Rice Bran and Vitamin B6 Suppress Pathological Neovascularization in a Murine Model of Age-Related Macular Degeneration as Novel HIF Inhibitors

Abstract

Pathological neovascularization in the eye is a leading cause of blindness in all age groups from retinopathy of prematurity (ROP) in children to age-related macular degeneration (AMD) in the elderly. Inhibiting neovascularization via antivascular endothelial growth factor (VEGF) drugs has been used for the effective treatment. However, anti-VEGF therapies may cause development of chorioretinal atrophy as they affect a physiological amount of VEGF essential for retinal homeostasis. Furthermore, anti-VEGF therapies are still ineffective in some cases, especially in patients with AMD. Hypoxia-inducible factor (HIF) is a strong regulator of VEGF induction under hypoxic and other stress conditions. Our previous reports have indicated that HIF is associated with pathological retinal neovascularization in murine models of ROP and AMD, and HIF inhibition suppresses neovascularization by reducing an abnormal increase in VEGF expression. Along with this, we attempted to find novel effective HIF inhibitors from natural foods of our daily lives. Food ingredients were screened for prospective HIF inhibitors in ocular cell lines of 661W and ARPE-19, and a murine AMD model was utilized for examining suppressive effects of the ingredients on retinal neovascularization. As a result, rice bran and its component, vitamin B6 showed inhibitory effects on HIF activation and suppressed VEGF mRNA induction under a CoCl2-induced pseudo-hypoxic condition. Dietary supplement of these significantly suppressed retinal neovascularization in the AMD model. These data suggest that rice bran could have promising therapeutic values in the management of pathological ocular neovascularization.

Fenofibrate Protects against Retinal Dysfunction in a Murine Model of Common Carotid Artery Occlusion-Induced Ocular Ischemia

“…Extraction of total retinal protein and electrophoresis followed by visualization of target bands were conducted as same as described in our previous papers [ 19 , 35 , 36 , 68 , 69 ]. Primary antibodies that we used in this study are anti-HIF-1α (1:500, Cat #36169, Cell Signaling Technology, Danvers, MA, USA), anti-synaptophysin (1:1000, Cat #SAB4502906, Sigma, Tokyo, Japan), and anti-β-Actin (1:5000, #3700, Cell Signaling Technology, USA).…”

Hypoxia-Mediated Complement 1q Binding Protein Regulates Metastasis and Chemoresistance in Triple-Negative Breast Cancer and Modulates the PKC-NF-κB-VCAM-1 Signaling Pathway

“…Both the mRNA and protein levels of C1QBP increased under hypoxic conditions and decreased upon treatment with the HIF-1α inhibitor as expected ( Figure 1E ). Accordingly, we further detected the protein level of vascular endothelial growth factor (VEGF), von Hippel-Lindau tumor suppressor (VHL), E-cadherin 1 (E-cad), and β-tubulin, that are reported to be regulated by hypoxia and/or HIF-1α ( Bordji et al, 2014 ; Ning et al, 2018 ; Ibuki et al, 2020 ; Urrutia et al, 2020 ; Yang et al, 2020 ) ( Supplementary Figure 2B ). Based on the data from the JASPAR database, we generated several primers for HIF-1α containing multiple binding sites on the C1QBP promoter ( Figure 1F ).…”

Retinal Diseases Regulated by Hypoxia—Basic and Clinical Perspectives: A Comprehensive Review

“…Ibuki et al, discovered several HIF inhibitors through extensive screenings of food ingredients, and found that a diet containing these ingredients was effective in reducing the risk of laser-induced CNV in mice [ 38 , 39 , 40 ]. Furthermore, treatment of these ingredients/compounds reduced V egf mRNA expression as well as HIF activation under CoCl 2 -induced pseudo hypoxic conditions [ 38 , 39 , 40 ].…”

“…Ibuki et al, discovered several HIF inhibitors through extensive screenings of food ingredients, and found that a diet containing these ingredients was effective in reducing the risk of laser-induced CNV in mice [ 38 , 39 , 40 ]. Furthermore, treatment of these ingredients/compounds reduced V egf mRNA expression as well as HIF activation under CoCl 2 -induced pseudo hypoxic conditions [ 38 , 39 , 40 ]. Otherwise, Lee et al found that resveratrol significantly reduced the expression of HIF-1α and VEGF-A in human ARPE19 cells and CNV mouse models by inhibiting the PI3K/AKT/mTOR signaling pathway, which promotes proteasome-mediated degradation of HIF-1α.…”