Bioactive Flavonoids and Catechols as Hif1 and Nrf2 Protein Stabilizers - Implications for Parkinson's Disease

Flavonoids are known to trigger the intrinsic genetic adaptive programs to hypoxic or oxidative stress via estrogen receptor engagement or upstream kinase activation. To reveal specific structural requirements for direct stabilization of the transcription factors responsible for triggering the antih...

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Published in:Aging and disease 2016-12, Vol.7 (6), p.745-762
Main Authors: Smirnova, Natalya A, Kaidery, Navneet Ammal, Hushpulian, Dmitry M, Rakhman, Ilay I, Poloznikov, Andrey A, Tishkov, Vladimir I, Karuppagounder, Saravanan S, Gaisina, Irina N, Pekcec, Anton, Leyen, Klaus Van, Kazakov, Sergey V, Yang, Lichuan, Thomas, Bobby, Ratan, Rajiv R, Gazaryan, Irina G
Format: Article
Language:English
Subjects:
Antioxidants (Nutrients)
Care and treatment
Catechin
Development and progression
DNA binding proteins
Estrogens
Flavonoids
Health aspects
Isoflavones
Journalists
L-dopa
Luciferase
Original
Oxidative stress
Parkinson disease
Phenols (Class of compounds)
Physiological aspects
Resveratrol
Transcription factors
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Summary:Flavonoids are known to trigger the intrinsic genetic adaptive programs to hypoxic or oxidative stress via estrogen receptor engagement or upstream kinase activation. To reveal specific structural requirements for direct stabilization of the transcription factors responsible for triggering the antihypoxic and antioxidant programs, we studied flavones, isoflavones and catechols including dihydroxybenzoate, didox, levodopa, and nordihydroguaiaretic acid (NDGA), using novel luciferase-based reporters specific for the first step in HIF1 or Nrf2 protein stabilization. Distinct structural requirements for either transcription factor stabilization have been found: as expected, these requirements for activation of HIF ODD-luc reporter correlate with binding to HIF prolyl hydroxylase. By contrast, stabilization of Nrf2 requires the presence of 3,4-dihydroxy- (catechol) groups. Thus, only some but not all flavonoids are direct activators of the hypoxic and antioxidant genetic programs. NDGA from the Creosote bush resembles the best flavonoids in their ability to directly stabilize HIF1 and Nrf2 and is superior with respect to LOX inhibition thus favoring this compound over others. Given much higher bioavailability and stability of NDGA than any flavonoid, NDGA has been tested in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-animal model of Parkinson's Disease and demonstrated neuroprotective effects.
ISSN:2152-5250
2152-5250
DOI:10.14336/ad.2016.0505