研究者詳細 - 栗原　俊英

論文 - 栗原　俊英

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Axial Length Shortened in Approximately 20% of Patients Wearing Extended Depth-of-Focus Contact Lenses

Hazra D*, Yotsukura E*, Oyama S*, Shigeno Y, Mori K, Takeuchi R, Nakajima Y, Hanyuda A, Ogawa M, Kurihara T, Torii H†, Negishi K†

J Clin Med. 14 （ 5 ） 1750 2025年03月

査読有り

Background/Objectives: Preceding studies have reported the efficacy of multifocal contact lenses (MFCLs) in slowing myopia progression. Recently, a novel type of MFCL, i.e., extended depth-of-focus (EDOF) contact lens (CL), was designed. Here, we retrospectively investigated myopia progression associated with EDOF CL wear. Methods: Twenty-four consecutive myopic children (24 eyes; mean age, 13.9 years) received EDOF CLs to control myopia progression and participated in the study. We measured the axial length (AL), spherical equivalent (SE), and choroidal thickness (CT) at baseline and after 1 year of lens wear and compared the changes. Results: The mean baseline AL, SE, and CT were, respectively, 26.31 mm, −6.38 diopter (D), and 235 μm, and at 1 year 26.40 mm (p = 0.03), −6.61 D (p = 0.05), and 244 μm (p = 0.18). The AL decreased in 20.8% of cases (≧−0.05 mm/year), whereas 20.8% and 58.4% of cases had stabilization of the AL or an increased AL (≧+0.05 mm/year), respectively. The patients with a decreased AL engaged in a mean outdoor activity time of 200.6 min/day, the patients with an increased AL (≧+0.05 mm/year) engaged in a mean outdoor activity time of 126.7 min/day. The change in the AL was correlated significantly with the change in the CT (β = −0.46, p < 0.05), and 80% of patients with a shortened AL had increased CT (≧+20 μm/year). Conclusions: Our data showed that the AL stabilized or decreased in over 40% of myopic patients wearing EDOF CLs.

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Tropism of the AAV6.2 Vector in the Murine Retina

Suzuki R*, Katada Y*, Fujii M, Serizawa N, Negishi K, Kurihara T†

Int J Mol Sci. 26 （ 4 ） 1580 2025年02月

最終著者, 責任著者, 査読有り, ISSN 16616596

Retinitis pigmentosa (RP) is a progressive inherited retinal dystrophy (IRD) that primarily affects rod photoreceptor cells, leading to the degeneration of photoreceptors and the gradual loss of vision. While RP is one of the most studied IRDs, other neurodegenerative diseases affecting the retina and optic nerve, such as glaucoma, also involve common mechanisms of cellular stress and degeneration. Current therapeutic approaches under investigation include gene therapy, retina prosthesis, and neuroprotection. Among these approaches, gene therapy has shown promise, though challenges related to viral vector tropism and transduction efficiency persist. The adeno-associated virus (AAV) vector is commonly employed for gene delivery, but novel serotypes and engineered variants are being explored to improve specificity and efficacy. This study evaluates the gene transfer efficiency of the AAV6.2 vector following intravitreal injection into the murine retina. Male C57BL/6 mice (9 weeks old) were intravitreally injected with 1 µL of AAV2-CMV-EGFP, AAV6-CMV-EGFP, or AAV6.2-CMV-EGFP at a titer of 3.2 × 1012 vg/mL per eye. Retinal transduction was assessed using in vivo fluorescence imaging, flat-mount imaging, and immunohistochemistry. EGFP expression in retinal ganglion cells, Müller cells, amacrine cells, and bipolar cells was quantitatively analyzed. All three AAV serotypes effectively transduced retinal ganglion cells, but AAV6.2 exhibited enhanced transduction in Müller cells and other neuronal retinal cells, including bipolar and amacrine cells. AAV6.2 demonstrated more localized expression around retinal blood vessels compared to the diffuse expression observed with AAV2. Immunohistochemical analysis revealed that AAV6.2 had significantly higher transduction efficiency in Müller cells (p < 0.001) compared to AAV2 and AAV6. AAV6.2 shows superior transduction efficiency in Müller cells, positioning it as a promising vector for gene therapies targeting retinal degenerative diseases such as RP. Its ability to effectively transduce Müller cells suggests potential applications in neuroprotection and gene replacement therapies.

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幼少期の強膜穿孔創から58年経過して外因性細菌性眼内炎を発症した1例

上村綾音, 伴紀充, 國見洋光, 富田洋平, 栗原俊英, 篠田肇, 根岸一乃

眼科臨床紀要 17 （ 10 ） 749 - 752 2024年12月

査読有り

Acquisition of high-sensitivity human aqueous humor Raman spectra

Shinojima A, Sawada M, Kuroda M,Lee D, Kinoshita T, Negishi K, Kurihara T†

Res Sq. 2024年10月

最終著者, 責任著者

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Deep Spectral Library of Mice Retina for Myopia Research: Proteomics Dataset generated by SWATH and DIA-NN

Sze YH, Tse DYY, Zuo B, Li KK, Zhao Q, Jiang X, Kurihara T, Tsubota K, Lam TC†

Sci Data. 11 （ 1 ） 1115 - 1115 2024年10月

査読有り

The retina plays a crucial role in processing and decoding visual information, both in normal development and during myopia progression. Recent advancements have introduced a library-independent approach for data-independent acquisition (DIA) analyses. This study demonstrates deep proteome identification and quantification in individual mice retinas during myopia development, with an average of 6,263 ± 86 unique protein groups. We anticipate that the use of a predicted retinal-specific spectral library combined with the robust quantification achieved within this dataset will contribute to a better understanding of the proteome complexity. Furthermore, a comprehensive mice retinal-specific spectral library was generated, encompassing a total identification of 9,401 protein groups, 70,041 peptides, 95,339 precursors, and 761,868 transitions acquired using SWATH-MS acquisition on a ZenoTOF 7600 mass spectrometer. This dataset surpasses the spectral library generated through high-pH reversed-phase fractionation by data-dependent acquisition (DDA). The data is available via ProteomeXchange with the identifier PXD046983. It will also serve as an indispensable reference for investigations in myopia research and other retinal or neurological diseases.

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Myopic shift in female mice after ovariectomy

Zhang Y, Mori K, Jeong H, Chen J, Liang Y, Negishi K, Tsubota K†, Kurihara T†

Sci Rep. 14 （ 1 ） 22946 - 22946 2024年10月

最終著者, 責任著者, 査読有り

Myopia is a global public health concern, with a higher prevalence in women than that in male. As the relationship between sex hormone and myopia remains unclear, we aimed to reveal the relationship between sex hormone and myopia by removing the ovaries of mice and measuring changes in ocular parameters related to myopia. Lens-induced myopia (LIM) surgeries were performed on 3-week-old male mice and age-matched female mice to evaluate the effects of sex on myopia development, which indicated a high degree of myopia and rapid progression of axial elongation in male mice. Bilateral ovariectomy (OVX) performed on 4-week-old female mice induced myopic refraction status in ovariectomized mice. Although axial length elongation was larger in ovariectomized mice than that in sham control mice, the result was insignificant. To further reveal the relationship between female sex hormones and myopia, LIM combined with OVX was performed, which revealed a magnified myopic refraction status in ovariectomized mice. Nevertheless, elongation of the anterior chamber depth in the − 30 D lens-treated eyes significantly increased in LIM + OVX mice compared with the frame-treated eyes in LIM + OVX mice and − 30 D lens-treated eyes in LIM + Sham surgery mice. Sex hormones play a role in regulating myopia development in female mice.

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Recent Insights into Roles of Hypoxia-Inducible Factors in Retinal Diseases

Lee D, Tomita Y, Miwa Y, Kunimi H, Nakai A, Shoda C, Negishi K, Kurihara T†

Int J Mol Sci. 25 （ 18 ） 10140 2024年09月

最終著者, 責任著者, 査読有り, ISSN 16616596

Hypoxia-inducible factors (HIFs) are transcriptional factors that function as strong regulators of oxygen homeostasis and cellular metabolisms. The maintenance of cellular oxygen levels is critical as either insufficient or excessive oxygen affects development and physiologic and pathologic conditions. In the eye, retinas have a high metabolic demand for oxygen. Retinal ischemia can cause visual impairment in various sight-threating disorders including age-related macular degeneration, diabetic retinopathy, and some types of glaucoma. Therefore, understanding the potential roles of HIFs in the retina is highly important for managing disease development and progression. This review focuses on the physiologic and pathologic roles of HIFs as regulators of oxygen homeostasis and cellular metabolism in the retina, drawing on recent evidence. Our summary will promote comprehensive approaches to targeting HIFs for therapeutic purposes in retinal diseases.

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Fundus Image Analysis of Retinitis Pigmentosa Using Artificial Intelligence

Ubukata S*, Masayoshi K*, Katada Y†, Yang L, Ozawa N, Ibuki M, Negishi K, Kurihara T†

Res Sq. 2024年09月

最終著者, 責任著者

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Establishment of an in vitro choroid complex system for vascular response screening

Jeong H, Lee D, Negishi K, Tsubota K†, Kurihara T†

Sci Rep. 14 （ 1 ） 16129 2024年07月

責任著者, 査読有り

The choroid, a vascularized tissue situated between the retina and the sclera, plays a crucial role in maintaining ocular homeostasis. Despite its significance, research on choroidal abnormalities and the establishment of effective in vitro models have been limited. In this study, we developed an in vitro choroid model through the co-culture of human induced pluripotent stem cells (hiPSC)-derived endothelial cells (ECs) and mouse choroidal fibroblasts (msCFs) with hiPSC-derived retinal pigment epithelial (RPE) cells via a permeable membrane. This model, inclusive of ECs, CFs, and RPE cells, exhibited similarities with in vivo choroidal vessels, as confirmed through immunohistochemistry of extracellular matrix markers and vascular-related markers, as well as choroid angiogenesis sprouting assay analysis. The effectiveness of our in vitro model was demonstrated in assessing vascular changes induced by drugs targeting vasoregulation. Our model offers a valuable tool for gaining insights into the pathological mechanisms underlying choroid development and the progression of choroidal vascular diseases.

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抗血管内皮増殖因子薬療法を施行された滲出型加齢黄斑変性の病型別の長期視力変化

加藤想史, 内田敦郎†, 永井紀博, 鈴木美砂,南早紀子, 篠島亜里,伴紀充,堀内直樹,藤岡俊平, 栗原俊英,篠田肇,小沢洋子,根岸一乃

日眼会誌 128 （ 6 ） 473 - 486 2024年06月

査読有り

Choroidal thinning in myopia is associated with axial elongation and severity of myopic maculopathy

Midorikawa M*, Mori K*, Torii H, Tomita Y, Zhang Y, Tsubota K, Kurihara T†, Negishi K

Res Sq. （Research Square Platform LLC） 14 （ 1 ） 17600 2024年05月

責任著者

High myopia can lead to pathologic myopia and visual impairment, whereas its causes are unclear. We retrospectively researched high myopia cases from patient records to investigate the association between axial elongation and myopic maculopathy. Sixty-four eyes were examined in patients who visited the department between July 2017 and June 2018, had an axial length of 26 mm or more, underwent fundus photography, and had their axial length measured twice or more. The average axial length was 28.29 ± 1.69 mm (mean ± standard deviation). The average age was 58.3 ± 14.4 years old. Myopic maculopathy was categorized as mild (grades 0 and 1) and severe (grades 2, 3, and 4). The severe group had longer axial lengths than the mild group (P < 0.05). Moreover, the severe group exhibited thinner choroidal thickness than the mild group (P < 0.05). When subjects were grouped by axial elongation over median value within a year, the elongation group showed thinner central choroidal thickness than the non-elongation group (142.1 ± 91.9 vs. 82.9 ± 69.8, P < 0.05). In conclusion, in patients with high myopia, the severity of maculopathy correlated with choroidal thickness and axial length. Thinner choroidal thickness was associated with axial elongation based on the baseline axial length.

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Myopia Is an Ischemic Eye Condition: A Review from the Perspective of Choroidal Blood Flow

Baksh J*, Lee D*, Mori K, Zhang Y, Torii H, Jeong H, Hou J, Negishi K, Tsubota K†, Kurihara T†

J Clin Med. （Journal of Clinical Medicine） 13 （ 10 ） 2777 - 2777 2024年05月

最終著者, 責任著者, 査読有り

Myopia is a common refractive error that affects a large proportion of the population. Recent studies have revealed that alterations in choroidal thickness (ChT) and choroidal blood flow (ChBF) play important roles in the progression of myopia. Reduced ChBF could affect scleral cellular matrix remodeling, which leads to axial elongation and further myopia progression. As ChT and ChBF could be used as potential biomarkers for the progression of myopia, several recent myopia treatments have targeted alterations in ChT and ChBF. Our review provides a comprehensive overview of the recent literature review on the relationship between ChBF and myopia. We also highlight the importance of ChT and ChBF in the progression of myopia and the potential of ChT as an important biomarker for myopia progression. This summary has significant implications for the development of novel strategies for preventing and treating myopia.

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Retinal ischemic diseases and promising therapeutic molecular targets

Lee D*, Tomita Y*, Negishi K, Kurihara T†

Histol Histopathol. 40 （ 1 ） 18756 - 20 2024年05月

最終著者, 責任著者, 査読有り, ISSN 02133911

Retinal ischemia is a fundamental pathologic condition associated with retinal vascular occlusion, glaucoma, diabetic retinopathy, age-related macular degeneration, and other eye diseases. Extensive inflammation, redox imbalance, apoptosis, and abnormal vascular formation in retinal ischemia could lead to visual impairments. Developing or finding effective treatments is urgently needed to protect the eye against retinal ischemia and related damage. To address the demand, we have searched for promising therapeutic molecular targets in the eye (e.g., hypoxia-inducible factor [HIF], peroxisome proliferator-activated receptor-alpha [PPARα], and nicotinamide adenine dinucleotide [NAD+]), and found that modulations of each molecular target might protect the eye against retinal ischemic damage in terms of complex pathologic mechanisms. In the current article, we review and update the therapeutic evidence of modulation of HIF, PPARα, or NAD+ and discuss future directions for developing promising drugs based on these molecular targets. This summary urges research to obtain more solid evidence of each molecular target in retinal ischemic diseases.

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Drusen in AMD from the Perspective of Cholesterol Metabolism and Hypoxic Response

Ban N, Shinojima A, Negishi K, Kurihara T*

J Clin Med. （Journal of Clinical Medicine） 13 （ 9 ） 2608 2024年04月

最終著者, 責任著者, 査読有り

Drusen are one of the most characteristic pathologies of precursor lesion of age-related macular degeneration (AMD). Drusen comprise a yellowish white substance that accumulates typically under the retinal pigment epithelium (RPE), and their constituents are lipids, complement, amyloid, crystallin, and others. In the past, many researchers have focused on drusen and tried to elucidate the pathophysiology of AMD because they believed that disease progression from early AMD to advanced AMD might be based on drusen or drusen might cause AMD. In fact, it is well established that drusen are the hallmark of precursor lesion of AMD and a major risk factor for AMD progression mainly based on their size and number. However, the existence of advanced AMD without drusen has long been recognized. For example, polypoidal choroidal vasculopathy (PCV), which comprises the majority of AMD cases in Asians, often lacks drusen. Thus, there is the possibility that drusen might be no more than a biomarker of AMD and not a cause of AMD. Now is the time to reconsider the relationship between AMD and drusen. In this review, we focus on early AMD pathogenesis based on basic research from the perspective of cholesterol metabolism and hypoxic response in the retina, and we discuss the role of drusen.

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Halofuginone prevents outer retinal degeneration in a mouse model of light-induced retinopathy

Miwa Y*, Lee D*, Shoda C, Jeong H, Negishi K, Kurihara T†

PLOS ONE （PLoS ONE） 19 （ 3 ） e0300045 2024年03月

最終著者, 責任著者, 査読有り

Photoreceptor cell death can cause progressive and irreversible visual impairments. Still, effective therapies on retinal neuroprotection are not available. Hypoxia-inducible factors (HIFs) are transcriptional factors which strongly regulate angiogenesis, erythropoiesis, intracellular metabolism, and programed cell death under a hypoxic or an abnormal metabolic oxidative stress condition. Therefore, we aimed to unravel that inhibition of HIFs could prevent disease progression in photoreceptor cell death, as recent studies showed that HIFs might be pathologic factors in retinal diseases. Adult male balb/cAJcl (8 weeks old; BALB/c) were used to investigate preventive effects of a novel HIF inhibitor halofuginone (HF) on a murine model of light-induced retinopathy. After intraperitoneal injections of phosphate-buffered saline (PBS) or HF (0.4 mg/kg in PBS) for 5 days, male BALB/c mice were subjected to a dark-adaption to being exposed to a white LED light source at an intensity of 3,000 lux for 1 hour in order to induce light-induced retinal damage. After extensive light exposure, retinal damage was evaluated using electroretinography (ERG), optical coherence tomography (OCT), and TUNEL assay. Light-induced retinal dysfunction was suppressed by HF administration. The amplitudes of scotopic a-wave and b-wave as well as that of photopic b-wave were preserved in the HF-administered retina. Outer retinal thinning after extensive light exposure was suppressed by HF administration. Based on the TUNEL assay, cell death in the outer retina was seen after light exposure. However, its cell death was not detected in the HF-administered retina. Halofuginone was found to exert preventive effects on lightinduced outer retinal cell death.

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Scleral remodeling during myopia development in mice eyes: a potential role of thrombospondin-1

Chen J*, Ikeda SI*, Yang Y, Zhang Y, Ma Z, Liang Y, Negishi K, Tsubota K†, Kurihara T†

Mol Med. （Molecular Medicine） 30 （ 1 ） 25 2024年02月

最終著者, 責任著者, 査読有り, ISSN 10761551

Background: Scleral extracellular matrix (ECM) remodeling plays a crucial role in the development of myopia, particularly in ocular axial elongation. Thrombospondin-1 (THBS1), also known as TSP-1, is a significant cellular protein involved in matrix remodeling in various tissues. However, the specific role of THBS1 in myopia development remains unclear. Method: We employed the HumanNet database to predict genes related to myopic sclera remodeling, followed by screening and visualization of the predicted genes using bioinformatics tools. To investigate the potential target gene Thbs1, we utilized lens-induced myopia models in male C57BL/6J mice and performed Western blot analysis to detect the expression level of scleral THBS1 during myopia development. Additionally, we evaluated the effects of scleral THBS1 knockdown on myopia development through AAV sub-Tenon’s injection. The refractive status and axial length were measured using a refractometer and SD-OCT system. Results: During lens-induced myopia, THBS1 protein expression in the sclera was downregulated, particularly in the early stages of myopia induction. Moreover, the mice in the THBS1 knockdown group exhibited alterations in myopia development in both refraction and axial length changed compared to the control group. Western blotting analysis confirmed the effectiveness of AAV-mediated knockdown, demonstrating a decrease in COLA1 expression and an increase in MMP9 levels in the sclera. Conclusion: Our findings indicate that sclera THBS1 levels decreased during myopia development and subsequent THBS1 knockdown showed a decrease in scleral COLA1 expression. Taken together, these results suggest that THBS1 plays a role in maintaining the homeostasis of scleral extracellular matrix, and the reduction of THBS1 may promote the remodeling process and then affect ocular axial elongation during myopia progression.

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Slowing of Greater Axial Length Elongation Stemming from the COVID-19 Pandemic with Increasing Time Outdoors: The Tokyo Myopia Study

Yotsukura E, Torii H†, Mori K, Ogawa M, Hanyuda A, Negishi K, Kurihara T†, Tsubota K†

Ophthalmol Sci. （Ophthalmology Science） 4 （ 5 ） 100491 - 100491 2024年02月

責任著者, 査読有り, ISSN 2666-9145

Purpose: To investigate the changes in axial length (AL) elongation and other ocular parameters before and during the coronavirus disease 2019 pandemic. Design: A longitudinal school-based study. Participants: Public elementary schoolchildren in Tokyo (grades 1–6; age, 6–12 years) participated in this study from 2018 to 2021. Methods: All participants underwent eye examinations and provided written consent to measurements of the noncycloplegic refraction and ocular biometry including AL, among others. The students’ parents also completed a questionnaire about the students’ lifestyles. We included the right eye in our analysis and compared the changes in the ocular parameters among the periods using a linear mixed-effects model for repeated measures and examined the univariate and step-wise multiple regression analyses to evaluate the associations between myopia and other covariates. Main Outcome Measures: Changes in AL elongation and other ocular parameters from 2018 to 2019 (prepandemic), that of 2019 to 2020 (immediately after the pandemic onset), and that of 2020 to 2021 (during the pandemic). Results: A total of 578 students before the pandemic period, 432 immediately after the pandemic onset, and 457 during the pandemic period were evaluated. The changes in the ALs and spherical equivalents (SEs) a year before, immediately after onset, and during the pandemic were 0.31 mm/−0.20 diopter, 0.38 mm/−0.27 diopter, and 0.28 mm/−0.47 diopter, respectively (ALs, P < 0.001; SEs, P = 0.014). The results of the questionnaire showed that time spent outdoors daily had changed during the 3 years to 79, 63, and 77 minutes/day, respectively (P < 0.001). Time spent using smartphones or tablets increased year by year to 41, 52, and 62 minutes/day (P < 0.001). The greatest AL elongation occurred during the period when the shortest amount of time was spent outdoors during the 3 years. Conclusions: These results suggested that the school closures and decreasing time spent outdoors might have caused greater AL elongation among schoolchildren in Tokyo; however, it is possible that, although the time spent in near work still increased, the return to the time spent outdoors to the prepandemic levels may have affected the slowing of AL elongation after lockdown. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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Deep Learning Segmentation of Non-perfusion Area from Color Fundus Images and AI-generated Fluorescein Angiography

Masayoshi K*, Katada Y*, Ozawa N, Ibuki M, Negishi K, Kurihara T†

Res Sq. （Research Square Platform LLC） 14 （ 1 ） https://doi.org/10.21203/rs.3.rs-3871406/v1 2024年01月

最終著者, 責任著者

The non-perfusion area (NPA) of the retina is an important indicator in the visual prognosis of patients with branch retinal vein occlusion (BRVO). However, the current evaluation method of NPA, fluorescein angiography (FA), is invasive and burdensome. In this study, we examined the use of deep learning models for detecting NPA in color fundus images, bypassing the need for FA, and we also investigated the utility of synthetic FA generated from color fundus images. The models were evaluated using the Dice score and Monte Carlo dropout uncertainty. We retrospectively collected 403 sets of color fundus and FA images from 319 BRVO patients. We trained three deep learning models on FA, color fundus images, and synthetic FA. As a result, though the FA model achieved the highest score, the other two models also performed comparably. We found no statistical significance in median Dice scores between the models. However, the color fundus model showed significantly higher uncertainty than the other models (p < 0.05). In conclusion, deep learning models can detect NPAs from color fundus images with reasonable accuracy, though with somewhat less prediction stability. Synthetic FA stabilizes the prediction and reduces misleading uncertainty estimates by enhancing image quality.

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Modulation of Hypoxia-Inducible Factors and Vascular Endothelial Growth Factor Expressions by Superfood Camu-Camu (Myrciaria dubia) Treatment in ARPE-19 and Fetal Human RPE Cells

Nakai A, Lee D, Shoda C, Negishi K, Nakashizuka H, Yamagami S, Kurihara T†

J Ophthalmol. （Journal of Ophthalmology） 2023 6617981 2023年12月

最終著者, 責任著者, 査読有り, ISSN 2090-004X

Background. Anti-vascular endothelial growth factor (anti-VEGF) therapy via intravitreal injection is an effective treatment for patients with abnormal ocular neovascularization, such as age-related macular degeneration (AMD) and diabetic macular edema (DME). However, prolonged and frequent anti-VEGF treatment is associated with a risk of local and systemic adverse events, including geographic atrophy, cerebrovascular disease, and death. Furthermore, some patients do not adequately respond to anti-VEGF therapy. Hypoxia-inducible factor (HIF) is a transcription factor that controls the expression of hypoxia-responsive genes involved in angiogenesis, inflammation, and metabolism. The HIF/VEGF pathway plays an important role in neovascularization, and the inhibition of HIF activation could be an effective biomolecular target for neovascular diseases. The demand for disease prevention or treatment using functional foods such as superfoods has increased in recent years. Few reports to date have focused on the antineovascular effects of superfoods in the retinal pigment epithelium (RPE). In light of the growing demand for functional foods, we aimed to find novel HIF inhibitors from superfoods worked in RPE cells, which could be an adjuvant for anti-VEGF therapy. Methods. Seven superfoods were examined to identify novel HIF inhibitor candidates using luciferase assay screening. We used the human RPE cell line ARPE-19 and fetal human RPE (fhRPE) to investigate the biomolecular actions of novel HIF inhibitors using quantitative PCR and western blotting. Results. Under CoCl2-induced pseudohypoxic condition and 1% oxygen hypoxic incubation, camu-camu (Myrciaria dubia) showed HIF inhibitory effects determined by luciferase assays. Camu-camu downregulated HIF-1α and VEGFA mRNA expressions in a concentration-dependent manner. Camu-camu also inhibited HIF-1α protein expressions, and its inhibitory effect was greater than that of vitamin C, which is present at high levels in camu-camu. Conclusion. The camu-camu extract suppressed the activation of HIF and VEGF in RPE cells. This could assist anti-VEGF therapy in patients with abnormal ocular neovascularization.

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Inhibition of hypoxia-inducible factors suppresses subretinal fibrosis

Shoda C*, Lee D*, Miwa Y, Yamagami S, Nakashizuka H, Nimura K, Okamoto K, Kawagishi H, Negishi K, Kurihara T†

bioRxiv. （FASEB Journal） 38 （ 13 ） 571193 2023年12月

最終著者, 責任著者, ISSN 08926638

Age-related macular degeneration (AMD) is a common cause of vision loss. The aggressive form of AMD is associated with ocular neovascularization and subretinal fibrosis, representing a responsive outcome against neovascularization mediated by epithelial–mesenchymal transition of retinal pigment epithelium (RPE) cells. A failure of the current treatment (anti-vascular endothelial growth factor therapy) has also been attributed to the progression of subretinal fibrosis. Hypoxia-inducible factors (HIFs) increase gene expressions to promote fibrosis and neovascularization. HIFs act as a central pathway in the pathogenesis of AMD. HIF inhibitors may suppress ocular neovascularization. Nonetheless, further investigation is required to unravel the aspects of subretinal fibrosis. In this study, we used RPE-specific HIFs or von Hippel–Lindau (VHL, a regulator of HIFs) conditional knockout (cKO) mice, along with pharmacological HIF inhibitors, to demonstrate the suppression of subretinal fibrosis. Fibrosis was suppressed by treatments of HIF inhibitors, and similar suppressive effects were detected in RPE-specific Hif1a/Hif2a- and Hif1a-cKO mice. Promotive effects were observed in RPE-specific Vhl-cKO mice, where fibrosis-mediated pathologic processes were evident. Marine products' extracts and their component taurine suppressed fibrosis as HIF inhibitors. Our study shows critical roles of HIFs in the progression of fibrosis, linking them to the potential development of therapeutics for AMD.

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