title: Bioactive Flavonoids and Catechols as Hif1 and Nrf2 Protein Stabilizers - Implications for Parkinson's Disease.
abstract: 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 within silicobinding 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.
authors.affiliation: 1Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605, USA; 2D. Rogachev Federal Scientific and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Moscow 117997, Russia.
authors.forename: Natalya A
authors.initials: NA
authors.lastname: Smirnova
authors.affiliation: 3Departments of Pharmacology, Toxicology & Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Navneet Ammal
authors.initials: NA
authors.lastname: Kaidery
authors.affiliation: 2D. Rogachev Federal Scientific and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Moscow 117997, Russia; 4ValentaPharm, Moscow 119530, Russia.
authors.forename: Dmitry M
authors.initials: DM
authors.lastname: Hushpulian
authors.affiliation: 1Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605, USA.
authors.forename: Ilay I
authors.initials: II
authors.lastname: Rakhman
authors.affiliation: 2D. Rogachev Federal Scientific and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Moscow 117997, Russia.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Poloznikov
authors.affiliation: 5Department of Chemical Enzymology, Moscow State University, Moscow 119992, Russia.
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Tishkov
authors.affiliation: 1Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605, USA.
authors.forename: Saravanan S
authors.initials: SS
authors.lastname: Karuppagounder
authors.affiliation: 6Department of Medicinal Chemistry and Pharmacology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Irina N
authors.initials: IN
authors.lastname: Gaisina
authors.affiliation: 7Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Pekcec
authors.affiliation: 7Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Klaus Van
authors.initials: KV
authors.lastname: Leyen
authors.affiliation: 8Department of Chemistry and Physical Sciences, Dyson College, Pace University, Pleasantville, NY 10570, USA.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Kazakov
authors.affiliation: 3Departments of Pharmacology, Toxicology & Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Lichuan
authors.initials: L
authors.lastname: Yang
authors.affiliation: 3Departments of Pharmacology, Toxicology & Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Bobby
authors.initials: B
authors.lastname: Thomas
authors.affiliation: 1Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605, USA.
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Ratan
authors.affiliation: 1Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605, USA; 5Department of Chemical Enzymology, Moscow State University, Moscow 119992, Russia; 8Department of Chemistry and Physical Sciences, Dyson College, Pace University, Pleasantville, NY 10570, USA.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Gazaryan
keywords: HIF prolyl hydroxylase; Keap1; Parkinson’s disease model; fisetin; glutathione depletion model; lipoxygenase; luteolin