The Novel Application of EUK‐134 in Retinal Degeneration: Preventing Mitochondrial Oxidative Stress‐Triggered Retinal Pigment Epithelial Cell Apoptosis by Suppressing MAPK/p53 Signaling Pathway

IF 4.4 3区医学 Q2 ENVIRONMENTAL SCIENCES

Environmental Toxicology Pub Date : 2024-09-13 DOI:10.1002/tox.24416

Shang‐Chun Tsou, Chen‐Ju Chuang, Chin‐Lin Hsu, Tzu‐Chun Chen, Jui‐Hsuan Yeh, Meilin Wang, Inga Wang, Yuan‐Yen Chang, Hui‐Wen Lin

{"title":"The Novel Application of EUK‐134 in Retinal Degeneration: Preventing Mitochondrial Oxidative Stress‐Triggered Retinal Pigment Epithelial Cell Apoptosis by Suppressing MAPK/p53 Signaling Pathway","authors":"Shang‐Chun Tsou, Chen‐Ju Chuang, Chin‐Lin Hsu, Tzu‐Chun Chen, Jui‐Hsuan Yeh, Meilin Wang, Inga Wang, Yuan‐Yen Chang, Hui‐Wen Lin","doi":"10.1002/tox.24416","DOIUrl":null,"url":null,"abstract":"Age‐related macular degeneration (AMD), a leading cause of blindness, is characterized by mitochondrial dysfunction of retinal pigment epithelium (RPE) cells. EUK‐134 is a mimetic of SOD2 and catalase, widely used for its antioxidant properties in models of light‐induced damage or oxidative stress. However, its effects on the retina are not yet clear. Here, we investigated the capability of EUK‐134 in averting AMD using sodium iodate (NaIO3)‐induced Balb/c mouse and ARPE‐19 cells (adult RPE cell line). In vivo, EUK‐134 effectively antagonized NaIO3‐induced retinal deformation and prevented outer and inner nuclear layer thinning. In addition, it was found that the EUK‐134‐treated group significantly down‐regulated the expression of cleaved caspase‐3 compared with the group treated with NaIO3 alone. Our results found that EUK‐134 notably improved cell viability by preventing mitochondrial ROS accumulation‐induced membrane potential depolarization‐mediated apoptosis in NaIO3‐inducted ARPE‐19 cells. Furthermore, we found that EUK‐134 could inhibit p‐ERK, p‐p38, p‐JNK, p‐p53, Bax, cleaved caspase‐9, cleaved caspase‐3, and cleaved PARP by increasing Bcl‐2 protein expression. Additionally, we employed MAPK pathway inhibitors by SB203580 (a p38 inhibitor), U0126 (an ERK inhibitor), and SP600125 (a JNK inhibitor) to corroborate the aforementioned observation. The results support that EUK‐134 may effectively prevent mitochondrial oxidative stress‐mediated retinal apoptosis in NaIO3‐induced retinopathy.","PeriodicalId":11756,"journal":{"name":"Environmental Toxicology","volume":null,"pages":null},"PeriodicalIF":4.4000,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Environmental Toxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/tox.24416","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENVIRONMENTAL SCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Age‐related macular degeneration (AMD), a leading cause of blindness, is characterized by mitochondrial dysfunction of retinal pigment epithelium (RPE) cells. EUK‐134 is a mimetic of SOD2 and catalase, widely used for its antioxidant properties in models of light‐induced damage or oxidative stress. However, its effects on the retina are not yet clear. Here, we investigated the capability of EUK‐134 in averting AMD using sodium iodate (NaIO3)‐induced Balb/c mouse and ARPE‐19 cells (adult RPE cell line). In vivo, EUK‐134 effectively antagonized NaIO3‐induced retinal deformation and prevented outer and inner nuclear layer thinning. In addition, it was found that the EUK‐134‐treated group significantly down‐regulated the expression of cleaved caspase‐3 compared with the group treated with NaIO3 alone. Our results found that EUK‐134 notably improved cell viability by preventing mitochondrial ROS accumulation‐induced membrane potential depolarization‐mediated apoptosis in NaIO3‐inducted ARPE‐19 cells. Furthermore, we found that EUK‐134 could inhibit p‐ERK, p‐p38, p‐JNK, p‐p53, Bax, cleaved caspase‐9, cleaved caspase‐3, and cleaved PARP by increasing Bcl‐2 protein expression. Additionally, we employed MAPK pathway inhibitors by SB203580 (a p38 inhibitor), U0126 (an ERK inhibitor), and SP600125 (a JNK inhibitor) to corroborate the aforementioned observation. The results support that EUK‐134 may effectively prevent mitochondrial oxidative stress‐mediated retinal apoptosis in NaIO3‐induced retinopathy.

查看原文本刊更多论文

EUK-134 在视网膜退化中的新应用：通过抑制 MAPK/p53 信号通路防止线粒体氧化应激引发视网膜色素上皮细胞凋亡

老年性黄斑变性（AMD）是导致失明的主要原因，其特征是视网膜色素上皮细胞（RPE）线粒体功能障碍。EUK-134 是 SOD2 和过氧化氢酶的模拟物，因其抗氧化特性而被广泛用于光诱导损伤或氧化应激模型。然而，它对视网膜的影响尚不明确。在此，我们使用碘酸钠（NaIO3）诱导的 Balb/c 小鼠和 ARPE-19 细胞（成人 RPE 细胞系）研究了 EUK-134 在避免 AMD 方面的能力。在体内，EUK-134 能有效拮抗 NaIO3 诱导的视网膜变形，并防止核外层和核内层变薄。此外，与单用 NaIO3 处理组相比，EUK-134 处理组显著下调了裂解的 Caspase-3 的表达。我们的研究结果发现，EUK-134 通过阻止线粒体 ROS 积累诱导的膜电位去极化介导的细胞凋亡，明显提高了 NaIO3 诱导的 ARPE-19 细胞的存活率。此外，我们还发现 EUK-134 可通过增加 Bcl-2 蛋白的表达来抑制 p-ERK、p-p38、p-JNK、p-p53、Bax、裂解的 caspase-9、裂解的 caspase-3 和裂解的 PARP。此外，我们还采用了 MAPK 通路抑制剂 SB203580（p38 抑制剂）、U0126（ERK 抑制剂）和 SP600125（JNK 抑制剂）来证实上述观察结果。这些结果证明，EUK-134 可有效防止 NaIO3 诱导的视网膜病变中线粒体氧化应激介导的视网膜凋亡。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Environmental Toxicology 环境科学-毒理学

CiteScore

7.10

自引率

8.90%

发文量

261

审稿时长

4.5 months

期刊介绍： The journal publishes in the areas of toxicity and toxicology of environmental pollutants in air, dust, sediment, soil and water, and natural toxins in the environment.Of particular interest are: Toxic or biologically disruptive impacts of anthropogenic chemicals such as pharmaceuticals, industrial organics, agricultural chemicals, and by-products such as chlorinated compounds from water disinfection and waste incineration; Natural toxins and their impacts; Biotransformation and metabolism of toxigenic compounds, food chains for toxin accumulation or biodegradation; Assays of toxicity, endocrine disruption, mutagenicity, carcinogenicity, ecosystem impact and health hazard; Environmental and public health risk assessment, environmental guidelines, environmental policy for toxicants.