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 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.

Lysyl oxidase induces epithelial‐mesenchymal transition and predicts intrahepatic metastasis of hepatocellular carcinoma

“…In addition, Erler et al and Reynaud et al showed that LOX expression was increased by HIF‐1α in the intratumoral hypoxic condition, and resulted in distant metastasis or bone metastasis. In the current study, comprehensive analysis using a large HCC transcriptome matrix showed that high LOX expression correlates with the expression of HIF‐1α and the hypoxia pathway.…”

“…This result may suggest that early recurrence mainly occurred from IM recurrence. On the other hands, LOX expression in the background liver may influence tumorigenesis by MC and develop the late recurrence.In addition, Erler et al and Reynaud et al33,[40][41][42][43] showed that LOX expression was increased by HIF-1α in the intratumoral hypoxic condition, and resulted in distant metastasis or bone metastasis. In the current study, comprehensive analysis using a large HCC transcriptome matrix showed that high LOX expression correlates with the expression of HIF-1α and the hypoxia pathway.…”

Floridoside Exhibits Antioxidant Properties by Activating HO-1 Expression via p38/ERK MAPK Pathway

“…Nuclear factor-erythroid-2-related factor 2 (Nrf2)/antioxidant response element (ARE) antioxidant pathway is the most important endogenous antioxidant signaling pathway discovered so far [19,20]. Many antioxidants, such as flavonoids, polyphenols, and carotenoids, can exert antioxidant effects by activating this pathway [21][22][23]. However, it still remains unknown whether floridoside can also activate such pathway.…”

Brief Challenges on Medicinal Plants: An Eye‐Opening Look at Ageing‐Related Disorders

“…The activity of Nrf2 is primarily regulated via its interaction with Keap1 (Kelch‐like ECH‐associated protein 1), which directs the transcription factor for proteasomal degradation. Phytochemicals are also good activators of the Nfr2 activity , and this ability makes phytochemicals able to prevent cell ageing‐related disorders . In this sense, the indirect antioxidant activity of natural products resulting in the production cytoprotective proteins (phase 2 enzymes) and endogenous direct antioxidants seems to be more important than their direct antioxidant activity.…”