Inhibitor of Nuclear Factor kB

Bayon Y, Alonso A, Crespo MS. 4-Trifluoromethyl derivatives of salicylate, triflusal and its main metabolite 2-hydroxy-4-trifluoromethylbenzoic acid, are potent inhibitor of nuclear factor kB activation. Br J Pharmacol 1999 126 1359-1466. 

Schreck R, Meier B, Mannel DN, Droge W, Baeuerle PA Dithiocarbamates as potent inhibitors of nuclear factor kB activation in intact cells. J Exp Med 1992 175 1181-1194. 

Members of the akuammiline alkaloid family also hold promise for treatment of pain and inflammation. Scholarisin I (60) and scholarisin VI (65) were claimed as selective inhibitors of COX-2, while pseudoakuammigine (13) has been reported to have in vivo anti-inflammatory and analgesic activity in rats observed via the carrageenan-induced paw edema and tail flick models respectively. " Picrinine (5) has also been su ested to have antiinflammatory and analgesic activity in mice based on results from various in vivo assays, while (Z)-alstoscholarine (29) was disclosed to be an inhibitor of nuclear factor-KB. ... 

Pradeep and Kuttan [24] established that piperine is a potent inhibitor of nuclear factor - kB (NF- kB), c-Fos, CREB, ATF-2, and proinflammatory cytokine gene expression in B16F-10 melanoma cells. 

Perivascular and intra-arterial administration of neutral sphingomyelinase or exogenous short-chain ceramide resulted in a potent concentration-dependent constriction of cortical venules, followed by increased venular waU permeability, post-capillary venule rupture and micro-hemorrhaging (Altura et al, 2002). Treatment with antioxidants, calcium channel blockers and inhibitors of nuclear factor-KB activation could attenuate the effects of neutral sphingomyelinase and ceramide. These results suggest that ceramide can play a role in vasoconstriction and may be involved in the mechanisms resulting in brain injury and stroke. 

Although ingenol derivatives are highly potent inhibitors of HIV-1 replication in acutely infected cells, it was recently shown that some ingenol derivatives enhance HIV-1 replication in chronically infected cells, whether or not through activation of the nuclear factor kB (NF-kB) and protein kinase C (PKC). 

The flavonoid crysin and benzothiophenes have been shown to inhibit casein kinase II (CKII), a cellular protein that may regulate HIV-1 transcription by phosphorylating (other) cellular proteins involved in the HIV-1 transcription transactivation process. This mechanism of action is independent of the nuclear factor kB-driven transcription pathway. Thus, flavonoids interfere with HIV-1 transcription and hence prevent HIV expression in latently infected cells. Their specificity and usefulness as HIV transcription inhibitors remain to be assessed. 

Singh, S. et al.. Capsaicin is a potent inhibitor of nuclear transcription factor-KB activation by diverse agents, J. Immunol, 157, 4412, 1996. 

The interaction of NF-kB with IkB provides a wealth of examples of several different kinds of order-disorder processes. This work was started in our lab as a collaboration with Dr. E.A. Komives at the University of California, San Diego. Nuclear factor-kappaB (NF-kB) is a dimeric transcription factor widely employed for the transcription of stress-response genes, as it binds to kB upstream enhancer DNA sequences, where it recruits the transcriptional activator CBP. In an unstressed cell, the majority of the NF-kB resides in the cytoplasm, in complex with the inhibitor of NF-kB (IkB). Response to stress involves phosphorylation and ubiquitination of IkB and its subsequent degradation by the proteasome. The free NF-kB is transported to the nucleus, where it binds to the kB enhancer sequences and mediates the transcription of genes that include that of IkB, which acts subsequently to remove NF-kB from the DNA and return it to the cytoplasm as the NF-kB-IkB complex. 

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