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Bioactive Flavonoids and Catechols as Hif1 and Nrf2 Protein Stabilizers - Implications for Parkinson's Disease.
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.
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  • Smirnova NA; 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.
  • Kaidery NA; 3Departments of Pharmacology, Toxicology & Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
  • Hushpulian DM; 2D. Rogachev Federal Scientific and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Moscow 117997, Russia; 4ValentaPharm, Moscow 119530, Russia.
  • Rakhman II; 1Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605, USA.
  • Poloznikov AA; 2D. Rogachev Federal Scientific and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Moscow 117997, Russia.
  • Tishkov VI; 5Department of Chemical Enzymology, Moscow State University, Moscow 119992, Russia.
  • Karuppagounder SS; 1Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605, USA.
  • Gaisina IN; 6Department of Medicinal Chemistry and Pharmacology, University of Illinois at Chicago, Chicago, IL 60612, USA.
  • Pekcec A; 7Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Leyen KV; 7Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Kazakov SV; 8Department of Chemistry and Physical Sciences, Dyson College, Pace University, Pleasantville, NY 10570, USA.
  • Yang L; 3Departments of Pharmacology, Toxicology & Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
  • Thomas B; 3Departments of Pharmacology, Toxicology & Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
  • Ratan RR; 1Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605, USA.
  • Gazaryan IG; 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, US
Aging Dis ; 7(6): 745-762, 2016 Dec.
Article en En | MEDLINE | ID: mdl-28053825
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 in silico 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Aging Dis Año: 2016 Tipo del documento: Article País de afiliación: Rusia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Aging Dis Año: 2016 Tipo del documento: Article País de afiliación: Rusia Pais de publicación: Estados Unidos