Inhibition mechanisms, protein kinase

There are several mechanisms involved in the vasodilator effect of flavonoids. The main mechanism seems to be related to the inhibition of protein kinase C or some of the processes activated by this protein. The inhibition of other protein kinases and cyclic nucleotide phosphodiesterase activity and blockage of calcium entry can also contribute to this effect to a greater or lesser extent (Alvarez Castro and Orallo, 2003 Herrera and others 1996). Certain flavonoids, like the flavonol myricetin, have a two-phase action on blood vessels vasoconstrictor in lowest active concentrations and vasodilator in higher concentrations (Alvarez Castro and Orallo, 2003). 

Furthermore, the expression and function of the Pgp can be modulated by indirect mechanisms, such as interactions with membrane lipids [67] or inhibition of protein kinase C. The reversal of MDR is established using tumor cells lines that are made resistant by the exposure to an anticancer agent or by transfection of the mdrl or mrpl genes. The parameter most widely used to show the activity of MDR reversal agents is reversal factor (RF). This type of assay assumes that the reversal agent does not show inherent cytotoxicity at the concentrations tested. 

Apigenin, a flavonoid found in chamomile, has been found to suppress 12-G-tetradecanoyl-phorbol- l 3-acetate (TPA)-induced tumor promotion in mouse skin. Inhibition of protein kinase C, and thus protooncogene expression, by competing with ATP is the proposed mechanism of action (Huang et al.,... 

Activation of G-protein-coupled receptors. There are many routes by which ligandbinding to G-protein-coupled receptors can transmit signals to the ERK pathway (review Liebmann, 2001), and activation of the ERK pathway is frequently observed upon ligand binding to G-protein-coupled receptors. A main entry point is the Raf kinase, which can be activated by protein kinase C and inhibited by protein kinase A. As outlined in Sections 7.3 and 7.4, both enzyme families can be activated via G-protein-signaling pathways by multiple mechanisms. 

Inhibition of protein kinases has been a powerful tool to study signal transduction pathways. It is easily achieved by inhibitors such as staurosporine. However, staurosporine inhibits a broad spectrum of kinases, therefore it is not suited for therapeutic purposes [11], As the understanding of kinase mechanism and inhibition has advanced in the past years, there is now an increasing number of kinase inhibitors that are specific for one particular kinase. The discovery of such specific inhibitors has in turn enhanced our understanding of kinase action and signal transduction pathways. 

Some investigators have employed the enhancement of vascular tone in vivo after treatment with these drugs to inhibit amine reuptake where the flavonoids act as antagonists of plasma membrane amine transporters [104]. The vasodilatory mechanism of flavonoids seems to be mediated by the inhibition of protein kinase C [105]. Oilier recent studies on the potential vasorelaxant, antioxidant, and cyclic nucleotide phosphodiesterase (PDE) inhibitory effects of the citrus-fruit flavonoids nar-ingenin and hesperetin in intact rat aortic rings have shown that their vasorelaxant effects were mediated by the inhibition of different PDE isoenz5Tnes [106,107]. 

High vitamin E intakes are associated with an increased tendency to bleed. It is not known if this is a result of decreased platelet aggregation caused by an inhibition of protein kinase C by a-tocopherol, some other platelet-related mechanism, or decreased clotting due to a vitamin K and E interaction causing abnormal blood clotting. 

The OP group of receptois share common effector mechanisms. All receptois couple via pertussis toxin-sensitive Go and Gi proteins leading to (i) inhibition of adenylate cyclase (ii) reduction of Ca2+ currents via diverse Ca2+ channels (hi) activation of inward rectifying K+ channels. In addition, the majority of these receptors cause the activation of phospholipase A2 (PLA2), phospholipase C 3 (PLC 3), phospholipase D2 and of MAP (mitogen-activated protein) kinase (Table 3). 

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