Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of cyclooxygenase-2 (COX-2) is a characteristic response to inflammation, which can be inhibited with sodium salicylate. IL-1beta and TNF-alpha can induce extracellular signal-regulated kinase (ERK), IKK, IkappaB degradation and NF-kappaB activation. Salicylate inhibited the IL-1beta and TNF-alpha-induced COX-2 expressions, regulated the activation of ERK, IKK and IkappaB degradation, and the subsequent activation of NF-kappaB, in neonatal rat ventricular cardiomyocytes. The inhibition of the ERK pathway, with a selective inhibitor, PD098059, blocked the expressions of IL-1beta and TNF-alpha-induced COX-2 and PGE2 release. The antioxidant, N-acetyl-cysteine, also reduced the glutathione or catalase- attenuated COX-2 expressions in IL-1beta and TNF-alpha-treated cells. This antioxidant also inhibited the activation of ERK and NF-kappaB in neonatal rat cardiomyocytes. In addition, IL-1beta and TNF-alpha stimulated the release of reactive oxygen species (ROS) in the cardiomyocytes. However, salicylate had no inhibitory effect on the release of ROS in the DCFDA assay. The results showed that salicylate inhibited the activation of ERK and IKK, IkappaB degradation and NF-kappaB activation, independently of the release of ROS, which suggested that salicylate exerts its anti-inflammatory action through the inhibition of ERK, IKK, IkappaB and NF-kappaB, and the resultant COX-2 expression pathway in neonatal rat ventricular cardiomyocytes.
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PMID:Sodium salicylate inhibits expression of COX-2 through suppression of ERK and subsequent NF-kappaB activation in rat ventricular cardiomyocytes. 1293 47

The expression of cyclooxygenase-2 (COX-2) is a characteristic response to inflammation and can be inhibited with sodium salicylate. TNF-alpha plus IFN-gamma can induce extracellular signal-regulated kinase (ERK), IKK, IkappaB degradation and NF-kappaB activation. The inhibition of the ERK pathway with selective inhibitor, PD098059, blocked cytokine-induced COX-2 expression and PGE2 release. Salicylate treatment inhibited COX-2 expression induced by TNF-alpha/IFN-gamma and regulated the activation of ERK, IKK and IkappaB degradation and subsequent NF-kappaB activation in MC3T3E1 osteoblasts. As well, antioxidant-catalase, N-acetyl-cysteine or reduced glutathione-attenuated COX-2 expression in combined cytokines-treated cells. These antioxidants also inhibited the activation of ERK, IKK and NF-kappaB in MC3T3E1 osteoblasts. In addition, TNF-alpha/IFN-gamma stimulated ROS release in the osteoblasts. However salicylate had no obvious effect on ROS release in DCFDA assay. The results showed that salicylate inhibited the activation of ERK and IKK, IkappaB degradation and NF-kappaB activation independent of ROS release and suggested that salicylate exerts its anti-inflammatory action in part through inhibition of the ERK, IKK, IkappaB, NF-kappaB and resultant COX-2 expression pathway.
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PMID:Salicylate regulates COX-2 expression through ERK and subsequent NF-kappaB activation in osteoblasts. 1510 33

In the high proportion of vascular disorders associated with excessive oxidative stress and production of pro-inflammatory cytokines, activation of NF-kappaB plays a key pathogenic role. Thus, there is considerable evidence that NF-kappaB is a mediator of atherogenesis, plaque destabilization, ischemia-reperfusion damage, cardiac remodeling, atrial fibrillation, and aneurysm formation and rupture; some studies suggest that it may also play a role in the microvascular complications of diabetes. I kappaB kinase-beta (IKK beta) is the upstream kinase that appears to be primarily responsible for NF-kappaB activation in these disorders; moreover, chronic IKK beta activation plays a prominent role in induction of insulin resistance in the metabolic syndrome. Salicylate inhibits IKK beta in concentrations that are achievable with dose schedules traditionally used in treating rheumatoid arthritis (3-4.5 g daily); indeed, this is likely to be the mechanism responsible for salicylate's utility in this disorder. Salicylate, unlike aspirin, is only a very weak, reversible inhibitor of cyclooxygenase in clinical doses, and thus is not associated with the potentially dangerous side effects seen with NSAIDs; fully reversible ototoxicity, the dose-limiting side effect in salicylate therapy, can be avoided in most patients by dosage adjustment. Hence, it is proposed that salicylate may have practical utility in the prevention or management of a wide range of vascular disorders as well as of metabolic syndrome and diabetes; its efficacy in these regards would likely be complemented by effective antioxidant measures, which would lessen the stimulus to NF-kappaB activation while providing benefits independent of NF-kappaB activity. Salsalate, consisting of two salicylate molecules united by an ester bond, is a venerable drug that may be the best tolerated delivery vehicle for salicylate. Appropriate rodent studies should pave the way for clinical trials with salsalate in patients at vascular risk.
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PMID:Salsalate may have broad utility in the prevention and treatment of vascular disorders and the metabolic syndrome. 2008 Mar 59