/GSK3beta interaction is warranted. We screened an arrayed lentivirus library expressing small hairpin RNAs (shRNAs) targeting 5,201 human druggable genes for silencing events that activate a beta-catenin pathway reporter (BAR) in synergy with 6-bromoindirubin-3'oxime (BIO), a specific inhibitor of GSK3beta. Top screen hits included shRNAs targeting dihydrofolate reductase (DHFR), the target of the anti-inflammatory compound methotrexate. Exposure of cells to BIO plus methotrexate resulted in potent synergistic activation of BAR activity, reduction of beta-catenin phosphorylation at GSK3-specific sites, and accumulation of nuclear beta-catenin. Furthermore, the observed synergy correlated with inhibitory phosphorylation of GSK3beta and was neutralized upon inhibition of phosphatidyl inositol 3-kinase (PI3K). Linking these observations to inflammation, we also observed synergistic inhibition of lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines (TNFalpha, IL-6, and IL-12), and increased production of the anti-inflammatory cytokine IL-10 in peripheral blood mononuclear cells exposed to GSK3 inhibitors and methotrexate. Our data establish DHFR as a novel modulator of beta-catenin and GSK3 signaling and raise several implications for clinical use of combined methotrexate and GSK3 inhibitors as treatment for inflammatory disease.
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PMID:A lentivirus-mediated genetic screen identifies dihydrofolate reductase (DHFR) as a modulator of beta-catenin/GSK3 signaling. 1972 91


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