論文 - 栗原　俊英

Nicotinamide Mononucleotide Prevents Retinal Dysfunction in a Mouse Model of Retinal Ischemia/Reperfusion Injury

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

Int J Mol Sci. （International Journal of Molecular Sciences）  23 （ 19 ） 11228 2022年09月

最終著者, 責任著者, 査読有り,  ISSN  16616596

　概要を見る

Retinal ischemia/reperfusion (I/R) injury can cause severe vision impairment. Retinal I/R injury is associated with pathological increases in reactive oxygen species and inflammation, resulting in retinal neuronal cell death. To date, effective therapies have not been developed. Nicotinamide mononucleotide (NMN), a key nicotinamide adenine dinucleotide (NAD+) intermediate, has been shown to exert neuroprotection for retinal diseases. However, it remains unclear whether NMN can prevent retinal I/R injury. Thus, we aimed to determine whether NMN therapy is useful for retinal I/R injury-induced retinal degeneration. One day after NMN intraperitoneal (IP) injection, adult mice were subjected to retinal I/R injury. Then, the mice were injected with NMN once every day for three days. Electroretinography and immunohistochemistry were used to measure retinal functional alterations and retinal inflammation, respectively. The protective effect of NMN administration was further examined using a retinal cell line, 661W, under CoCl2-induced oxidative stress conditions. NMN IP injection significantly suppressed retinal functional damage, as well as inflammation. NMN treatment showed protective effects against oxidative stress-induced cell death. The antioxidant pathway (Nrf2 and Hmox-1) was activated by NMN treatment. In conclusion, NMN could be a promising preventive neuroprotective drug for ischemic retinopathy.

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Vascular endothelial growth factor from retinal pigment epithelium is essential in choriocapillaris and axial length maintenance

Zhang Y*, Jeong H*, Mori K, Ikeda SI, Shoda C, Miwa Y, Nakai A, Chen J, Ma Z, Jiang X, Torii H, Kubota Y, Negishi K, Kurihara T†, Tsubota K†

PNAS Nexus （PNAS Nexus）  1 （ 4 ） pgac166 2022年08月

責任著者, 査読有り

　概要を見る

Myopia,which prevalence is rapidly increasing, causes visual impairment; however, the onset mechanism of pathological axial length (AL) elongation remains unclear. A highly vascularized choroid between the retinal pigment epithelium (RPE) and sclera not only maintains physiological activities, but also contributes to ocular development and growth regulation. Vascular endothelial growth factor (VEGF) secreted from the RPE to the choroid is essential for retinal function and maintenance of the choriocapillaris. Herein, we demonstrated that the loss of VEGF secreted fromthe RPE caused abnormal choriocapillaris development and AL elongation, with features similar to those of the lens-induced myopia (LIM) mouse model, whereas VEGF overexpression by knocking-out von Hippel Lindau (VHL) specific to the RPE expands the choriocapillaris and shortens the AL. Additionally, LDL Receptor Related Protein 2 (LRP2) deletion in the RPE downregulated VEGF expression and leads to pathological AL elongation. Furthermore, high-myopia patientswithout choriocapillaris demonstrated longer ALs than did those with preserved choriocapillaris. These results suggest that physiological secretion of VEGF from the RPE is required for proper AL development by maintaining the choriocapillaris. The pinpoint application of VEGF to the choriocapillaris may become a potential intervention for the prevention and treatment of axial myopia progression.

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Automatic segmentation of non-perfusion area from fluorescein angiography using deep learning with uncertainty estimation

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

Inform Med Unlocked. （Informatics in Medicine Unlocked）  32   101060 - 101060 2022年08月

最終著者, 責任著者, 査読有り,  ISSN  2352-9148

　概要を見る

The non-perfusion area (NPA) of the retina is an important indicator in the visual prognosis of patients with retinal vein occlusion. Therefore, automatic detection of NPA will help its management. Deep learning models for NPA segmentation in fluorescein angiography have been reported. However, typical deep learning models do not adequately address the uncertainty of the prediction, which may lead to missed lesions and difficulties in working with medical professionals. In this study, we developed deep segmentation models with uncertainty estimation using Monte Carlo dropout and compared the accuracy of prediction and reliability of uncertainty in different models (U-Net, PSPNet, and DeepLabv3+) and uncertainty measures (standard deviation and mutual information). The study included 403 Japanese fluorescein angiography images of retinal vein occlusion. The mean Dice scores were 65.6 ± 9.6%, 66.8 ± 12.3%, and 73.6 ± 9.4% for U-Net, PSPNet, and DeepLabv3+, respectively. The uncertainty scores were best for U-Net, which suggests that the model complexity may deteriorate the quality of uncertainty estimation. Over-looked lesions and inconsistent prediction led to high uncertainty values. The results indicated that the uncertainty estimation would help decrease the risk of missed lesions.

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Retinal degeneration induced in a mouse model of ischemia–reperfusion injury and its management by pemafibrate treatment

Lee D, Nakai A, Miwa Y, Tomita Y, Kunimi H, Chen J, Ikeda SI, Tsubota K, Negishi K, Kurihara T†

FASEB J. （FASEB Journal）  36 （ 9 ） e22497 2022年08月

最終著者, 責任著者, 査読有り,  ISSN  08926638

　概要を見る

Retinal ischemia–reperfusion (I/R) injury is a common cause of visual impairment. To date, no effective treatment is available for retinal I/R injury. In addition, the precise pathological mechanisms still need to be established. Recently, pemafibrate, a peroxisome proliferator-activated receptor α (PPARα) modulator, was shown to be a promising drug for retinal ischemia. However, the role of pemafibrate in preventing retinal I/R injury has not been documented. Here, we investigated how retinal degeneration occurs in a mouse model of retinal I/R injury by elevation of intraocular pressure and examined whether pemafibrate could be beneficial against retinal degeneration. Adult mice were orally administered pemafibrate (0.5 mg/kg/day) for 4 days, followed by retinal I/R injury. The mice were continuously administered pemafibrate once every day until the end of the experiments. Retinal functional changes were measured using electroretinography. Retina, liver, and serum samples were used for western blotting, quantitative PCR, immunohistochemistry, or enzyme linked immunosorbent assay. Retinal degeneration induced by retinal inflammation was prevented by pemafibrate administration. Pemafibrate administration increased the hepatic PPARα target gene expression and serum levels of fibroblast growth factor 21, a neuroprotective molecule in the eye. The expression of hypoxia-response and pro-and anti-apoptotic/inflammatory genes increased in the retina following retinal I/R injury; however, these changes were modulated by pemafibrate administration. In conclusion, pemafibrate is a promising preventive drug for ischemic retinopathies.

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Children in Tokyo Have a Long Sustained Axial Length from Age 3 Years: The Tokyo Myopia Study

Maruyama T*, Yotsukura E*, Torii H*†, Mori K, Inokuchi M, Tokumura M, Hazra D, Ogawa M, Hanyuda A, Tsubota K, Kurihara T†, Negishi K†

J Clin Med. （Journal of Clinical Medicine）  11 （ 15 ） 4413 2022年07月

責任著者, 査読有り

　概要を見る

Background: myopia prevalence is high among Japanese schoolchildren, but the underlying causes are unclear. Objective: To examine the distributions of ocular biometry and refraction and their associations with lifestyle variables among Japanese schoolchildren. Methods: This cross-sectional school-based study included 2140 children aged 3–14 years in Tokyo, Japan, and evaluated the distributions under non-cycloplegic conditions and the associated environmental factors. Results: The prevalence of spherical equivalent (SE) ≤−0.75 diopter among preschoolers (aged 3–6 years), elementary school students (aged 6–11 years), and junior high school students (aged 12–14 years) was 49.7%, 72.4%, and 87.7%, respectively. Multiple linear regression analyses showed that the time spent using digital devices was associated positively with lens thickness (β = 0.010; p < 0.050) but not SE, axial length, or vitreous chamber depth. The time spent reading was associated negatively with lens thickness (β = −0.012; p < 0.050), SE (β = −0.152; p < 0.010), axial length (β = 0.110; p < 0.001), and vitreous chamber depth (β = 0.110; p < 0.001). Conclusions: The data indicated that almost half of preschoolers may be myopic. The association with the lens thickness differed depending on the type of near work performed.

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Lipidomic analysis revealed n-3 polyunsaturated fatty acids suppressed choroidal thinning and myopia progression in mice

Mori K., Kuroha S., Hou J., Jeong H., Ogawa M., Ikeda S.I., Kang J.X., Negishi K., Torii H., Arita M., Kurihara T., Tsubota K.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology （FASEB journal : official publication of the Federation of American Societies for Experimental Biology）  36 （ 6 ） e22312 2022年06月

査読有り,  ISSN  08926638

　概要を見る

Myopia is increasing worldwide and its preventable measure should urgently be pursued. N-3 polyunsaturated fatty acids (PUFAs) have been reported to have various effects such as vasodilative and anti-inflammatory, which myopia may be involved in. This study is to investigate the inhibitory effect of PUFAs on myopia progression. A lens-induced myopia (LIM) model was prepared using C57B L6/J 3-week-old mice, which were equipped with a -30 diopter lens to the right eye. Chows containing two different ratios of n-3/n-6 PUFA were administered to the mice, and myopic shifts were confirmed in choroidal thickness, refraction, and axial length in the n-3 PUFA-enriched chow group after 5 weeks. To exclude the possibility that the other ingredients in the chow may have taken the suppressive effect, fat-1 transgenic mice, which can produce n-3 PUFAs endogenously, demonstrated significant suppression of myopia. To identify what elements in n-3 PUFAs took effects on myopia suppression, enucleated eyes were used for targeted lipidomic analysis, and eicosapentaenoic acid (EPA) were characteristically distributed. Administration of EPA to the LIM model confirmed the inhibitory effect on choroidal thinning and myopia progression. Subsequently, to identify the elements and the metabolites of fatty acids effective on myopia suppression, targeted lipidomic analysis was performed and it demonstrated that metabolites of EPA were involved in myopia suppression, whereas prostaglandin E2 and 14,15-dihydrotestosterone were associated with progression of myopia. In conclusion, EPA and its metabolites are related to myopia suppression and inhibition of choroidal thinning.

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Multiple Factors Causing Myopia and the Possible Treatments: A Mini Review

Shinojima A., Negishi K., Tsubota K., Kurihara T.

Frontiers in Public Health （Frontiers in Public Health）  10   897600 2022年05月

　概要を見る

The myopia epidemic has become a global public health problem. Although myopia is progressing worldwide, the recent coronavirus infections 2019 (COVID-19) outbreak has spurred myopia progression. The current evidence-based treatments for humans are atropine eye drops, optical treatment with defocus, use of orthokeratology, extending proximity working distance, pausing from near work every half hour and increased time outside the home. Studies on myopia using animal models have been conducted for more than 40 years. In recent years, new mechanisms of myopia suppression have been revealed from animal experiments such as inflammation control, intraocular pressure control, light control, and the activity of early growth response protein 1 control. This mini-review provides a summary of the scientific evidence currently available on the control of myopia, and the possible treatments mitigating myopia.

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Ocular Ischemic Syndrome and Its Related Experimental Models

Lee D., Tomita Y., Yang L., Negishi K., Kurihara T.

International Journal of Molecular Sciences （International Journal of Molecular Sciences）  23 （ 9 ） 5249 - 5249 2022年05月

査読有り,  ISSN  16616596

　概要を見る

Ocular ischemic syndrome (OIS) is one of the severe ocular disorders occurring from stenosis or occlusion of the carotid arteries. As the ophthalmic artery is derived from the branch of the carotid artery, stenosis or occlusion of the carotid arteries could induce chronic ocular hypoperfusion, finally leading to the development of OIS. To date, the pathophysiology of OIS is still not clearly unraveled. To better explore the pathophysiology of OIS, several experimental models have been developed in rats and mice. Surgical occlusion or stenosis of common carotid arteries or internal carotid arteries was conducted bilaterally or unilaterally for model development. In this regard, final ischemic outcomes in the eye varied depending on the surgical procedure, even though similar findings on ocular hypoperfusion could be observed. In the current review, we provide an overview of the pathophysiology of OIS from various experimental models, as well as several clinical cases. Moreover, we cover the status of current therapies for OIS along with promising preclinical treatments with recent advances. Our review will enable more comprehensive therapeutic approaches to prevent the development and/or progression of OIS.

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Non-Perfusion Area Index for Prognostic Prediction in Diabetic Retinopathy

Ofuji Y., Katada Y., Tomita Y., Nagai N., Sonobe H., Watanabe K., Shinoda H., Ozawa Y., Negishi K., Tsubota K., Kurihara T.

Life （Life）  12 （ 4 ） 542 - 542 2022年04月

査読有り

　概要を見る

Fundus fluorescent angiography is a standard examination in Japan that can directly visualize the circulatory failure in diabetic retinopathy but is not used in Western countries. In this study, we examine the relationship between the non-perfusion area in fundus fluorescent angiography and the progression of diabetic retinopathy. We evaluated 22 eyes between 22 patients who had their first fundus fluorescent angiography during a clinical episode at Keio University Hospital from January 2012 to May 2015, were diagnosed as having preproliferative diabetic retinopathy, and could be followed for at least three years. The non-perfusion area index (%) in nine segmented fundi in the initial fundus fluorescent angiography was calculated, and the progression to proliferative diabetic retinopathy over three years was evaluated. Three out of the 22 eyes (13.6%) developed proliferative diabetic retinopathy over three years. The non-perfusion area index for the initial fundus fluorescent angiography was significantly associated with progression to proliferative diabetic retinopathy. The non-perfusion area index in the posterior pole was most strongly correlated with the progression to proliferative diabetic retinopathy. Thus, the non-perfusion area index in the posterior pole among those with preproliferative diabetic retinopathy may predict the progression to proliferative diabetic retinopathy in the subsequent three years.

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HIF Inhibition Therapy in Ocular Diseases

Lee D., Miwa Y., Kunimi H., Ibuki M., Shoda C., Nakai A., Kurihara T.

Keio Journal of Medicine （Keio Journal of Medicine）  71 （ 1 ） 1 - 12 2022年

査読有り,  ISSN  00229717

　概要を見る

The uncontrolled growth of blood vessels is a major pathological factor in human eye diseases that can result in blindness. This effect is termed ocular neovascularization and is seen in diabetic retinopathy, age-related macular degeneration, glaucoma and retinopathy of prematurity. Current treatments for these diseases include laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents and vitreoretinal surgery. Although strategies to inhibit VEGF have proved to be dramatically successful in some clinical studies, there remains the possibility of significant adverse effects regarding the blockade of crucial physiological roles of VEGF and the invasive nature of the treatments. Moreover, it is evident that other pro-angiogenic factors also play important roles in the development of these diseases, as seen in cases in which antiVEGF therapies have failed. Therefore, new types of effective treatments are required. In this review, we discuss a promising strategy for the treatment of ocular neovascular diseases, i.e., the inhibition of hypoxia-inducible factor (HIF), a master regulator of angiogenesis. We also summarize promising recently investigated HIF inhibitors as treatments for ocular diseases. This review will facilitate more comprehensive approaches to understanding the protective aspects of HIF inhibition in the prevention of ocular diseases. (DOI: 10.2302/kjm.2021-0004-IR; Keio J Med 71 (1): 1–12, March 2022).

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Retinal diseases regulated by hypoxia—basic and clinical perspectives: A comprehensive review

Shinojima A., Lee D., Tsubota K., Negishi K., Kurihara T.

Journal of Clinical Medicine （Journal of Clinical Medicine）  10 （ 23 ） 5496 2021年12月

査読有り

　概要を見る

In recent years, the number of patients with age-related macular degeneration (AMD) is increasing worldwide along with increased life expectancy. Currently, the standard treatment for wet-AMD is intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs. The upstream of VEGF is hypoxia-inducible factor (HIF), a master regulator of hypoxia-responsive genes responsive to acute and chronic hypoxia. HIF activation induces various pathological pro-angiogenic gene expressions including VEGF under retinal hypoxia, ultimately leading to the development of ocular ischemic neovascular diseases. In this regard, HIF is considered as a promising therapeutic target in ocular ischemic diseases. In clinical ophthalmology, abnormal hypofluorescent areas have been detected in the late-phase of indocyanine green angiography, which are thought to be lipid deposits at the level of Bruch’s membrane to choriocapillaris in vitreoretinal diseases. These deposits may interfere with the oxygen and nutrients that should be supplied to the retinal pigment epithelium, and that HIF/VEGF is highly suspected to be expressed in the hypoxic retinal pigment epithelium, leading to neovascularization. In this review, we comprehensively summarize pathophysiology of AMD-related ocular diseases with the HIF/VEGF pathway from basic and clinic researches with recent findings.

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Association between ocular axial length and anthropometrics of Asian adults

Shinojima A., Kurihara T., Mori K., Iwai Y., Hanyuda A., Negishi K., Torii H., Tsubota K.

BMC Research Notes （BMC Research Notes）  14 （ 1 ） 328 - 328 2021年12月

査読有り

　概要を見る

Objective: The purpose of this study is to analyze axial length, body height, hand length, and foot length to find new factors that predict myopia and to identify gender differences as one of the factors of high myopia. A cross-sectional study was conducted as a single observation. Body height, hand length, and foot length were measured according to standard anthropometric methods. Axial length, retinal thickness, and choroidal thickness were measured using the IOL Master 700 and the Heidelberg Spectralis-OCT. To account for body height differences among participants, foot length/body height and hand length/body height were analyzed using a mixed-effects model. Results: A total of 80 eyes (men, n = 20, 40 eyes; women, n = 20, 40 eyes) were analyzed. The mean age was 33.5 years (range 21–59 years, SD: 9.6). For choroidal thickness, there was a significant association with axial length in men (p < 0.001) and a trend toward an association in women (p = 0.072). There was also a significant association between foot length/body height and axial length in men (p = 0.015), but not in women (p = 0.58). These results suggest that factors that determine body height and foot length may be related to axial length, although they vary by gender.

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Pparα modulation-based therapy in central nervous system diseases

Lee D., Tomita Y., Allen W., Tsubota K., Negishi K., Kurihara T.

Life （Life）  11 （ 11 ）  2021年11月

査読有り

　概要を見る

The burden of neurodegenerative diseases in the central nervous system (CNS) is increasing globally. There are various risk factors for the development and progression of CNS diseases, such as inflammatory responses and metabolic derangements. Thus, curing CNS diseases requires the modulation of damaging signaling pathways through a multitude of mechanisms. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ), and they work as master sensors and modulators of cellular metabolism. In this regard, PPARs have recently been suggested as promising therapeutic targets for suppressing the development of CNS diseases and their progressions. While the therapeutic role of PPARγ modulation in CNS diseases has been well reviewed, the role of PPARα modulation in these diseases has not been comprehensively summarized. The current review focuses on the therapeutic roles of PPARα modulation in CNS diseases, including those affecting the brain, spinal cord, and eye, with recent advances. Our review will enable more comprehensive therapeutic approaches to modulate PPARα for the prevention of and protection from various CNS diseases.

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Effect of violet light-transmitting eyeglasses on axial elongation in myopic children: A randomized controlled trial

Mori K., Torii H., Hara Y., Hara M., Yotsukura E., Hanyuda A., Negishi K., Kurihara T., Tsubota K.

Journal of Clinical Medicine （Journal of Clinical Medicine）  10 （ 22 ） 5462 2021年11月

査読有り

　概要を見る

The fact that outdoor light environment is an important suppressive factor against myopia led us to invent violet light-transmitting eyeglasses (VL glasses) which can transmit violet light (VL), 360–400 nm in wavelength, for the suppression of myopia, and can meanwhile block harmful ultra-violet waves from sunlight. The current study is a double-blinded randomized clinical trial to investigate the myopia-suppressive effect of VL glasses compared to conventional eyeglasses (placebo glasses) that do not transmit VL. The subjects were children aged from 6 to 12 years old, the population in which myopia progression is generally accelerated, and the myopia suppressive effect was followed up for two years in a city in Japan. Periodical ophthalmic examinations, interviews, and measurements of reflection and axial length under mydriasis were performed at the initial visit (the baseline) and at 1, 6, 12, 18, and 24 months. The mean change in axial length in the VL glasses group was significantly smaller than in the placebo glasses group when time for near-work was less than 180 min and when the subjects were limited to those who had never used eyeglasses before this trial (p < 0.01); however, this change was not significant without subgrouping. The suppressive rate for axial elongation in the VL glasses group was 21.4% for two years.

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Updates on the current treatments for diabetic retinopathy and possibility of future oral therapy

Tomita Y., Lee D., Tsubota K., Negishi K., Kurihara T.

Journal of Clinical Medicine （Journal of Clinical Medicine）  10 （ 20 ） 4666 2021年10月

査読有り

　概要を見る

Diabetic retinopathy (DR) is a complication of diabetes and one of the leading causes of vision loss worldwide. Despite extensive efforts to reduce visual impairment, the prevalence of DR is still increasing. The initial pathophysiology of DR includes damage to vascular endothelial cells and loss of pericytes. Ensuing hypoxic responses trigger the expression of vascular endothelial growth factor (VEGF) and other pro-angiogenic factors. At present, the most effective treatment for DR and diabetic macular edema (DME) is the control of blood glucose levels. More advanced cases require laser, anti-VEGF therapy, steroid, and vitrectomy. Pan-retinal photocoagulation for non-proliferative diabetic retinopathy (NPDR) is well established and has demonstrated promising outcomes for preventing the progressive stage of DR. Furthermore, the efficacy of laser therapies such as grid and subthreshold diode laser micropulse photocoagulation (SDM) for DME has been re-ported. Vitrectomy has been performed for vitreous hemorrhage and tractional retinal detachment for patients with PDR. In addition, anti-VEGF treatment has been widely used for DME, and re-cently its potential to prevent the progression of PDR has been remarked. Even with these treat-ments, many patients with DR lose their vision and suffer from potential side effects. Thus, we need alternative treatments to address these limitations. In recent years, the relationship between DR, lipid metabolism, and inflammation has been featured. Research in diabetic animal models points to peroxisome proliferator-activated receptor alpha (PPARα) activation in cellular metabolism and inflammation by oral fenofibrate and/or pemafibrate as a promising target for DR. In this paper, we review the status of existing therapies, summarize PPARα activation therapies for DR, and discuss their potentials as promising DR treatments.

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Shorter axial length is a risk factor for proliferative vitreoretinopathy grade C in eyes unmodified by surgical invasion

Minami S., Uchida A., Nagai N., Shinoda H., Kurihara T., Ban N., Terasaki H., Takagi H., Tsubota K., Sakamoto T., Ozawa Y.

Journal of Clinical Medicine （Journal of Clinical Medicine）  10 （ 17 ） 3944 2021年09月

査読有り

　概要を見る

Purpose: To investigate the risk factors for the development of proliferative vitreoretinopathy grade C (PVR-C), independent of prior surgical invasion. Methods: Patients who underwent surgery for rhegmatogenous retinal detachment were prospectively registered with the Japan-Retinal Detachment Registry, organized by the Japanese Retina and Vitreous Society, between February 2016 and March 2017. Data obtained from general ophthalmic examinations performed before and at 1, 3, and 6 months after surgery were analyzed. Results: We included 2013 eyes of 2013 patients (men, 1326 (65.9%); mean age, 55.2 ± 15.2 years) from amongst 3446 registered patients. Preoperative PVR-C was observed in 3.6% of patients. Propensity score matching revealed that a shorter axial length (AL) was a risk factor for preoperative PVR-C (OR (Odds Ratio), 0.81; 95%CI (Confidence Interval), 0.69 to 0.96; p = 0.015), which was a risk factor for surgical failure (OR, 4.22; 95%CI, 1.12 to 15.93; p = 0.034); the association was particularly significant for eyes with an AL < 25.0 mm (p = 0.016), while it was insignificant for eyes with an AL ≥ 25.0 mm. Conclusions: A shorter AL was related to the development of PVR-C before surgical invasion. Our results will help elucidate the fundamental pathogenesis of PVR and caution clinicians to meticulously examine eyes with a shorter AL to detect retinal detachment before PVR development.

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Pemafibrate prevents retinal dysfunction in a mouse model of unilateral common carotid artery occlusion

Lee D., Tomita Y., Jeong H., Miwa Y., Tsubota K., Negishi K., Kurihara T.

International Journal of Molecular Sciences （International Journal of Molecular Sciences）  22 （ 17 ） 9408 - 9408 2021年09月

査読有り,  ISSN  16616596

　概要を見る

Cardiovascular diseases lead to retinal ischemia, one of the leading causes of blindness. Retinal ischemia triggers pathological retinal glial responses and functional deficits. Therefore, maintaining retinal neuronal activities and modulating pathological gliosis may prevent loss of vi-sion. Previously, pemafibrate, a selective peroxisome proliferator-activated receptor alpha modu-lator, was nominated as a promising drug in retinal ischemia. However, a protective role of pem-afibrate remains untouched in cardiovascular diseases-mediated retinal ischemia. Therefore, we aimed to unravel systemic and retinal alterations by treating pemafibrate in a new murine model of retinal ischemia caused by cardiovascular diseases. Adult C57BL/6 mice were orally administered pemafibrate (0.5 mg/kg) for 4 days, followed by unilateral common carotid artery occlusion (UCCAO). After UCCAO, pemafibrate was continuously supplied to mice until the end of exper-iments. Retinal function (a-and b-waves and the oscillatory potentials) was measured using elec-troretinography on day 5 and 12 after UCCAO. Moreover, the retina, liver, and serum were sub-jected to qPCR, immunohistochemistry, or ELISA analysis. We found that pemafibrate enhanced liver function, elevated serum levels of fibroblast growth factor 21 (FGF21), one of the neuropro-tective molecules in the eye, and protected against UCCAO-induced retinal dysfunction, observed with modulation of retinal gliosis and preservation of oscillatory potentials. Our current data suggest a promising pemafibrate therapy for the suppression of retinal dysfunction in cardiovascular diseases.

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Glucose levels between the anterior chamber of the eye and blood are correlated based on blood glucose dynamics

Kurihara T., Lee D., Shinojima A., Kinoshita T., Nishizaki S., Arita Y., Hidaka Y., Nishi Y., Shirakawa Y., Kimura S., Tsuneyoshi Y., Torii H., Tsubota K., Negishi K.

PLoS ONE （PLoS ONE）  16 （ 9 September ） e0256986 2021年09月

査読有り

　概要を見る

Glycemic control is essential to manage metabolic diseases such as diabetes. Frequent measurements of systemic glucose levels with prompt managements can prevent organ damages. The eye is a glucose highly demanding organ in our body, and the anterior chamber (AC) in the eye has been suggested for a noninvasive blood glucose monitoring site. However, calculating blood glucose levels from measuring glucose levels in AC has been difficult and unclear. In this study, we aimed to examine glucose levels from AC and find a correlation with blood glucose levels. A total of 30 patients with cataracts (men and women, study 1; 7 and 3, study 2; 9 and 11) who visited Keio University Hospital from 2015 to 2018 and agreed to participate in this study were recruited. Glucose levels from AC and the blood were examined by a UV-hexokinase or H2O2-electrode method before/during the cataract surgery. These values were analyzed with regression analyses depending on the groups (blood glucose-ascending and descending groups). In the blood glucose-descending group, glucose levels from AC were strongly correlated with blood glucose levels (a high R2 value, 0.8636). However, the relatively moderate correlation was seen in the blood glucose-ascending group (a low R2 value, 0.5228). Taken together, we showed different correlation ratios on glucose levels between AC and the blood, based on blood glucose dynamics. Stacking data regarding this issue would enable establishing noninvasive blood glucose monitoring from measuring glucose levels in AC more correctly, which will be helpful for proper and prompt managements for glucose-mediated complications.

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Inhibition of the HIF-1α/BNIP3 pathway has a retinal neuroprotective effect

Kunimi H., Lee D., Ibuki M., Katada Y., Negishi K., Tsubota K., Kurihara T.

FASEB Journal （FASEB Journal）  35 （ 8 ） e21829 2021年08月

査読有り,  ISSN  08926638

　概要を見る

Retinal ischemia is a leading cause of irreversible blindness worldwide. Inner retinal dysfunction including loss of retinal ganglion cells is encountered in a number of retinal ischemic disorders. We previously reported administration of two different hypoxia-inducible factor (HIF) inhibitors exerted neuroprotective effects in a murine model of retinal ischemia/reperfusion (I/R) which mimics these disorders, as inner retinal degeneration could be involved in pathological HIF induction. However, this notion needs further investigation. Therefore, in this study, we attempted to use retina-specific Hif-1α conditional knockout (cKO) mice to uncover this notion more clearly under the same condition. Hif-1α cKO mice showed inner retinal neurodegeneration to a lesser extent than control mice. Hif-1α depletion in a murine 661W retinal cell line reduced cell death under pseudohypoxic and hypoxic conditions. Among hypoxia-related genes, the expression of BCL2 19 kDa protein-interacting protein 3 (Bnip3) was substantially upregulated in the inner retinal layer after retinal I/R. In this regard, we further examined Bnip3 depletion in retinal neurons in vitro and in vivo and found the similar neuroprotective effects. Our results support the notion that the HIF-1α/BNIP3 pathway may have a critical role in inner retinal neurodegeneration, which can be linked with the development of new promising therapeutics for inner retinal ischemic disorders.

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Retinal dysfunction induced in a mouse model of unilateral common carotid artery occlusion

Lee D., Jeong H., Miwa Y., Shinojima A., Katada Y., Tsubota K., Kurihara T.

PeerJ （PeerJ）  9   e11665 2021年06月

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Background. Retinal ischemic stresses are associated with the pathogenesis of various retinal vascular diseases. To investigate pathological mechanisms of retinal ischemia, reproducible, robust and clinically significant experimental rodent models are highly needed. Previously, we established a stable murine model of chronic hypoperfusion retinal injuries by permanent unilateral common carotid artery occlusion (UCCAO) and demonstrated chronic pathological processes in the ischemic retina after the occlusion; however, retinal functional deficits and other acute retinal ischemic injuries by UCCAO still remain obscure. In this study, we attempted to examine retinal functional changes as well as acute retinal ischemic alterations such as retinal thinning, gliosis and cell death after UCCAO. Methods. Adult mice (male C57BL/6, 6–8 weeks old) were subjected to UCCAO in the right side, and retinal function was primarily measured using electroretinography for 14 days after the surgery. Furthermore, retinal thinning, gliosis and cell death were investigated using optical coherence tomography, immunohistochemistry and TUNEL assay, respectively. Results. Functional deficits in the unilateral right retina started to be seen 7 days after the occlusion. Specifically, the amplitude of b-wave dramatically decreased while that of a-wave was slightly affected. 14 days after the occlusion, the amplitudes of both waves and oscillatory potentials were significantly detected decreased in the unilateral right retina. Even though a change in retinal thickness was not dramatically observed among all the eyes, retinal gliosis and cell death in the unilateral right retina were substantially observed after UCCAO. Conclusions. Along with previous retinal ischemic results in this model, UCCAO can stimulate retinal ischemia leading to functional, morphological and molecular changes in the retina. This model can be useful for the investigation of pathological mechanisms for human ischemic retinopathies and furthermore can be utilized to test new drugs for various ischemic ocular diseases.

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