Modulation of valosin-containing protein by Kyoto University Substances (KUS) as a novel therapeutic strategy for ischemic neuronal diseases.
Modulation of valosin-containing protein by Kyoto University Substances (KUS) as a novel therapeutic strategy for ischemic neuronal diseases.
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DOI：
10.4103/1673-5374.213540
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发表时间：
2017-08
影响因子：
6.1
通讯作者：
Ikeda HO
中科院分区：
文献类型：
--
作者：
Hata M;Ikeda HO
视网膜缺血导致几种威胁视力的疾病，包括糖尿病视网膜病变、视网膜动脉阻塞和视网膜静脉阻塞。细胞内三磷酸腺苷（ATP）耗尽和随后诱导的内质网（ER）应激被认为是缺血性视网膜细胞死亡的潜在机制。最近，我们发现萘衍生物可以抑制含有缬草酸的蛋白的ATP酶活性，所述蛋白在包括视网膜神经细胞在内的各种类型的细胞中普遍表达，具有强的细胞保护活性。基于其化学结构，我们开发了新型的含缬沙素的蛋白质调节剂，京都大学物质（KUSs），不仅抑制细胞内ATP耗竭，而且改善ER应激。通过KUSs抑制ER应激与几种神经退行性疾病（如青光眼和视网膜变性）的动物模型中的神经细胞存活相关。鉴于缺血性视网膜疾病的主要病理学，而不是细胞内ATP耗竭，是ER应激诱导的细胞死亡，KUSs可能提供一种新的策略，在缺血性条件下的细胞保护。因此，我们研究了KUS 121在视网膜缺血性损伤大鼠模型中的功效。玻璃体内注射KUS 121，这是视网膜疾病中临床上优选的药物施用途径，显著抑制了视网膜内变薄和视网膜细胞死亡，并维持了视觉功能。通过KUS调节含Valosin的蛋白是一种有前途的治疗缺血性视网膜疾病的新策略。
Retinal ischemia causes several vision-threatening diseases, including diabetic retinopathy, retinal artery occlusion, and retinal vein occlusion. Intracellular adenosine triphosphate (ATP) depletion and subsequent induced endoplasmic reticulum (ER) stress are proposed to be the underlying mechanisms of ischemic retinal cell death. Recently, we found that a naphthalene derivative can inhibit ATPase activity of valosin-containing protein, universally expressed within various types of cells, including retinal neural cells, with strong cytoprotective activity. Based on the chemical structure, we developed novel valosin-containing protein modulators, Kyoto University Substances (KUSs), that not only inhibit intracellular ATP depletion, but also ameliorate ER stress. Suppressing ER stress by KUSs is associated with neural cell survival in animal models of several neurodegenerative diseases, such as glaucoma and retinal degeneration. Given that a major pathology of ischemic retinal diseases, other than intracellular ATP depletion, is ER stress-induced cell death, KUSs may provide a novel strategy for cell protection in ischemic conditions. Hence, we investigated the efficacy of KUS121 in a rat model of retinal ischemic injury. Intravitreal injections of KUS121, which is clinically preferable route of drug administration in retinal diseases, significantly suppressed inner retinal thinning and retinal cell death, and maintained visual functions. Valosin-containing protein modulation by KUS is a promising novel therapeutic strategy for ischemic retinal diseases.
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影响因子：
4.6
作者：
Hasegawa T;Muraoka Y;Ikeda HO;Tsuruyama T;Kondo M;Terasaki H;Kakizuka A;Yoshimura N
通讯作者：
Yoshimura N
影响因子：
4
作者：
Nakano N;Ikeda HO;Hasegawa T;Muraoka Y;Iwai S;Tsuruyama T;Nakano M;Fuchigami T;Shudo T;Kakizuka A;Yoshimura N
通讯作者：
Yoshimura N
影响因子：
2.5
作者：
Li, Huiling;Zhu, Xiaohua;Tang, Luosheng
通讯作者：
Tang, Luosheng
影响因子：
13.7
作者：
Park, Sang Jun;Choi, Nam-Kyong;Woo, Se Joon
通讯作者：
Woo, Se Joon
影响因子：
30.8
作者：
Watts, GDJ;Wymer, J;Kimonis, VE
通讯作者：
Kimonis, VE