著者

小川 健二郎 原 英彰 オガワ ケンジロウ ハラ ヒデアキ Kenjiro OGAWA Hideaki HARA

雑誌

岐阜薬科大学紀要 = The annual proceedings of Gifu Pharmaceutical University

巻号頁・発行日

vol.65, pp.20-27, 2016-06-30

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わたし達の目は、日常的に太陽の紫外線や酸素などの影響を受けている。加えて、スマートフォンやパソコンなど電子端末機器の普及が進む現代社会において、目に関するトラブルの増加が懸念される。視機能の維持は我々のQOLに大きく関わるため、薬剤による治療や進行の抑制とともに、食品の機能性による予防も重要である。健康食品素材として広く利用されるビルベリーは、ブルーベリーの近縁種にあたる果実であり、果皮および果実内部にポリフェノールの一種であるアントシアニン色素を多く含んでいる。ビルベリー由来アントシアニンが目に与える機能性としては、in vitroおよびin vivo 試験において、網膜神経節細胞保護作用や光刺激に対する網膜視細胞保護作用、血管新生抑制作用、網膜炎症の軽減による視機能低下抑制作用などが報告されている。一方で、ヒト臨床試験の報告が少ないことが課題とされていたが、2015 年4 月より新たな食品表示基準として機能性表示食品制度が施行されたことにより、ヒト臨床試験の報告が増えてきている。ビルベリーエキスに含まれるアントシアニン(以下、ビルベリー由来アントシアニン)においても新たな報告がなされている。ビルベリー由来アントシアニンを健常人が接種することで得られる機能性として、物の遠近を見る近見視力や毛様体筋の緊張状態、眼精疲労の客観的指標であるフリッカー値、および目の疲労感の主観的指標であるvisual analogue scale(VAS)スコアや自覚症状アンケートにおいて、プラセボ接種群と比較して有意な改善が示されている。そのため、機能性表示食品として、目のピント調節力を改善すること、目の疲労感を和らげることが表示されている。今後もさらにヒト臨床試験が実施されることで、新たな機能性が明らかになることが予想される。

著者

Takuya Ohba Shinichi Domoto Miyu Tanaka Shinsuke Nakamura Masamitsu Shimazawa Hideaki Hara

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.42, no.7, pp.1140-1145, 2019-07-01 (Released:2019-07-01)

参考文献数

36

被引用文献数

5 7

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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue of at least 6 months, in addition to symptoms such as muscle pain and muscle weakness. There is no treatment provides long-term benefits to most patients. Recently, clinical research suggested the involvement of pyruvate dehydrogenase (PDH) in ME/CFS. PDH is a crucial enzyme in the mitochondria matrix that links glycolysis to the tricarboxylic acid cycle and oxidative phosphorylation. However, it is little known whether PDH could be a therapeutic target. The purpose of this study was to establish ME/CFS in mice and to investigate the involvement of PDH in ME/CFS. To induce the chronic fatigue in mice, a repeated forced swimming test was conducted. To evaluate fatigue, we measured immobility time in forced swimming test and starting time of grooming. An open field test was conducted on day 8. After 25 d of the forced swimming test, the mitochondrial fraction in gastrocnemius muscle was isolated and PDH activity was measured. Moreover, we evaluated the effect of PDH activation by administering sodium dichloroacetate (DCA). In ME/CFS mice group, the immobility time and starting time of grooming increased time-dependently. In addition, the moved distance was decreased in ME/CFS mice. PDH activity was decreased in the mitochondrial fraction of the gastrocnemius muscle of the forced swimming group. DCA treatment may be beneficial in preventing fatigue-like behavior in ME/CFS. These findings indicate that ME/CFS model was established in mice and that a decrease in mitochondrial PDH activity is involved with the symptom of ME/CFS.

著者

Honoka Fujimori Takuya Ohba Shinsuke Nakamura Masamitsu Shimazawa Hideaki Hara

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.46, no.8, pp.1032-1040, 2023-08-01 (Released:2023-08-01)

参考文献数

61

被引用文献数

2

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Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor symptoms and neuropathological features, such as loss of dopaminergic neurons in the substantia nigra pars compacta and accumulation of alpha-synuclein (α-Syn). Progranulin (PGRN) is a secreted growth factor that exhibits anti-inflammatory properties and regulates lysosomal function. Although autophagy-lysosome pathway is the main degradative pathway for α-Syn, the molecular mechanistic relationship between PD and PGRN remains unclear. In this study, we investigated the role of PGRN in PD pathology. PGRN protein expression in striatum was increased in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice. Intracerebroventricular (i.c.v.) administration of PGRN ameliorated the decrease in expression of tyrosine hydroxylase, a dopaminergic neuron marker, in MPTP-treated mice. Furthermore, i.c.v. administration of PGRN ameliorated 6-hydroxydopamine-induced motor deficits. In SH-SY5Y human neuroblastoma cells, 1-methyl-4-phenylpyridinium ion (MPP+), an active metabolite of MPTP, increased α-Syn expression. In contrast, PGRN ameliorated MPP+-induced increase in α-Syn expression. Although PGRN decreased the levels of autophagy-related proteins Sequestosome-1 (p62) and MAP1LC3 (LC3)-II, PGRN did not influence the phosphorylation of AMP-activated protein kinase and mechanistic target of rapamycin, which are also proteins that regulate autophagy. Immunostaining analysis showed that PGRN ameliorated MPP+-induced increase of LC3 puncta, indicator of autophagosome, and co-localization of LC3 and α-Syn. The DALGreen assay showed that PGRN ameliorated MPP+-induced decreasing trend of autolysosomes. These results suggest that PGRN participates in α-Syn degradation via acceleration of the autophagy-lysosome pathway and is a potential therapeutic target for PD.

著者

Tomohiro Yako Yoshiki Kuse Shinsuke Nakamura Masamitsu Shimazawa Takashi Motomura Hideaki Hara

出版者

The Illuminating Engineering Institute of Japan

雑誌

Journal of Science and Technology in Lighting (ISSN:24323225)

巻号頁・発行日

vol.42, pp.29-32, 2019-03-27 (Released:2019-04-01)

参考文献数

12

被引用文献数

1

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Blue light emitting diode (LED) light is being used various devices for recent decades. Blue LED light has the 450–500 nm wavelengths, and high photon energy compared with green or red LED light. It is known that the exposure to blue LED light causes retinal photoreceptor cells damage. It is unknown whether the blue LED light cut particle containing lens has a protective effect against blue LED light-induced cell damage although the absorbance by colored lens shows a protective effect. Thus, the purpose of this study was to reveal that the protective effect of blue LED light cutting particle containing lens against photoreceptor and corneal epithelial cell damage induced by blue LED light exposure. We irradiated blue LED light to the mouse photoreceptor cells and human cornea epithelial cells with or without lens. The lens containing about one third blue LED light cutting particle (TECHPOLYMER) decreased production of reactive oxygen species and improved cell death rate and cell viability rate. These findings show that TECHPOLYMER containing lens may protect photoreceptor and cornea cells by reducing of reactive oxygen species.

著者

Mitsue Ishisaka Kenichi Kakefuda Mika Yamauchi Kazuhiro Tsuruma Masamitsu Shimazawa Akifumi Tsuruta Hideaki Hara

出版者

公益社団法人日本薬学会

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.34, no.9, pp.1481-1486, 2011-09-01 (Released:2011-09-01)

参考文献数

34

被引用文献数

18 71

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Depression is a significant public health problem and some reports indicate an association between depression and endoplasmic reticulum stress. Luteolin is a flavonoid contained in many plants and with a variety of known pharmacological properties such as anti-inflammatory, anti-anxiety, and memory-improving effects, suggesting that luteolin penetrates into the brain. In the present study, we investigated the effects of luteolin on endoplasmic reticulum stress-induced neuronal cell death. Luteolin significantly suppressed tunicamycin-induced cell death at 1 to 10 μM in human neuroblastoma cells. Luteolin increased in the expression of the 78 kDa glucose-regulated protein and 94 kDa glucose-regulated protein and decreased in the cleavage activation of caspase-3. Additionally, to investigate whether chronic luteolin treatment has an antidepression effect, we performed some behavioral tests. Chronic luteolin treatment showed antidepressant-like effects in behavioral tests and, luteolin attenuated the expression of endoplasmic reticulum stress-related proteins in the hippocampus of corticosterone-treated depression model mice. These findings indicate that luteolin has antidepressant-like effects, partly due to the suppression of endoplasmic reticulum stress.

著者

Wataru Otsu Hideaki Hara Kenjiro Ogawa

出版者

Japanese Society for Food Science and Technology

雑誌

Food Science and Technology Research (ISSN:13446606)

巻号頁・発行日

pp.FSTR-D-23-00032, (Released:2023-06-19)

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Retinal pigment epithelium (RPE) is an essential vision component of the human eye due to its nutritional and functional support to photoreceptors. Age-related macular degeneration (AMD) is a progressive, degenerative retinal disease characterized by RPE loss. Ultraviolet (UV) light exposure induces injurious effects on human eyes by generating excess reactive oxygen species (ROS) and is responsible for photoaging. Bilberry (Vaccinium myrtillus L.) and its extract (VME) are known for their potent antioxidant properties. In the present study, we examined the effect of VME on UVA-induced RPE injury. Using an in vitro system with human RPE (ARPE-19) cells, pretreatment with VME suppressed cell death, mitochondrial superoxide production, and activation of the stress response that occurs following UVA irradiation. Furthermore, VME attenuated rotenone-induced mitochondrial ROS and concomitant reduction in cell viability. Our findings suggest that VME has a protective effect against UVA-induced RPE cell damage.

著者

Kenjirou Ogawa Takara Karitani Wataru Otsu Kazuo Nishiyama Hisato Kunitake Yo Goto Shota Nomiyama Hideaki Hara Masao Yamasaki

出版者

The Pharmaceutical Society of Japan

雑誌

BPB Reports (ISSN:2434432X)

巻号頁・発行日

vol.6, no.3, pp.87-97, 2023 (Released:2023-05-26)

参考文献数

29

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Background: Blue light causes retinal photoreceptor damage via oxidative and endoplasmic reticulum (ER) stress. A previous study showed that blueberry stem extract (BStEx) and its active components have cytoprotective effects against blue-light-induced photoreceptor cell damage by suppressing oxidative stress. This study demonstrated the inhibitory effect of BStEx against blue light-induced ER stress in photoreceptor cells. Methods: The photoreceptor cells treated with BStEx or the antioxidant N-Acetyl-L-cysteine (NAC) as a positive control were used and then exposed to blue light. The cytoprotective effects of BStEx and NAC were evaluated using CCK-8. The ER stress-related protein expression changes over time, and its levels were measured after each exposure time to blue light in photoreceptor cells treated with BStEx or NAC. Results: BStEx and NAC showed protective effects against blue-light-induced photoreceptor morphological abnormalities and cell damage. Although blue light triggered ER stress factors such as BiP, PERK, ATF6, eIF2α, ATF4, and CHOP, which in turn stimulated cell cycle arrest factors p53 and p21 and upregulation of apoptosis-inducing factors caspase-3. However, BStEx suppressed the increase in expression of BiP, ATF4, ATF6, CHOP, p53, p21, and caspase-3, but not mitochondrial apoptotic factors Bax and cytochrome c. Furthermore, the antioxidant NAC showed similar suppressive effects on BStEx. Conclusion: Our findings suggest that blue light-induced ER stress is primarily caused by oxidative stress, and BStEx might suppress ER stress via an antioxidant effect. The antioxidant NAC contributes to the cell proliferative capacity and suppression of apoptosis in photoreceptor cells.

著者

Kodai Ishida Tomohiro Yako Miruto Tanaka Wataru Otsu Shinsuke Nakamura Masamitsu Shimazawa Hideshi Tsusaki Hideaki Hara

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.44, no.7, pp.937-946, 2021-07-01 (Released:2021-07-01)

参考文献数

45

被引用文献数

4

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The corneal epithelium is continuously exposed to oxygen, light, and environmental substances. Excessive exposure to those stresses is thought to be a risk factor for eye diseases. Photokeratitis is damage to the corneal epithelium resulting in a painful eye condition caused by unprotected exposure to UV rays, usually from sunlight, and is often found in people who spend a long time outdoors. In modern life, human eyes are exposed to artificial light from light-emitting diode (LED) displays of computers and smartphones, and it has been shown that short-wavelength (blue) LED light can damage eyes, especially photoreceptors. However, the effect of blue LED light on the cornea is less understood. In addition, it is important to develop new treatments for preserving human eyesight and eye health from light stress. Here, we used human corneal epithelial cells-transformed (HCE-T) cells as an in-vitro model to investigate the protective effect of NSP-116, an imidazolyl aniline derivative, against the oxidative stress induced by light in the corneal epithelium. Treatment with 10 µM NSP-116 significantly increased the cell viability and reduced the death ratio following UV or blue LED light exposure. Furthermore, NSP-116 treatment decreased light-induced reactive oxygen species production and preserved the mitochondrial membrane potential. Immunoblotting data showed that NSP-116 suppressed the stress response pathway. Finally, NSP-116 treatment prevented corneal epithelial apoptosis induced by blue LED light in an in-vivo mouse model. In conclusion, NSP-116 has a protective effect against oxidative stress and corneal cell death from both UV and blue LED light exposure.

著者

Yuichi Saito Hiroyuki Okuyoshi Shinsuke Nakamura Wataru Otsu Akihiro Yamaguchi Peter F. Hitchcock Mikiko Nagashima Masamitsu Shimazawa Hideaki Hara

出版者

The Pharmaceutical Society of Japan

雑誌

BPB Reports (ISSN:2434432X)

巻号頁・発行日

vol.3, no.3, pp.92-96, 2020 (Released:2020-11-26)

参考文献数

37

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Regenerative medicine aims to replenish damaged tissue. Boosting the capacity of intrinsic stem cells to proliferate is one key for successful regeneration. Adult zebrafish possess tissue resident stem and progenitor cells, which contribute to homeostatic growth and tissue regeneration. In the intact retina, Müller glia sporadically divide to generate fate restricted, proliferative precursors. Cell death reprograms Müller glia into stem cells that divide and produce multi-potent retinal progenitors. Using zebrafish, we evaluated the effect of taurine-conjugated bile acid, Tauroursodeoxycholic acid (TUDCA) on retinal regeneration. In the intact retina, treatment with TUDCA significantly promotes proliferation of the fate restricted precursors, but has no effect on Müller glia. Following constant light exposure, TUDCA attenuates photoreceptor death, indicating that TUDCA is neuroprotective. Following a stab wound, which initiates death of retinal neurons and reprogramming of Müller glia, treatment with TUDCA significantly increases the number of proliferating cells. In the intact retina, TUDCA-induced proliferation was accompanied by decreased expression of cell cycle inhibitors. These results suggest that TUDCA promotes proliferation of actively-cycling stem and progenitors, identifying TUDCA as a potential reagent to promote regeneration of retinal neurons.

著者

Maho Nakamura Yoshiki Kuse Kazuhiro Tsuruma Masamitsu Shimazawa Hideaki Hara

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.40, no.8, pp.1219-1225, 2017-08-01 (Released:2017-08-01)

参考文献数

32

被引用文献数

1 43

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The aim of study was to establish a mouse model of blue light emitting diode (LED) light-induced retinal damage and to evaluate the effects of the antioxidant N-acetylcysteine (NAC). Mice were exposed to 400 or 800 lx blue LED light for 2 h, and were evaluated for retinal damage 5 d later by electroretinogram amplitude and outer nuclear layer (ONL) thickness. Additionally, we investigated the effect of blue LED light exposure on shorts-wave-sensitive opsin (S-opsin), and rhodopsin expression by immunohistochemistry. Blue LED light induced light intensity dependent retinal damage and led to collapse of S-opsin and altered rhodopsin localization from inner and outer segments to ONL. Conversely, NAC administered at 100 or 250 mg/kg intraperitoneally twice a day, before dark adaptation and before light exposure. NAC protected the blue LED light-induced retinal damage in a dose-dependent manner. Further, blue LED light-induced decreasing of S-opsin levels and altered rhodopsin localization, which were suppressed by NAC. We established a mouse model of blue LED light-induced retinal damage and these findings indicated that oxidative stress was partially involved in blue LED light-induced retinal damage.