論文 - 栗原　俊英

Nicotinamide mononucleotide, a potential future treatment in ocular diseases

Lee D, Tomita Y, Shinojima A, Ban N, Yamaguchi S, Nishioka K, Negishi K, Yoshino J, Kurihara T†

Graefes Arch Clin Exp Ophthalmol. （Graefe's Archive for Clinical and Experimental Ophthalmology）  262 （ 3 ） 689 - 700 2023年06月

最終著者, 責任著者, 査読有り,  ISSN  0721832X

　概要を見る

Purpose: The burden of ocular diseases has been gradually increasing worldwide. Various factors are suggested for the development and progression of ocular diseases, such as ocular inflammation, oxidative stress, and complex metabolic dysregulation. Thus, managing ocular diseases requires the modulation of pathologic signaling pathways through many mechanisms. Nicotinamide mononucleotide (NMN) is a bioactive molecule naturally found in life forms. NMN is a direct precursor of the important molecule nicotinamide adenine dinucleotide (NAD+), an essential co-enzyme required for enormous cellular functions in most life forms. While the recent experimental evidence of NMN treatment in various metabolic diseases has been well-reviewed, NMN treatment in ocular diseases has not been comprehensively summarized yet. In this regard, we aimed to focus on the therapeutic roles of NMN treatment in various ocular diseases with recent advances. Methods: How we came to our current opinion with a recent summary was described based on our own recent reports as well as a search of the related literature. Results: We found that NMN treatment might be available for the prevention of and protection from various experimental ocular diseases, as NMN treatment modulated ocular inflammation, oxidative stress, and complex metabolic dysregulation in murine models for eye diseases such as ischemic retinopathy, corneal defect, glaucoma, and age-related macular degeneration. Conclusion: Our current review suggests and discusses new modes of actions of NMN for the prevention of and protection from various ocular diseases and can urge future research to obtain more solid evidence on a potential future NMN treatment in ocular diseases at the preclinical stages.

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The orientation of choroidal macrophage polarization significantly influences the development of myopia in murine models

Hou J*, Ikeda SI*, Mori K, Jeong H, Torii H, Negishi K, Tsubota K†, Kurihara T†

bioRxiv. （Cold Spring Harbor Laboratory）     544445 2023年06月

最終著者, 責任著者

　概要を見る

Abstract

Myopia is a primary contributor to visual impairment and has emerged as a global public health concern. Evidence indicates that one of the main structural features of myopia is the corresponding decrease in choroidal thickness, and choroidal macrophages play an important role in maintaining the choroidal thickness. Nevertheless, the effect of choroidal macrophages on myopia remains unclear. Here, we discovered that the continuous intraperitoneal injection of clodronate liposomes depleted choroidal macrophages and leads to myopia, which confirmed that the presence of choroidal macrophages plays an important role in myopia development.

Subsequently, based on the phenotypic characteristics of macrophages, experiments were designed to study the effects of different polarization directions of macrophages on myopia development. We found that lipopolysaccharides (LPS) injection can induce the polarization of choroidal M1 macrophages and result in myopia. Conversely, IL-4 or IL-13 injection causes choroidal M2 macrophage polarization and suppresses the progression of myopia. Additionally, we demonstrated that the opposite effects of M1 and M2 macrophages on myopia development may be related to their impacts on inflammation and oxidative stress response. These findings establish that choroidal macrophages are critically important in the development of myopia and provide new strategies for the development of myopic therapies.

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Encephalopsin (OPN3) is required for normal refractive development and the GO/GROW response to induced myopia

Linne C, Mon KY, D’Souza S, Jeong H, Jiang X, Brown DM, Zhang K, Vemaraju S, Tsubota K, Kurihara T, Pardue MT, Lang RA†

Mol Vis. （Molecular vision）  29   39 - 57 2023年05月

査読有り

　概要を見る

Purpose: Myopia, or nearsightedness, is the most common form of refractive error and is increasing in prevalence. While significant efforts have been made to identify genetic variants that predispose individuals to myopia, these variants are believed to account for only a small portion of the myopia prevalence, leading to a feedback theory of emmetropization, which depends on the active perception of environmental visual cues. Consequently, there has been renewed interest in studying myopia in the context of light perception, beginning with the opsin family of G-protein coupled receptors (GPCRs). Refractive phenotypes have been characterized in every opsin signaling pathway studied, leaving only Opsin 3 (OPN3), the most widely expressed and blue-light sensing noncanonical opsin, to be investigated for function in the eye and refraction. Methods: Opn3 expression was assessed in various ocular tissues using an Opn3eGFP reporter. Weekly refractive development in Opn3 retinal and germline mutants from 3 to 9 weeks of age was measured using an infrared photorefractor and spectral domain optical coherence tomography (SD-OCT). Susceptibility to lens-induced myopia was then assessed using skull-mounted goggles with a -30 diopter experimental and a 0 diopter control lens. Mouse eye biometry was similarly tracked from 3 to 6 weeks. A myopia gene expression signature was assessed 24 h after lens induction for germline mutants to further assess myopia-induced changes. Results: Opn3 was found to be expressed in a subset of retinal ganglion cells and a limited number of choroidal cells. Based on an assessment of Opn3 mutants, the OPN3 germline, but not retina conditional Opn3 knockout, exhibits a refractive myopia phenotype, which manifests in decreased lens thickness, shallower aqueous compartment depth, and shorter axial length, atypical of traditional axial myopias. Despite the short axial length, Opn3 null eyes demonstrate normal axial elongation in response to myopia induction and mild changes in choroidal thinning and myopic shift, suggesting that susceptibility to lens-induced myopia is largely unchanged. Additionally, the Opn3 null retinal gene expression signature in response to induced myopia after 24 h is distinct, with opposing Ctgf, Cx43, and Egr1 polarity compared to controls. Conclusions: The data suggest that an OPN3 expression domain outside the retina can control lens shape and thus the refractive performance of the eye. Prior to this study, the role of Opn3 in the eye had not been investigated. This work adds OPN3 to the list of opsin family GPCRs that are implicated in emmetropization and myopia. Further, the work to exclude retinal OPN3 as the contributing domain in this refractive phenotype is unique and suggests a distinct mechanism when compared to other opsins.

Myopia Is suppressed by digested lactoferrin or holo-lactoferrin administration

Liang Y, Ikeda SI, Chen J, Zhang Y, Negishi K, Tsubota K†, Kurihara T†

Int J Mol Sci. （International Journal of Molecular Sciences）  24 （ 6 ） 5815 2023年03月

最終著者, 責任著者, 査読有り,  ISSN  16616596

　概要を見る

Myopia is becoming a leading cause of vision impairment. An effective intervention is needed. Lactoferrin (LF) is a protein that has been reported to inhibit myopia progression when taken orally. This study looked at the effects of different forms of LF, such as native LF and digested LF, on myopia in mice. Mice were given different forms of LF from 3 weeks of age, and myopia was induced with minus lenses from 4 weeks of age. Results showed that mice given digested LF or holo-LF had a less elongated axial length and thinned choroid, compared to those given native-LF. Gene expression analysis also showed that the groups given native-LF and its derivatives had lower levels of certain cytokines and growth factors associated with myopia. These results suggest that myopia can be more effectively suppressed by digested LF or holo-LF than native-LF.

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Contralateral effect in progression and recovery of lens-induced myopia in mice

Ma Z*, Jeong H*, Yang Y, Jiang X, Ikeda SI, Negishi K, Kurihara T†, Tsubota K†

Ophthal Physiol Opt. （Ophthalmic and Physiological Optics）  00 （ 3 ） 1 - 8 2023年03月

責任著者, 査読有り,  ISSN  02755408

　概要を見る

Purpose: Apart from genetic factors, recent animal studies on myopia have focused on localised mechanisms. In this study, we aimed to examine the contralateral effects of monocular experimental myopia and recovery, which cannot be explained by a mere local mechanism. Methods: One eye of 3-week-old C57BL/6 male mice was fitted with a −30 dioptre (D) lens. The mice were distributed into two groups based on different conditions in the contralateral eye: either no lens (NLC) (n = 10) or a Plano lens on the contralateral eye (PLC) group (n = 6). Mice receiving no treatment on either eye were set as a control group (n = 6). Lenses were removed after 3 weeks of myopia induction. All mice were allowed to recover for 1 week in the same environment. Refractive status, axial length (AL) and choroidal thickness were measured before myopia induction, after 1 and 3 weeks of lens wear and after 1 week of recovery. Results: One week after removing the lenses, complete recovery was observed in the eyes that wore the −30 D lenses. In both the PLC and NLC groups, the refractive status showed a myopic shift after lens removal. Additionally, the choroid was significantly thinned in these eyes. The −30 D wearing eye showed a significant increase in AL after 3 weeks of lens wear. While the AL of the −30 D wearing eye ceased to grow after the lens was removed, the AL in the PLC and NLC contralateral eyes increased, and the binocular ALs gradually converged. Conclusions: Recovery of lens-induced myopia was observed in mouse models. In the fellow eyes, the effects, including thinning of the choroid and changes in refractive status, were triggered by contralateral visual cues.

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Molecular and cellular regulations in the development of the choroidal circulation system

Imanishi S, Tomita Y, Negishi K, Tsubota K†, Kurihara T†

Int J Mol Sci. （International journal of molecular sciences）  24 （ 6 ） 5371 2023年03月

最終著者, 責任著者, 査読有り,  ISSN  16616596

　概要を見る

Disorders in the development and regulation of blood vessels are involved in various ocular disorders, such as persistent hyperplastic primary vitreous, familial exudative vitreoretinopathy, and choroidal dystrophy. Thus, the appropriate regulation of vascular development is essential for healthy ocular functions. However, regulation of the developing choroidal circulation system has not been well studied compared with vascular regulation in the vitreous and the retina. The choroid is a vascular-rich and uniquely structured tissue supplying oxygen and nutrients to the retina, and hypoplasia and the degeneration of the choroid are involved in many ocular disorders. Therefore, understanding the developing choroidal circulation system expands our knowledge of ocular development and supports our understanding of ocular disorders. In this review, we examine studies on regulating the developing choroidal circulation system at the cellular and molecular levels and discuss the relevance to human diseases.

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Ginkgo biloba extracts improve choroidal circulation leading to suppression of myopia in mice

Hou J*, Mori K*, Ikeda SI, Jeong H, Torii H, Negishi K, Kurihara T†, Tsubota K†

Sci Rep. （Scientific Reports）  13 （ 1 ） 3772 2023年03月

責任著者, 査読有り

　概要を見る

Myopia is becoming more common across the world, necessitating the development of preventive methods. We investigated the activity of early growth response 1 (EGR-1) protein and discovered that Ginkgo biloba extracts (GBEs) activated EGR-1 in vitro. In vivo, C57BL/6 J mice were fed either normal or 0.0667% GBEs (200 mg/kg) mixed chow (n = 6 each), and myopia was induced with − 30 diopter (D) lenses from 3 to 6 weeks of age. Refraction and axial length were measured by an infrared photorefractor and an SD-OCT system, respectively. In lens-induced myopia mice, oral GBEs significantly improved refractive errors (− 9.92 ± 1.53 D vs. − 1.67 ± 3.51 D, p < 0.001) and axial elongation (0.22 ± 0.02 mm vs. 0.19 ± 0.02 mm, p < 0.05). To confirm the mechanism of GBEs in preventing myopia progression, the 3-week-old mice were divided into normally fed with either myopic-induced or non-myopic-induced groups and GBEs fed with either myopic-induced or non-myopic-induced groups (n = 10 each). Choroidal blood perfusion was measured with optical coherence tomography angiography (OCTA). In both non-myopic induced groups, compared to normal chow, oral GBEs significantly improved choroidal blood perfusion (8.48 ± 15.75%Area vs. 21.74 ± 10.54%Area, p < 0.05) and expression of Egr-1 and endothelial nitric oxide synthase (eNOS) in the choroid. In both myopic-induced groups, compared to normal chow, oral GBEs also improved choroidal blood perfusion (− 9.82 ± 9.47%Area vs. 2.29 ± 11.84%Area, p < 0.05) and was positively correlated with the change in choroidal thickness. These findings suggest that GBEs may inhibit the progression of myopia by improving choroidal blood perfusion.

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Suppressive effects of violet light transmission on myopia progression in a mouse model of lens-induced myopia

Jeong H, Kurihara T†, Jiang X, Kondo S, Ueno Y, Hayashi Y, Lee D, Ikeda SI, Mori K, Torii H, Negishi K, Tsubota K†

Exp Eye Re. （Experimental Eye Research）  228   109414 2023年02月

責任著者, 査読有り,  ISSN  0014-4835

　概要を見る

The prevalence of myopia has been steadily increasing for several decades, and this condition can cause extensive medical and economic issues in society. Exposure to violet light (VL), a short wavelength (360–400 nm) of visible light from sunlight, has been suggested as an effective preventive and suppressive treatments for the development and progression of myopia. However, the clinical application of VL remains unclear. In this study, we aimed to investigate the preventive and suppressive effects of VL on myopia progression. Various transmittances of VL (40%, 70%, and 100%) were tested in C57BL/6J mice with lens-induced myopia (LIM). Changes in the refractive error, axial length, and choroid thickness during the 3-week LIM were measured. The myopic shift in refractive error and difference in axial length between the 0 and -30 diopter lens was lessened in a transmission-dependent manner. Choroidal thinning, which was observed in myopic conditions, was suppressed by VL exposure and affected by its transmission. The results suggest that myopia progression can be managed using VL transmittance. Therefore, these factors should be considered for the prevention and treatment of myopia.

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Pemafibrate prevents choroidal neovascularization in a mouse model of neovascular age-related macular degeneration

Lee D, Nakai A, Miwa Y, Negishi K, Tomita Y, Kurihara​ T†

PeerJ. （PeerJ）  11   e14611 2023年01月

最終著者, 責任著者, 査読有り

　概要を見る

Background. Pathological choroidal neovascularization (CNV) is one of the major causes of visual impairment in neovascular age-related macular degeneration (AMD). CNV has been suppressed by using anti-vascular endothelial growth factor (VEGF) antibodies. However, some clinical cases have demonstrated the failure of anti-VEGF therapies. Furthermore, anti-VEGF agents might induce the development of ocular atrophy. Recently, peroxisome proliferator-activated receptor alpha (PPARα) activation using pemafibrate treatment was suggested as one of the promising therapeutic targets in the prevention of ocular ischemia. However, the preventive role of pemafibrate remains unclear in CNV. We aimed to examine the preventive role of pemafibrate on laser-induced pathological CNV. Methods. Adult male C57BL/6 mice were orally supplied pemafibrate (0.5 mg/kg) for four days, followed by laser irradiation. Then, pemafibrate was consecutively given to mice with the same condition. CNV was visualized with isolectin-IB4. The eye (retina and/or retinal pigment epithelium [RPE]-choroid), liver, and serum were used for biomolecular analyses. Results. We found that pemafibrate administration suppressed CNV volumes. Pemafibrate administration activated PPARα downstream genes in the liver and eye (especially, RPE-choroid). Furthermore, pemafibrate administration elevated serum fibroblast growth factor 21 levels and reduced serum levels of triglycerides. Conclusions. Our data suggest a promising pemafibrate therapy for suppressing CNV in AMD.

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Association between fatty acid intakes and age-related macular degeneration in a Japanese population: JPHC-NEXT Eye Study

Yasukawa T*, Sasaki M*†, Motomura K, Yuki K, Kurihara T, Tomita Y, Mori K, Ozawa N, Ozawa Y, Yamagishi K†, Hanyuda A, Sawada N, Tsubota K, Tsugane S, Iso H

Transl Vis Sci Technol. （Translational Vision Science and Technology）  12 （ 1 ） 3 2023年01月

査読有り

　概要を見る

Purpose: To determine the associations between fatty acid intakes and the prevalence of age-related macular degeneration (AMD) under a population-based cross-sectional study. Methods: Residents of Chikusei City aged ≥40 years underwent systemic and eye screening. AMD was graded according to a modified version of the Age-Related Eye Disease Study classification. Dietary intake was assessed using a food frequency questionnaire and was adjusted for total energy intake. Results: Altogether, 10,788 eyes of 5394 participants, 2116 men (mean [standard devia-tion (SD)] age, 62.4 [9.4] years) and 3278 women (60.6 [9.5] years), were included. The mean daily total fat intakes were 52.8 g and 59.0 g in men and women, respectively. After adjustments for potential confounders, saturated fatty acid (SFA) intake was inversely associated with the prevalence of any AMD in men (for each energy-adjusted 1-SD increase: odds ratio [OR], 0.86; 95% confidence interval [CI], 0.74–1.00). Significant trends were found for decreasing odds ratios of AMD with increasing SFA, monounsaturated fatty acid (MUFA), and polyunsaturated fatty acid (PUFA) intake (P for trend = 0.02, 0.04, and 0.04, respectively). In women, only a significant association was observed between the second quartile of linolenic acid intake and the prevalence of any AMD (OR, 0.78; 95% CI, 0.62–0.99). Conclusions: We found an inverse association of SFA intake and a weak inverse association of MUFA and PUFA intakes with the prevalence of any AMD in a Japanese popula-tion. Translational Relevance: Adequate fatty acid intake may be necessary to prevent or decelerate AMD.

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Deep-learning-based AI for evaluating estimated nonperfusion areas requiring further examination in ultra-widefield fundus images

Inoda S, Takahashi H†, Yamagata H, Hisadome Y, Kondo Y, Tampo H, Sakamoto S, Katada Y, Kurihara T, Kawashima H, Yanagi Y

Sci Rep. （Scientific Reports）  12 （ 1 ） 21826 2022年12月

査読有り

　概要を見る

We herein propose a PraNet-based deep-learning model for estimating the size of non-perfusion area (NPA) in pseudo-color fundus photos from an ultra-wide-field (UWF) image. We trained the model with focal loss and weighted binary cross-entropy loss to deal with the class-imbalanced dataset, and optimized hyperparameters in order to minimize validation loss. As expected, the resultant PraNet-based deep-learning model outperformed previously published methods. For verification, we used UWF fundus images with NPA and used Bland–Altman plots to compare estimated NPA with the ground truth in FA, which demonstrated that bias between the eNPA and ground truth was smaller than 10% of the confidence limits zone and that the number of outliers was less than 10% of observed paired images. The accuracy of the model was also tested on an external dataset from another institution, which confirmed the generalization of the model. For validation, we employed a contingency table for ROC analysis to judge the sensitivity and specificity of the estimated-NPA (eNPA). The results demonstrated that the sensitivity and specificity ranged from 83.3–87.0% and 79.3–85.7%, respectively. In conclusion, we developed an AI model capable of estimating NPA size from only an UWF image without angiography using PraNet-based deep learning. This is a potentially useful tool in monitoring eyes with ischemic retinal diseases.

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Axl, Immune Checkpoint Molecules and HIF Inhibitors from the Culture Broth of Lepista luscina

Kotajima M*, Choi JH*, Kondo M, D’Alessandro-Gabazza CN, Toda M, Yasuma T, Gabazza EC, Miwa Y, Shoda C, Lee D, Nakai A, Kurihara T, Wu J, Hirai H, Kawagishi H†

Molecules. （Molecules）  27 （ 24 ） 8925 - 8925 2022年12月

査読有り

　概要を見る

Two compounds 1 and 2 were isolated from the culture broth of Lepista luscina. This is the first time that compound 1 was isolated from a natural source. The structure of compound 1 was identified via 1D and 2D NMR and HRESIMS data. Compounds 1 and 2 along with 8-nitrotryptanthrin (4) were evaluated for their biological activities using the A549 lung cancer cell line. As a result, 1 and 2 inhibited the expression of Axl and immune checkpoint molecules. In addition, compounds 1, 2 and 4 were tested for HIF inhibitory activity. Compound 2 demonstrated statistically significant HIF inhibitory effects on NIH3T3 cells and 1 and 2 against ARPE19 cells.

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Relationship of choroidal thickness and axial length with posterior vitreous detachment in patients with high myopia

Hanyuda A., Torii H., Hayashi K., Uchida A., Mori K., Yotsukura E., Ogawa M., Negishi K., Kurihara T., Tsubota K.

Scientific Reports （Scientific Reports）  12 （ 1 ） 4093 2022年12月

査読有り

　概要を見る

Although accumulating evidence suggests a higher prevalence of posterior vitreous detachment (PVD) in highly myopic eyes, the relation between ocular biometric features and PVD stages in such eyes remains unclear. Therefore, we enrolled 170 patients with high myopia (axial length ≥ 26.0 mm) to investigate the status of PVD regarding subfoveal choroidal thickness and axial length. Utilising swept-source optical coherence tomography, we classified the PVD status into five stages. The distribution of PVD grades increased as the choroidal thickness decreased and axial length increased (P < 0.01). On adjusting for age and sex, decreased choroidal thickness and increased axial length were associated with more advanced PVD stages: odds ratios with the highest vs. lowest groups were 0.31 (95% confidence interval [CI] 0.09–1.01; Ptrend = 0.009) for choroidal thickness and 5.16 (95% CI 1.34–19.80; Ptrend = 0.002) for axial length. The inverse association between choroidal thickness and PVD status seemed stronger in women than in men (Pinteraction = 0.05). In conclusion, we firstly observed a significant trend of decreased choroidal thickness, along with increased axial length, with increased grade of PVD, particularly among women with highly myopic eyes, suggesting that advanced morphological myopic changes contribute to PVD in middle-aged adults.

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Relation between dry eye and myopia based on tear film breakup time, higher order aberration, choroidal thickness, and axial length

Hazra D., Yotsukura E., Torii H., Mori K., Maruyama T., Ogawa M., Hanyuda A., Tsubota K., Kurihara T., Negishi K.

Scientific Reports （Scientific Reports）  12 （ 1 ） 10891 2022年12月

査読有り

　概要を見る

The purpose of this study was to investigate the association between dry eye disease (DED) and myopia by evaluating higher order aberrations (HOAs) and choroidal thickness (CT). We recruited 72 myopic children with DED symptoms (mean age 12.8 years), measured the tear film breakup time (TBUT), corneal/intraocular/total ocular HOAs, CT, and axial length (AL), administered lifestyle questionnaires, and evaluated the relationships among TBUT, HOAs, CT, and AL. The TBUT was correlated significantly with the corneal HOAs and intraocular HOAs but not with the total ocular HOAs. Multiple regression analyses showed that the AL was associated significantly with the TBUT (β = − 0.067, P = 0.004), the intraocular HOAs, and total ocular HOAs but not with the corneal HOAs. The CT was associated significantly with the TBUT and AL (β = 9.15 and − 7.85, respectively; P < 0.001 and = 0.01, respectively). Our data suggested the association between DED and myopia might be independent of the HOAs. We showed that the TBUT was associated with the CT, which is related to the AL. Because the parasympathetic nervous system affects the lacrimal glands and CT, the parasympathetic nervous system might be a common upstream factor in the association between DED and myopia.

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Nicotinamide Mononucleotide Protects against Retinal Dysfunction in a Murine Model of Carotid Artery Occlusion

Lee D, Tomita Y, Miwa Y, Jeong H, Shinojima A, Ban N, Yamaguchi S, Nishioka K, Negishi K, Yoshino J, Kurihara T†

Intl J Mol Sci. （International Journal of Molecular Sciences）  23 （ 23 ） 14711 2022年11月

最終著者, 責任著者, 査読有り,  ISSN  16616596

　概要を見る

Cardiovascular abnormality-mediated retinal ischemia causes severe visual impairment. Retinal ischemia is involved in enormous pathological processes including oxidative stress, reactive gliosis, and retinal functional deficits. Thus, maintaining retinal function by modulating those pathological processes may prevent or protect against vision loss. Over the decades, nicotinamide mononucleotide (NMN), a crucial nicotinamide adenine dinucleotide (NAD+) intermediate, has been nominated as a promising therapeutic target in retinal diseases. Nonetheless, a protective effect of NMN has not been examined in cardiovascular diseases-induced retinal ischemia. In our study, we aimed to investigate its promising effect of NMN in the ischemic retina of a murine model of carotid artery occlusion. After surgical unilateral common carotid artery occlusion (UCCAO) in adult male C57BL/6 mice, NMN (500 mg/kg/day) was intraperitoneally injected to mice every day until the end of experiments. Electroretinography and biomolecular assays were utilized to measure ocular functional and further molecular alterations in the retina. We found that UCCAO-induced retinal dysfunction was suppressed, pathological gliosis was reduced, retinal NAD+ levels were preserved, and the expression of an antioxidant molecule (nuclear factor erythroid-2-related factor 2; Nrf2) was upregulated by consecutive administration of NMN. Our present outcomes first suggest a promising NMN therapy for the suppression of cardiovascular diseases-mediated retinal ischemic dysfunction.

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Pemafibrate, a potent selective peroxisome proliferator-activated receptor α modulator, a promising novel treatment for ischemic retinopathy?

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

Neural Reg Res. （Neural Regeneration Research）  18 （ 7 ） 1495 - 1496 2022年11月

最終著者, 責任著者, 査読有り,  ISSN  1673-5374

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Therapeutic roles of PPARα activation in ocular ischemic diseases

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

Histol Histopathol. （Histology and histopathology）  38 （ 4 ） 18542 - 401 2022年10月

最終著者, 責任著者, 査読有り,  ISSN  02133911

　概要を見る

Ocular ischemia is one of the leading causes of blindness. It is related to various ocular diseases and disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma, and corneal injury. Ocular ischemia occurs due to an abnormal supply of oxygen and nutrients to the eye, resulting in ocular metabolic dysfunction. These changes can be linked with pathologic conditions in the eye, such as inflammation, neovascularization, and cell death, ultimately leading to vision loss. The current treatment care for ocular ischemia is limited. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor protein functioning in regulating lipid metabolism, fatty acid oxidation, and glucose homeostasis. Recently, PPARα activation has been suggested as a useful therapeutic target in treating ocular ischemia. However, its applications have not been well summarized. In this review, we cover an overview of the therapeutic roles of PPARα activation in various ocular ischemic conditions with recent experimental evidence and further provide clinical implications of its therapeutic applications. Our review will enable more approaches to comprehensively understand the therapeutic roles of PPARα activation for preventing ocular ischemic diseases.

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Short-Term Exposure to Violet Light Emitted from Eyeglass Frames in Myopic Children: A Randomized Pilot Clinical Trial

Torii H*†, Mori K*, Takashi Okano T, Kondo S, Yang HY, Yotsukura E, Hanyuda A, Ogawa M, Negishi K, Kurihara T†, Tsubota K†

J Clin Med. （Journal of Clinical Medicine）  11 （ 20 ） 6000 2022年10月

責任著者, 査読有り

　概要を見る

Violet light (VL), 360–400 nm wavelength, is contained in the sunlight and is an effective element for myopia suppression. This study is to investigate the safety and efficacy of novel eyeglasses that emit VL from the frames. This is a double-masked, randomized, pilot clinical trial conducted in a clinic in Japan. Forty-three children with myopia were enrolled. Participants were randomly assigned to two groups, wearing VL-emitting eyeglass frames (VLf) that emitted VL of 310 μW/cm2 (VLf group, n = 22) or pseudo-placebo eyeglass frames with a minimal emission of VL (<10 μW/cm2) (control group, n = 21). The exposure time was 3 h per day. The primary outcomes were visual acuity, tear film break-up time, corneal endothelial cell density, and the slit-lamp/fundus examinations. The secondary outcome was the 6-month changes in the axial lengths and cycloplegic refractions. Forty-one (95%) participants were included; twenty-one in the VLf group and twenty in the control group. No significant differences were seen in any safety evaluation. Significant changes were seen in axial elongation, choroidal thickness, and cycloplegic refractions in the subgroup analysis of 8- to 10-year-old children (p < 0.05), but otherwise no significant differences were seen. The VLf showed short-term safety and effectiveness against myopia progression.

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Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes

Ikeda SI, Kurihara T†, Jiang X, Miwa Y, Lee D, Serizawa N, Jeong H, Mori K, Katada Y, Kunimi H, Ozawa N, Shoda C, Ibuki M, Negishi K, Torii H, Tsubota K†

Nat Commun. （Nature Communications）  13 （ 1 ） 5859 2022年10月

責任著者, 査読有り

　概要を見る

Axial length is the primary determinant of eye size, and it is elongated in myopia. However, the underlying mechanism of the onset and progression of axial elongation remain unclear. Here, we show that endoplasmic reticulum (ER) stress in sclera is an essential regulator of axial elongation in myopia development through activation of both PERK and ATF6 axis followed by scleral collagen remodeling. Mice with lens-induced myopia (LIM) showed ER stress in sclera. Pharmacological interventions for ER stress could induce or inhibit myopia progression. LIM activated all IRE1, PERK and ATF6 axis, and pharmacological inhibition of both PERK and ATF6 suppressed myopia progression, which was confirmed by knocking down above two genes via CRISPR/Cas9 system. LIM dramatically changed the expression of scleral collagen genes responsible for ER stress. Furthermore, collagen fiber thinning and expression of dysregulated collagens in LIM were ameliorated by 4-PBA administration. We demonstrate that scleral ER stress and PERK/ATF6 pathway controls axial elongation during the myopia development in vivo model and 4-PBA eye drop is promising drug for myopia suppression/treatment.

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Degeneration of retinal ganglion cells in hypoxic responses: hypoxia-inducible factor inhibition, a new therapeutic insight

Lee D., Kunimi H., Negishi K., Kurihara T.

Neural Regeneration Research （Neural Regeneration Research）  17 （ 10 ） 2230 - 2231 2022年10月

査読有り,  ISSN  16735374

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