Lactoferrin Has a Therapeutic Effect via HIF Inhibition in a Murine Model of Choroidal Neovascularization

Ibuki, Mari; Shoda, Chiho; Miwa, Yukihiro; Ishida, Ayako; Ohta, Michio

doi:10.3389/fphar.2020.00174

Cited by 24 publications

(42 citation statements)

References 35 publications

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“…We examined whether AHX suppresses HIF downstream-target hypoxia-responsive gene expressions under CoCl 2 -induced hypoxic conditions ( Figure 3 ). After 6 h incubation of 200 µM CoCl 2 in 661W cells, the downregulation of Hif-1 α mRNA expression was detected due to a negative feedback from the post-translational HIF-1α protein modification ( Figure 3 A) [ 9 , 29 ]. We could not detect alteration of Hif-2 α mRNA expression ( Figure 3 B).…”

Section: Resultsmentioning

confidence: 99%

“…We could not detect alteration of Hif-2 α mRNA expression ( Figure 3 B). CoCl 2 induced the upregulation of Vegf , Bnip3 and Pdk1 mRNA expressions as a result of HIF-1α activation ( Figure 3 C–E) [ 9 , 29 ]. The upregulated mRNA expressions, especially Vegf and Pdk1 , were suppressed by AHX treatment ( Figure 3 C,E).…”

Section: Resultsmentioning

confidence: 99%

“…In our OIR model, we previously demonstrated no alteration in Hif-2α mRNA expression and a slight increase in Hif-2α protein expression in the retina while Hif-1α mRNA and Hif-1α protein expressions showed dramatic increases with statistical significances [ 11 ]. In addition, we found a significant reduction in neovascularization in the choroid in neural retina specific- Hif-1α conditional knockout mice in comparison with that in control mice [ 29 ]. In this study, we demonstrated that Hif-1α in retinal neuronal cells could be responsive to hypoxic stress but Hif-2α could not.…”

Section: Discussionmentioning

confidence: 99%

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A Fairy Chemical Suppresses Retinal Angiogenesis as a HIF Inhibitor

Lee

Miwa

et al. 2020

Biomolecules

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Neovascular retinal degeneration is a leading cause of blindness in advanced countries. Anti-vascular endothelial growth factor (VEGF) drugs have been used for neovascular retinal diseases; however, anti-VEGF drugs may cause the development of chorioretinal atrophy in chronic therapy as they affect the physiological amount of VEGF needed for retinal homeostasis. Hypoxia-inducible factor (HIF) is a transcription factor inducing VEGF expression under hypoxic and other stress conditions. Previously, we demonstrated that HIF was involved with pathological retinal angiogenesis in murine models of oxygen-induced retinopathy (OIR), and pharmacological HIF inhibition prevented retinal neovascularization by reducing an ectopic amount of VEGF. Along with this, we attempted to find novel effective HIF inhibitors. Compounds originally isolated from mushroom-forming fungi were screened for prospective HIF inhibitors utilizing cell lines of 3T3, ARPE-19 and 661W. A murine OIR model was used to examine the anti-angiogenic effects of the compounds. As a result, 2-azahypoxanthine (AHX) showed an inhibitory effect on HIF activation and suppressed Vegf mRNA upregulation under CoCl2-induced pseudo-hypoxic conditions. Oral administration of AHX significantly suppressed retinal neovascular tufts in the OIR model. These data suggest that AHX could be a promising anti-angiogenic agent in retinal neovascularization by inhibiting HIF activation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Fairy Chemical Suppresses Retinal Angiogenesis as a HIF Inhibitor

Lee

Miwa

et al. 2020

Biomolecules

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“…Fold changes between levels of different transcripts were calculated by the ∆∆C T method. Protein extraction, electrophoresis and visualization of protein bands were performed as the same as previously described in our papers [15][16][17]20]. Antibodies used were anti-HIF-1α (1:1000, Cat #36169, Cell Signaling Technology, Danvers, MA, USA), anti-HIF-2α (1:1000, Cat #NB100-122, Novus Biologicals, Centennial, CO, USA) and anti-β-Actin (1:5000, #3700, Cell Signaling Technology, Danvers, MA, USA).…”

Section: Quantitative Pcr and Western Blottingmentioning

confidence: 99%

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

Ibuki

Lee

Shinojima

et al. 2020

IJMS

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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.

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“…It has also been shown that lactoferrin, a type of glycoprotein, contained in exocrine fluids such as tears, breast milk, sweat and saliva, applied topically to the eyeball has a therapeutic effect in the mouse model of a dry eye. Studies have confirmed that the administration of lactoferrin had a significant inhibitory effect on HIF in retinal neuronal cells [10]. In 2019 search for new targeted therapies in the AMD studies also focus on genome editing by CRISPR/Cas9 viral delivery, which may include a new treatment option for inherited and acquired eye diseases.…”

Section: Description Of the State Of Knowledgementioning

confidence: 99%

Targeted therapy in age-related macular degeneration (AMD)

Szumna

Piędel

Rocka

et al. 2020

J Educ Health Sport

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Introduction and purpose: Age-related macular degeneration (AMD) is a major cause of blindness in highly developed countries, with blindness frequency of 8.7%. This article is a review of the latest therapeutic options for AMD.A brief description of the state of knowledge: AMD is a multifactorial disease which etiology is not completely understood. Its development is affected by disorders at the cellular level, environmental and genetic factors. Intraocular injections of anti-VEGF agents are currently considered as the basis of AMD neovascular treatment. In the search for better and better therapeutic agents, the effects of administration of bevacizumab and ranizumab were tested. Many clinical studies confirm long-term and effective improvement in patients' vision after using the above-mentioned drugs, indicating that the initial response to treatment and the persistence of the therapeutic effect is individually variable and may be associated with genotypic difference. Another promising alternative to AMD treatment is the use of specific viral vectors that transfer substances slowing down the disease into the vitreous. Another method of gene therapy is the use of HIF transcription factors (hypoxia-induced factors), for now, the research is performed on animal models. Patients with dry AMD also have a chance for successful treatment. Examined gene therapy in dry form of AMD, including retinal surgery combined with viral vector injection, is in I/II phase study in Great Britain. Conclusions: Looking at the number of blindness cases in highly developed countries caused by AMD, every effort should be made to introduce effective treatment that at least inhibits disease progression. Undoubtedly, more research is needed to confirm the efficacy and long-term safety of AMD.

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Lactoferrin Has a Therapeutic Effect via HIF Inhibition in a Murine Model of Choroidal Neovascularization

Cited by 24 publications

References 35 publications

A Fairy Chemical Suppresses Retinal Angiogenesis as a HIF Inhibitor

A Fairy Chemical Suppresses Retinal Angiogenesis as a HIF Inhibitor

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

Targeted therapy in age-related macular degeneration (AMD)

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