Ramalingam Mahesh, Jang Sujeong, Kim Seongryul, Bai Hyoungwoo, Jeong Gyeonghan, Kim Byeong C, Jeong Han-Seong
Department of Physiology, Chonnam National University Medical School, Hwasun 58128, Republic of Korea.
Department of Radiation Science, Korea Atomic Energy Research Institute (KAERI), Jeongeup 56212, Republic of Korea.
Biomedicines. 2024 Jul 31;12(8):1703. doi: 10.3390/biomedicines12081703.
Rotenone (ROT), the most significant rotenoid, which has shown anticancer activity, has also been reported to be toxic to normal cells, inducing Parkinson's disease (PD)-like neuronal loss with aggregation of α-synuclein (α-syn). To reduce the adverse effects of ROT, its derivative, rotenoisin A (ROA), is obtained by directly irradiating a ROT solution in methanol using γ-rays, which has been reported for potential anticancer properties. However, its PD-inducing effects have not yet been researched or reported. This study sought to compare the activities of ROA and ROT on the aggregation of α-syn, apoptosis, and autophagy in SH-SY5Y cells. ROA decreased cell survival less when compared with ROT on SH-SY5Y cells at 48 h in a dose-dependent manner. ROT (0.5 and 1 μM) and ROA (4 and 5 μM) decreased the expression of tyrosine hydroxylase. Western blot analysis of the Triton X-100 insoluble fraction revealed that both ROT and ROA significantly increased the levels of oligomeric, dimeric, and monomeric phosphorylated Serine129 α-syn and total monomeric α-syn. Moreover, both compounds decreased the proportion of neuronal nuclei, the neurofilament-heavy chain, and β3-tubulin. The phosphorylation of ERK and SAPK were reduced, whereas ROA did not act on Akt. Additionally, the increased Bax/Bcl-2 ratio further activated the downstream caspases cascade. ROT promoted the LC3BII/I ratio and p62 levels; however, different ROA doses resulted in different effects on autophagy while inducing PD-like impairments in SH-SY5Y cells.
鱼藤酮（ROT）是最重要的鱼藤酮类化合物，已显示出抗癌活性，但也有报道称其对正常细胞有毒性，可诱导帕金森病（PD）样神经元损失并伴有α-突触核蛋白（α-syn）聚集。为降低ROT的不良反应，其衍生物鱼藤素A（ROA）是通过使用γ射线直接照射甲醇中的ROT溶液获得的，据报道具有潜在的抗癌特性。然而，其诱导PD的作用尚未得到研究或报道。本研究旨在比较ROA和ROT对SH-SY5Y细胞中α-syn聚集、细胞凋亡和自噬的影响。在48小时时，与ROT相比，ROA以剂量依赖性方式对SH-SY5Y细胞的细胞存活率降低较少。ROT（0.5和1μM）和ROA（4和5μM）降低了酪氨酸羟化酶的表达。对Triton X-100不溶性部分的蛋白质免疫印迹分析表明，ROT和ROA均显著增加了寡聚体、二聚体和单体磷酸化丝氨酸129α-syn以及总单体α-syn的水平。此外，两种化合物均降低了神经元细胞核、神经丝重链和β3-微管蛋白的比例。ERK和SAPK的磷酸化降低，而ROA对Akt无作用。此外，Bax/Bcl-2比值的增加进一步激活了下游半胱天冬酶级联反应。ROT促进了LC3BII/I比值和p62水平；然而，不同剂量的ROA在诱导SH-SY5Y细胞出现PD样损伤的同时，对自噬产生了不同的影响。
