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Schematic representation of interaction of flavonoids with cell signalling pathways. As shown in figure, flavonoids activate various signalling pathways such as ERK, Akt/PKB, PI3K, and PKC to improve the cell survival. The symbol arrows show the activation, and the symbol box drawings light up and horizontal show deactivation of various signalling pathways. ERK extracellular signal-regulated protein kinase; JNK c-Jun N-terminal kinase; PI3K phosphatidylinositol-3 kinase; PKC protein kinase C; Akt/PKB protein kinase B; ARE antioxidant response element; CREB cAMP response element-binding protein; Nrf2 nuclear factor (erythroid-derived 2)-like 2; PM plasma membrane
Quercetin, a most abundant flavonoid found in many fruits and vegetables and EGCG, abundantly found in green tea, both inhibited H2O2-induced phosphorylation of JNK and p38 MAPK pathway after 60 min of exposure. Both quercetin and EGCG also inhibit H2O2-induced caspase-3 activation at the concentrations between 1 and 50 μM/L (Choi et al. 2005). Thus, MAPK-related signalling may regulate expression of apoptotic genes, preventing apoptosis, and promoting cell survival. Another observation demonstrates that EGCG at the concentrations between 5 and 25 μM/L inhibits angiotensin II-induced endothelial stress fibre formation and hyperpermeability via inactivation of p38/heat shock protein 27 (HSP27) pathway and suggests that EGCG may protect against endothelial barrier dysfunction and injury (Yang et al. 2010).
The flavonoids hesperetin and its structural counterparts, isorhamnetin, and isosakuranetin differentially activated pro-survival signalling molecules, including PI3K/Akt and other protein kinases. In nervous tissues, the hesperetin (100 nmol/L) and its metabolites 5-nitro-hesperetin were effective at preventing neuronal apoptosis via a mechanism involving both Akt/PKB activation/phosphorylation and also via an activation of ERK1/2 (Vauzour et al. 2007).
Myricetin induces cell survival via signal transduction pathway involving Akt activation. Cells induced with H2O2-induced apoptosis were rescued by myricetin (30 μM) treatment, and this survival mechanism was inhibited by the specific PI3K inhibitor (Kyoung et al. 2010). These observations suggest that PI3K/Akt and MAPK are the main signalling pathways by which myricetin prevents oxidative stress-induced apoptosis (Kyoung et al. 2010).
Brain injury induces acute inflammation, thereby exacerbating poststroke neuronal damage.1, 2, 3, 4 Although central nervous system (CNS) is known for its limited reparative capacity, inflammation is a strong stimulus for reparative mechanisms including activation of neurogenesis. However, the latter results in low survival of newly generated neural stem cells.5 These findings indicate the relevance of endogenous regulatory and/or environmental factors for survival and differentiation of neural stem cells.
HIF-1α stabilization and NF-κB activation may also have a role in promoting the survival of cancer cells, angiogenesis, neovascularization, glycolytic ATP generation, and tumor invasion. Therefore, hypoxia-induced mROS may promote cancer development and progression. However, overgeneration of mROS, occurring after mGSH depletion or by blocking mitochondrial respiration (84, 114), may sensitize tumor cells by inhibiting the NF-κB survival pathway (Fig. 8). Because hypoxia is expected to affect predominantly cells from solid tumors, more than cells from healthy tissues, the combination of mGSH depletion, or strategies that increase mROS, and hypoxia may be an interesting approach in cancer therapy that deserves further study.
mGSH depletion sensitizes tumor cells to hypoxia. HIF-1α stabilization and NF-κB activation participate in promoting survival of cancer cells under hypoxic conditions. However, overgeneration of mitochondrial ROS, as obtained after mGSH depletion, may sensitize tumor cells by inhibiting the NF-κB survival pathway, despite HIF stabilization.
In addition to marshalling immune and inflammatory responses, transcription factors of the NF-κB family control cell survival. This control is crucial to a wide range of biological processes, including B and T lymphopoiesis, adaptive immunity, oncogenesis and cancer chemoresistance. During an inflammatory response, NF-κB activation antagonizes apoptosis induced by tumor necrosis factor (TNF)-α, a protective activity that involves suppression of the Jun N-terminal kinase (JNK) cascade. This suppression can involve upregulation of the Gadd45-family member Gadd45β/Myd118, which associates with the JNK kinase MKK7/JNKK2 and blocks its catalytic activity. Upregulation of XIAP, A20 and blockers of reactive oxygen species (ROS) appear to be important additional means by which NF-κB blunts JNK signaling. These recent findings might open up entirely new avenues for therapeutic intervention in chronic inflammatory diseases and certain cancers; indeed, the Gadd45β-MKK7 interaction might be a key target for such intervention.
In multicellular organisms, cells are constantly faced with the choice of whether to live or die. The decision requires integration of a complex network of intracellular and extracellular signals, and making the right decision is essential for survival of these organisms. Programmed cell death (PCD) is crucial to tissue homeostasis, organ development and the elimination of defective or `dangerous' cells, such as cancerous and virus-infected cells (Danial and Korsmeyer, 2004; Rathmell and Thompson, 2002). Underscoring the importance of this process, numerous diseases arise from defects in the pathways controlling PCD. For instance, defective and excessive cell death respectively contribute to cancer and neurodegenerative disorders such as Alzheimer's disease (Danial and Korsmeyer, 2004; Rathmell and Thompson, 2002). Ultimately, the balance between life and death might depend on the ability of the cell to sustain activation of transcription factors of the NF-κB family.
TNFR1-induced pathways modulating apoptosis. Formation of complex I leads to NF-κB activation, Gadd45β induction, JNK inhibition and cell survival. Formation of complex II leads to caspase-8/10-mediated cleavage of Bid into tBid, which then targets mitochondria to induce cytochrome c release and, ultimately, cell death. The figure also depicts JNK activation, which results in formation of jBid; this promotes PCD by triggering release of Smac/Diablo into the cytosol, inhibiting the TRAF2-IAP1 complex and consequently activating caspase-8. The Gadd45β-MKK7 interaction linking the JNK and NF-κB pathways is also shown.
Numerous studies have shown that NF-κB has anti-apoptotic effects that have been implicated in a variety of biological processes. In the B-cell lineage, this activity is required for completion of various developmental steps, including differentiation into mature IgMlow/IgDhigh cells, as well as the response of these cells to antigen and CD40 costimulation (Gilmore et al., 2004; Gerondakis and Strasser, 2003). Likewise, during an immune reaction, survival of naive T cells depends on NF-κB activation by the T-cell receptor (TCR) and CD28 stimulation (Green, 2003; Zheng et al., 2003; Kane et al., 2002). NF-κB also plays an important pro-survival role during thymocyte development (Voll et al., 2000; Boothby et al., 1997; Esslinger et al., 1997).
The pro-survival activity of NF-κB also plays a crucial role in viral pathogenesis (reviewed by Kucharzack et al., 2003). Indeed, the need for an inducible gene expression program to maintain cell survival might have originally evolved as a mechanism for disposing of infected cells that, because of viral takeover, exhibit grossly defective transcription. Not surprisingly, many viruses have adapted to this host defense mechanism by developing their own anti-apoptotic strategies or acquiring genes that either induce or mimic NF-κB. Examples of such genes, many of which are implicated in viral oncogenesis, include: v-FLIP of human herpesvirus 8 (HHV-8), which is linked to Kaposi's sarcoma and lymphoma; Tax of HTLV-1, which causes adult T-cell leukemia (ATL); and of course v-Rel, which is encoded by the avian retrovirus REV-T (Kucharczak et al., 2003; Benedict et al., 2002).
The suppression of TNF-α-induced apoptosis by NF-κB is crucial for the survival of the organism and its response to injury. In mice lacking RelA, liver apoptosis and embryonic lethality are rescued by deletion of TNFR1 (Alcamo et al., 2001; Doi et al., 1999). The resistance to TNF-α-induced apoptosis that NF-κB confers on the liver has also been observed in adults (Chaisson et al., 2002; Maeda et al., 2003). Overactivation of NF-κB by TNF-α can be detrimental too. For instance, when caused by loss of the de-ubiquitinase CYLD, it inappropriately blocks apoptosis, thereby promoting oncogenesis (Brummelkamp et al., 2003; Kovalenko et al., 2003; Trompouki et al., 2003). NF-κB-mediated inhibition of TNFR-induced PCD is also involved in chronic inflammatory diseases (Liu and Pope, 2003) (see below).
The relevance of the JNK cascade to apoptosis signaling is highlighted by the finding that activation of this cascade is controlled by NF-κB. Indeed, suppression of NF-κB by ablation of RelA or IKKβ, or expression of IκBαM, leads to persistent (rather then transient) JNK induction by TNF-α, and it seems to be the persistence of this induction that ultimately causes the cell to succumb to PCD (De Smaele et al., 2001; Javelaud and Besancon, 2001; Tang et al., 2001) (see also Franzoso et al., 2003). Caspases can activate various MAPKKKs (Davis, 2000; Roulston et al., 1998), but the effects of NF-κB on JNK signaling are not affected by protective cell treatment with the caspase blocker z-VADfmk and so do not appear to be a secondary consequence of caspase inhibition (Javelaud and Besancon, 2001; Franzoso et al., 2003). In short, the containment of the JNK cascade is crucial for the control of TNF-α-induced apoptosis, and this critically depends on NF-κB. Curiously, although confirming the inhibitory effects of NF-κB on JNK signaling, another study has suggested that, in TNF-α-treated NF-κB-deficient cells, persistent JNK activation promotes cell survival (Reuther-Madrid et al., 2002). The bases for the discrepancy with other studies are not clear. 2b1af7f3a8