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| 1.
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Higuchi, Akihiro ; 樋口, 明弘
概要:
金沢大学先端科学・社会共創推進機構<br />Dry eye syndrome is a multifactorial condition on the tear and ocular surface. Autologous serum e
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ye drop is an effective method for treating dry eye. Autologous serum eye drops are now widely used by specialists since a first report in 1975. The results of a systematic study showed that the efficacy of autologous serum eye drops remains ambiguous because its preparation methods and clinical application have not been standardized. To elucidate the efficacy of autologous serum eye drops, well-designed, large-scale, high-quality randomized controlled trials need to be conducted with standardized treatment and use. Since serum components are partially similar to tear components, autologous serum eye drops improve dry eye by supplying tear components such as growth factors, proteins, and vitamins. Adding to the evidence based on the treatment of dry eye, we have found a new treatment candidate from serum: selenoprotein P (SeP). The efficacy of SeP as a treatment for dry eye was revealed by applying SeP eye drops to a dry eye rat model. Compared with phosphate-buffered saline treatment, SeP eye drops significantly reduced the fluorescein score of the cornea and suppressed the oxidative stress in the cornea, which is related to onset of dry eye, leading to improved corneal disorder. We have developed a new dry eye model caused by oxidative stress that will be used to screen candidate molecules for antioxidative activity. © 2018 The Authors.
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| 2.
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Higuchi, Akihiro ; Erina Oonishi ; Kawakita, Tetsuya ; Tsubota, Kazuo ; 樋口, 明弘
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金沢大学先端科学・社会共創推進機構<br />Purpose: 2-hydroxy estradiol (2-OHE2) is a catechol derivative of 17β -Estradiol (E2) and it is s
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ynthesized from E2 catalyzed by cytochrome P4501A1. Previous studies reported that 2-OHE2 is a physiologic antioxidant in lipoproteins, liver microsomes, and the brain. Catechol derivatives show an anti-inflammatory effect through the inhibition of prostaglandin endoperoxide synthase (PGS) activity. Corneal erosion caused by dry eye is related to an increase in oxidative stress and inflammation in ocular surface cells. We investigated the therapeutic effects of 2-OHE2 on corneal damage caused by dry eye. Methods: Steroidal radical scavenging activity was confirmed through the electron spin resonance (ESR) method. PGS activity was measured using the COX Fluorescent Activity Assay Kit. To evaluate the effect of 2-OHE2 on the treatment for dry eye, 2-OHE2 was applied as an eye drop experiment using dry eye model rats. Results: 2-OHE2 scavenged tyrosyl radical and possibly suppressed oxidative stress in corneal epithelial cells. In addition, 2-OHE2 inhibited PGS activity, and 2-OHE2 is probably a competitive inhibitor of PGS. Corneal PGS activity was upregulated in the dry eye group. Therefore, 2-OHE2 eye drops improved corneal erosion in dry eye model rats. Conclusions: 2-OHE2 is a candidate for the treatment of dry eye through the suppression of inflammation and oxidative stress in the cornea. © 2016 Molecular Vision.
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| 3.
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Higuchi, Akihiro ; Kawakita, Tetsuya ; Tsubota, Kazuo ; 樋口, 明弘
概要:
金沢大学先端科学・社会共創推進機構<br />Purpose: To investigate the effect of desiccation on secretion of inflammatory cytokines in corne
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al epithelial cells and in the rat desiccation model. Methods: A human corneal epithelial cell line (CEPI) was grown in keratinocyte growth medium 2 (KGM2) to approximately 80% confluence. The medium was aspirated and dishes were left for 0 to 30 min with the cover left open to dry the cells (short-term desiccation). After desiccation, KGM2 was added to the dishes and collected from the dishes 15 min later to measure the concentrations of cytokines in the medium by sandwich enzyme immunoassay (ELISA). Viability of the cells was estimated with alamer blue. To study the effect of long-term desiccation, cultivated cells on transwells were used. After dessiccation for up to 8 h, the viability of the cells and levels of cytokines in the culture medium were examined. The expression of cytokines in the cornea of the dry eye model rat was measured by real-time PCR. Results: Short-term dessication of CEPI cells significantly increased the interleukin (IL)-6 level and slightly increased the tumor necrosis factor (TNF)-α level. Anti-IL-6 antibody partially suppressed cell death caused by desiccation. Upon long-term desiccation, IL-6 and IL-8 levels were increased. In the dry eye model rats, the IL-6 mRNA level in the cornea significantly increased, whereas TNF-α mRNA level slightly increased. Conclusions: Desiccation induced IL-6 expression in corneal epithelial cells, suggesting that IL-6 participates in desiccation-induced cell death. © 2011 Molecular Vision.
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| 4.
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Higuchi, Akihiro ; Inoue, Hiroyoshi ; Kawakita, Tetsuya ; Ogishima, Tadashi ; Tsubota, Kazuo ; 樋口, 明弘
概要:
金沢大学先端科学・社会共創推進機構<br />The ocular surface is strongly affected by oxidative stress, and anti-oxidative systems are maint
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ained in corneal epithelial cells and tear fluid. Dry eye is recognized as an oxidative stress-induced disease. Selenium compound eye drops are expected to be a candidate for the treatment of dry eye. We estimated the efficacy of several selenium compounds in the treatment of dry eye using a dry eye rat model. All of the studied selenium compounds were uptaken into corneal epithelial cells in vitro. However, when the selenium compounds were administered as eye drops in the dry eye rat model, most of the selenium compounds did not show effectiveness except for Se-lactoferrin. Se-lactoferrin is a lactoferrin that we prepared that binds selenium instead of iron. Se-lactoferrin eye drops suppressed the up-regulated expression of heme oxygenase-1, cyclooxygenase-2, matrix metallopeptidase-9, and interleukin-6 and also suppressed 8-OHdG production in the cornea induced by surgical removal of the lacrimal glands. Compared with Se-lactoferrin, apolactoferrin eye drops weakly improved dry eye in high dose. The effect of Se-lactoferrin eye drops on dry eye is possibly due to the effect of selenium and also the effect of apolactoferrin. Se-lactoferrin is a candidate for the treatment of dry eye via regulation of oxidative stress in the corneal epithelium. © 2012 Higuchi et al.
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| 5.
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Higuchi, Akihiro ; Takahashi, Kazuhiko ; Hirashima, Masaki ; Kawakita, Tetsuya ; Tsubota, Kazuo ; 樋口, 明弘
概要:
金沢大学先端科学・社会共創推進機構<br />The ocular surface is always attacked by oxidative stress, and cornea epithelial cells are suppos
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ed to have their own recovery system against oxidative stress. Therefore we hypothesized that tears supply key molecules for preventing oxidative stress in cornea. The potential target key molecule we focused is selenoprotein P (SeP). SeP is a carrier of selenium, which is an essential trace element for many animals, for oxidative stress metabolism in the organism, and was extremely expressed in lacrimal gland. An experiment was performed with SeP eye drops in a rat dry eye model, prepared by removing the lacrimal glands. The anticipated improvement in corneal dry eye index and the suppression of oxidative stress markers were observed in SeP eye drop group. Furthermore, the concentration of SeP was significantly higher in dry eye patients compared with normal volunteers. Collectively, we concluded that tear SeP is a key molecule to protect the ocular surface cells against environmental oxidative stress. © 2010 Higuchi et al.
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| 6.
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Higuchi, Akihiro ; Inoue, Hiroyoshi ; Kaneko, Yoshio ; Oonishi, Erina ; Tsubota, Kazuo ; 樋口, 明弘
概要:
金沢大学先端科学・社会共創推進機構<br />The ocular surface is strongly affected by oxidative stress, which causes many ocular diseases in
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cluding dry eye. Previously, we showed that selenium compounds, e.g., selenoprotein P and Se-lactoferrin, were candidates for treatment of dry eye. This paper shows the efficacy of Se-lactoferrin for the treatment of dry eye compared with Diquas as a control drug using two dry eye models and incorporation of lactoferrin into corneal epithelial cells via lactoferrin receptors. We show the efficacy of Se-lactoferrin eye drops in the tobacco smoke exposure rat dry eye model and short-term rabbit dry eye model, although Diquas eye drops were only effective in the short-term rabbit dry eye model. These results indicate that Se-lactoferrin was useful in the oxidative stress-causing dry eye model. Se-lactoferrin was taken into corneal epithelium cells via lactoferrin receptors. We identified LRP1 as the lactoferrin receptor in the corneal epithelium involved in lactoferrin uptake. Se-lactoferrin eye drops did not irritate the ocular surface of rabbits. Se-lactoferrin was an excellent candidate for treatment of dry eye, reducing oxidative stress by a novel mechanism. © 2016 The Author(s).
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| 7.
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樋口, 明弘 ; Higuchi, Akihiro
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金沢大学先端科学・社会共創推進機構 / 慶應義塾大学<br />涙腺にはステロイド合成系が発現しており、数種類のステロイドホルモンが合成されている。本研究では、涙腺における局所ステロイド合成酵素の発現解析を行い、局所ステロイドホルモンの涙腺
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における生理的役割を検討する。ドライアイモデルラットの涙腺中ステロイド合成酵素の活性を測定したところ、シトクロムP45017α活性の上昇が確認できた。この活性上昇はP45017αおよびシトクロムb5発現の上昇によるものであった。ドライアイモデルでは涙腺中ジヒドロテストステロン濃度が上昇しており、この変動はP45017α活性上昇に起因すると考えられた。涙腺機能は局所ステロイドホルモンによる調節を受けていると思われる。<br />The lacrimal gland function was affected by steroid hormones. According to the classical theories of endocrinology, steroid hormones are synthesized in specific organs and affect the target tissues. Recent studies showed that locally-synthesized steroid hormones acted on neighboring tissues including themselves in the hippocampus, islets of Langerhans, and musculus skeleti.Expression of steroidogenic enzymes was elucidated by real-time RT-PCR and Immunohistochemical analysis. Activity of steroidogenic enzymes was assayed using LC-MS/MS. In dry eye model rat, the activity of cytochrome P45017α increased accompanied with increase of expressions of P45017α and cytochrome b5 compared with normal rat. LC-MS/MS analysis revealed that dihydrotestosterone (DHT) in lacrimal glands increased in dry eye model rat. Increase of DHT was thought to be caused by increase of P45017α activity. It was considered that the function of lacrimal gland was regulated by locally-produced steroid hormones.<br />研究課題/領域番号:25462733, 研究期間(年度):2013 - 2015
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