Signaling pathways, modulation

Encarnacion, M., Warner, G., Gray, C, Cheng, J., Keryakos, H., Nath, K., and Grande, J. (2008). Signaling pathways modulated by fish oil in salt-sensitive hypertension. Am. ]. Physiol. Renal Physiol. 294, F1323-F1335. 

Zhao, W.-N., Cheng, C., Theriault K.M. et al (2012) A high-throughput screen for Wnt/p-catenin signaling pathway modulators in human iPSC-derived neural progenitors. Journal of Biomolecular Screening, 17 (9), 1252-1263. 

Mironov SL, Richter DW. Intracellular signalling pathways modulate K(ATP) channels in inspiratory brainstem neurones and their hypoxic activation involvement of metabotropic receptors, G-proteins and cytoskeleton. Brain Res 2000 853 60-67. Cummins TR, Jiang C, Haddad GG. Human neocortical excitability is decreased during anoxia via sodium channel modulation. J Clin Invest 1993 91 608-615. Mironov SL, Richter DW. Cytoskeleton mediates inhibition of the fast Na+ current in respiratory brainstem neurons during hypoxia. Eur J Neurosci 1999 11 1831-1834. Mironov SL, Richter DW. Oscillations and hypoxic changes of mitochondrial variables in neurons of the brainstem respiratory centre of mice. J Physiol 2001 533 227-236. Mazza E Jr, Edelman NH, Neubauer JA. Hypoxic excitation in neurons cultured fi om the rostral ventrolateral medulla of the neonatal rat. J Appl Physiol 2000 88 2319-2329. 

In the case that the functional cellular target of the lead hits is known and validated, determine the in vitro biochemical half-maximal inhibitory concentrations (IC50) with an accepted assay method. If the capacity for generating this data does not exist institutionally, many fee-for-service resources are available. Without a known target but knowledge of the signaling pathway modulated by the lead hits, a cellular reporter assay can be used in lieu of a biochemical assay however, it is important to keep in mind that compensatory and multimodal effects can confound SAR efforts in cellular systems. These on-target biochemical and cellular assay profiles will serve as potency benchmarks for later SAR and optimization studies. 

Altogether, there is strong evidence that carotenoids can exert multiple effects via modulation of signaling pathways. Because oxidative stress can easily degrade carotenoids, it is not enough to investigate the effects of intact carotenoids, but it is necessary to elucidate the effects of their degradation products as well. 

Palozza, P, Serini, S, and Calviello, G, 2006. Carotenoids as modulators of intracellular signaling pathways. Curr Signal Transduct Ther 1, 325-335. 

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