Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serum triglyceride levels are significantly higher and serum high-density lipoprotein cholesterol levels are lower in patients with gout compared with healthy individuals. Whereas increased serum triglyceride levels exist intrinsically in gout, serum uric acid concentration correlates inversely with insulin sensitivity and positively with serum triglycerides. Interaction of monosodium urate crystals with granulocyte-macrophage colony-stimulating factor and with tumor necrosis factor-activated neutrophils favored the production of interleukin-1 over that of interleukin-1-Ra, resulting in a proinflammatory imbalance. Interaction of the crystals with iron or tyrosine kinase may modify their inflammatory response and can be an important modulating mechanism in gouty arthritis. E-selectin is a specific marker for synovial fluid soluble endothelial activity and is increased in the synovial fluid of patients with gouty arthritis, as well as in that of patients with other inflammatory arthritides. Similarly, E-selectin was found to be high in joints with monosodium urate crystal-induced synovitis. In addition, synovial fluid levels of interleukin-8 were found to be high in gout, rheumatoid arthritis, and osteoarthritis.
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PMID:Gout, uric acid metabolism, and crystal-induced inflammation. 754 16

Gout affects mostly males over 40 years old and, occasionally, postmenopausal women. This pattern coincides with the pattern of iron accumulation. On the other hand, menstruating women are seldom afflicted by gout, because the monthly blood loss causes them to accumulate iron to a much lesser degree. Gout involves seven aspects: (1) uric acid overproduction from increased purines in the diet; (2) uric acid overproduction from ATP degradation; (3) uric acid overproduction from increased de novo synthesis of purines; (4) uric acid overproduction from increased DNA breakdown from cell damage; (5) decreased uric acid elimination, caused by molybdenum and sulfur binding to copper in the kidneys; (6) precipitation of sodium urate-iron crystals in the joints due to high ferritin and saturated transferrin and low CuZn-SOD and Cu-thionein in the joint; (7) development of inflammation, triggered by tyrosine bonding to the sodium-urate-iron crystals and being transformed by tyrosine kinase. Alcohol and iron greatly affect most of these aspects. Therefore, phlebotomy is suggested as therapy for gout patients, in order to eliminate the accumulated Fe. Furthermore, yearly blood donation is recommended for males with a family history of gout, so as to prevent Fe accumulation and avoid gout.
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PMID:Effect of gradual accumulation of iron, molybdenum and sulfur, slow depletion of zinc and copper, ethanol or fructose ingestion and phlebotomy in gout. 1061 42

Neutrophil-dependent inflammation dependent on monosodium urate (MSU) crystal-induced IL-8 expression occurs in gout. MSU crystals activate phagocyte Src family tyrosine kinases and the serine/threonine kinase p70s6k. Thus, using monocytic THP-1 cells, we assessed the potential for Src family kinases and p70s6k to mediate MSU-induced IL-8 expression. MSU crystals induced phosphorylation of p70s6k and the Src kinases c-Src, Lyn, Hck, and Fyn. IL-8 expression was attenuated more by the Src kinase inhibitor PP1 than by the p70s6k inhibitor rapamycin. PP1 inhibited crystal-induced phosphorylation of ERK1/2 and IkappaBalpha and suppressed IkappaB kinase (IKK) activation and NF-kappaB binding to the IL-8 promoter, signals that mediate MSU-induced IL-8 expression. Transfection of the native Src inhibitor, C-terminal Src kinase (Csk), also suppressed crystal-induced c-Src, ERK1/2, and IkappaBalpha phosphorylation and IL-8 expression. We conclude that Src family tyrosine kinase signaling plays a significant role in MSU crystal-induced IL-8 expression via stimulation of ERK1/2 pathway and NF-kappaB activation.
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PMID:Src family protein tyrosine kinase signaling mediates monosodium urate crystal-induced IL-8 expression by monocytic THP-1 cells. 1173 59

The neutrophil cytoplasmic protein S100A8/A9 (along with S100A8 and S100A9) is chemotactic and stimulates neutrophil adhesion by activating the beta2-integrin CD11b/CD18. It is also essential to neutrophil migration in vivo in response to monosodium urate monohydrate (MSUM) crystals, the principal etiologic agent of gout. S100A8/A9 is present in the synovial fluid of patients with gout and arthritis and is secreted by activated monocytes; however, its mechanism of release by neutrophils remains unknown. The aim of this study was to identify the mechanism of stimulation of the release of S100A8/A9 by MSUM-activated neutrophils. Here, we show that S100A8/A9 is released by neutrophils stimulated with MSUM crystals and that this release could be enhanced by preincubating neutrophils with granulocyte macrophage-colony stimulating factor. Antibodies directed against CD11b and CD16 blocked the release induced by MSUM crystals, suggesting that Fc receptor for immunoglobulin G (FcgammaR)IIIB (CD16) and CD11b/CD18 were involved in the stimulation by MSUM crystals. Neutrophil preincubation with the Src kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine and the Syk tyrosine kinase inhibitor trans-3,3',4,5'-tetrahydrozystilbene significantly reduced the release of S100A8/A9, suggesting that the Src tyrosine kinase family and Syk were involved. In addition, wortmannin reduced neutrophil release of S100A8/A9, indicating a potential involvement of phosphatidylinolitol-3 kinase in this release. Preincubation of neutrophils with the tubulin depolymerization promoters nocodazole and vincristine reduced MSUM-induced release, suggesting a tubulin-associated pathway of release. These results indicate that S100A8/A9 is released by MSUM crystal-stimulated neutrophils following activation of CD11b, CD16, Src kinases, Syk, and tubulin polymerization.
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PMID:Monosodium urate monohydrate crystals induce the release of the proinflammatory protein S100A8/A9 from neutrophils. 1510 58

The deposition of monosodium urate (MSU) crystals in the joints of humans leads to an extremely acute, inflammatory reaction, commonly known as gout, characterized by a massive infiltration of neutrophils. Direct interactions of MSU crystals with human neutrophils and inflammatory mediators are crucial to the induction and perpetuation of gout attacks. The intracellular signaling events initiated by the physical interaction between MSU crystals and neutrophils depend on the activation of specific tyrosine kinases (Src and Syk, in particular). In addition, PI-3Ks may be involved. The present study investigates the involvement of the PI-3K family in the mediation of the responses of human neutrophils to MSU crystals. The results obtained indicate that the interaction of MSU crystals with human neutrophils leads to the stimulation of class Ia PI-3Ks by a mechanism that is dependent on the tyrosine kinase Syk. We also found an increase in the amount of p85 associated with the Nonidet P-40-insoluble fraction derived from MSU crystal-stimulated human neutrophils. Furthermore, MSU crystals induce the formation of a complex containing p85 and Syk, which is mediated by the Src family kinases. Finally, evidence is also obtained indicating that the activation of PI-3Ks by MSU crystals is a critical element regulating phospholipase D activation and degranulation of human neutrophils. The latter response is likely to be involved in the joint and tissue damage that occurs in gouty patients.
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PMID:Crystal-induced neutrophil activation. IX. Syk-dependent activation of class Ia phosphatidylinositol 3-kinase. 1753 83

Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints. Despite many treatment options for gout, there is a substantial need for alternative treatments for patients unresponsive to current therapies. Tyrosine kinase inhibitors have demonstrated therapeutic benefit in experimental models of antibody-dependent arthritis and in rheumatoid arthritis in humans, but to date, the potential effects of such inhibitors on gouty arthritis has not been evaluated. Here we demonstrate that treatment with the tyrosine kinase inhibitor imatinib mesylate (imatinib) can suppress inflammation induced by injection of MSU crystals into subcutaneous air pouches or into the ankle joint of wild type mice. Moreover, imatinib treatment also largely abolished the lower levels of inflammation which developed in IL-1R1-/- or KitW-sh/W-sh mice, indicating that this drug can inhibit IL-1-independent pathways, as well as mast cell-independent pathways, contributing to pathology in this model. Imatinib treatment not only prevented ankle swelling and synovial inflammation when administered before MSU crystals but also diminished these features when administrated after the injection of MSU crystals, a therapeutic protocol more closely mimicking the clinical situation in which treatment occurs after the development of an acute gout flare. Finally, we also assessed the efficiency of local intra-articular injections of imatinib-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles in this model of acute gout. Treatment with low doses of this long-acting imatinib:PLGA formulation was able to reduce ankle swelling in a therapeutic protocol. Altogether, these results raise the possibility that tyrosine kinase inhibitors might have utility in the treatment of acute gout in humans.
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PMID:The tyrosine kinase inhibitor imatinib mesylate suppresses uric acid crystal-induced acute gouty arthritis in mice. 2898 29