9E Health-Promoting Effects of Wine Phenolics 575
the redox-sensitive activation of the p38 MAPK pathway (Oak et al. 2003), while
MMP activity was reduced via direct inhibition of MT1-MMP activity, the phys-
iological activator of pro-MMP-2 (Oak et al. 2004; El Bedoui et al. 2005; Zhen
et al. 2006). Polyphenol-mediated inhibition of metastasis-specific MMPs in tumor
cells has been associated with the inhibition of activation of MAPK and nuclear
factor-B(NF-B) pathways (Vayalil et al. 2004).
NF-B is a transcription factor that plays a key role in various physiological
processes and human diseases (Karin and Greten 2005; Hoffmann et al. 2006). It
consists of different hetero- and homodimer proteins (RelA (p65), RelB, c-Rel,
p50, and p52), with the RelA:p50 heterodimer acting as the primary mediator of
NF-B transcriptional activity. Four IB proteins have been described in the NF-B
signaling module: IB ,- ,and-, and nfb2/p100 (Basak et al. 2007; Hoffmann
et al. 2006). Different stimuli that activate NF-B mediate the phosphorylation of
IB through several IB kinases (IKKs), and in this way IB becomes a target
for ubiquitination and subsequent proteasomal degradation. IB degradation leads
to the release from the cytosol of retained NF-B dimers, which then migrate to
the nucleus to exert transcriptional activity (Gilmore 2006; Hoffmann et al. 2006;
Karin and Ben-Neriah 2000). NF-B controls the expression of molecules impli-
cated in most inflammatory processes, including pro-inflammatory cytokines and
chemokines(IL-1,2,6,8,TNF , MCP-1, etc.), adhesion molecules (E-selectin,
ICAM, VCAM, etc.), and several other proteins (Hoffmann et al. 2006). Data from
in vitro models have shown that different polyphenols reduce NF-B DNA bind-
ing activity induced by different stimuli (Nam 2006; Schubert et al. 2002; Terra
et al. 2007). Our group and others have demonstrated that supplementation with a
source of polyphenols such as grape juice or red wine reduces serum/plasma lev-
els of MCP-1, VCAM, and ICAM (Blanco-Colio et al. 2007; Castilla et al. 2006;
Estruch et al. 2004). The mechanism involved in this effect may be through the
NF-B pathway. In vivo, ingestion of polyphenols from different sources, including
red wine, has been shown to effectively decrease NF-B activation in mononuclear
cells (Blanco-Colio et al. 2000, 2007; Davis et al. 2001). Concerning the mecha-
nism underlying these effects, it has been reported that certain polyphenols, but not
common dietary antioxidants, inhibit IKK activity induced by different stimuli and
p65 phosphorylation (Ukil et al. 2006; Wheeler et al. 2004; Yang F et al. 2001).
Inhibition of MAPK-mediated activation of NF-B has also been proposed as the
mechanism responsible for the effects of certain polyphenols (Hou et al. 2007;
Lee et al. 2006).
9E.3 NADPH Oxidase
Overproduction of superoxide (•O
−
2 ) has been implicated in the pathogenesis of
various cardiovascular diseases. The main sources of human superoxide include the
nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) enzyme
complex, cyclooxygenase, mitochondrial oxidases, xanthine oxidase, and nitric