Flavonoids are able to modulate proinflammatory signaling pa

Flavonoids are able to modulate proinflammatory signaling pathways to prevent OS and apoptosis [139]. Paraoxygenase-2 (PNO2) is an enzyme involved in neuroprotection by preventing OS mediated damage in mitochondria. Flavonoids can modulate the JNK/AP-1 pathway to increase expression of PNO2 [111]. Flavonoids are able to inhibit expression of TNF-α by modulating NF-κB, inducing expression of antioxidant molecules like PNO2. PNO2 is primarily located in the mitochondria. PNO2 exerts its neuroprotection primarily through protecting against mitochondrial mediated oxidative stress [112]. Flavonoids can directly scavenge free radicals, but they have limited accessibility to the brain; antioxidant concentration in the calmodulin dependent protein kinase is too low to have a significant impact on direct scavenging. Flavonoids exert their protective effects by modulation of cell signaling pathways and activation of cellular antioxidant defense mechanisms [112]. Flavonoids also inhibit AGE formation by preventing formation/presence of dicarbonyl compounds, and also attenuate damage [118]. Flavonoids were found to reduce MG mediated OS, and enhance the glyoxalase pathway activity [126].
Conclusion The glyoxalase pathway is an integral part of the body's antioxidant system. Dysregulation can have deleterious and catastrophic events, leading to high levels of OS, and also neurodegenerative disease. This seemingly innocuous pathway found in all cells of our body can be responsible for production and formation of toxic intermediaries that alter a cell's normal function and leading to Alzheimer's disease, Parkinson's disease, ASD and Aging. Flavonoids were found to be involved in the reduction of oxidative stress through mechanisms regulated by the glyoxalase pathway. Flavonoid compounds have shown the ability to scavenge ROS and regulate cell signaling pathways integral for antioxidant defense mechanisms and cellular survival. The glyoxalase pathway is a promising drug target for neurodegenerative diseases. Drug discovery [4], [140], [141], [142], [143], [144] and delivery [145], [146], [147] processes could be explored in this target against neurodegenerative diseases. Novel flavonoids could be designed, synthesized, and tested to protect neurodegenerative diseases through glyoxalase pathway.
Acknowledgements Funding is supported in part by a Nebraska Research Initiative Award (2014) to PN.
Introduction Glyoxalase I (GLO I) is a key enzyme in pathways leading to the detoxification of methylglyoxal (MG), one of the side-products of glycolysis, which is highly reactive with DNA and proteins, and thereby induces apoptosis. GLO I catalyzes the conversion of cytotoxic MG (as the glutathione (GSH) thiohemiacetal) to nontoxic S-d-lactoylglutathione.2, 3 This enzyme system is ubiquitously distributed in all mammalian cells and is involved in tissue maturation and cell death. Importantly, abnormal expression or higher activity of GLO I has been demonstrated in many human tumors including colon, prostate and lung.5, 6, 7 Moreover, GLO I has been shown to be highly expressed in antitumor agent-resistant human leukemia cells. These observations indicate that the increase of GLO I expression is closely associated with carcinogenesis5, 6, 7 and drug resistance. Thus, the inhibitors of GLO I are expected to offer possibilities for inhibiting carcinogenesis and overcoming drug resistance by the mechanism of accumulations of apoptosis-inducible MG in tumor cells. Berry fruits, such as bilberry, blackberry, black raspberry and cranberry, are widely consumed in our diet and have attracted much attention by their potential human health benefits. They have been shown to be rich sources of phytochemicals with the potential to prevent human cancers.10, 11, 12 Delphinidin, the major anthocyanidin present in berry fruits, has been shown to possess strong antioxidant, anti-inflammatory and anticancer effects.13, 14 However, the mechanism of the anticancer effect has not yet been fully elucidated.