Gong Xin, Tan Zhijian, Xu Henghui, Jiang Xu, Chen Lei
Department of Neurosurgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410005, P. R. China.
Am J Chin Med. 2024;52(7):2131-2159. doi: 10.1142/S0192415X24500824. Epub 2024 Nov 30.
This study is to explore the effects of paeoniflorin (PF) on oxidative stress (OS) and inflammation in Parkinson's disease (PD) via the HSF1-NRF1 axis. SH-SY5Y cells were pretreated with PF and induced with α-synuclein preformed fibrils (PFF), followed by gain- and loss-of-function assays. Afterward, detection was conducted on cell viability, mitochondrial membrane potential ([Formula: see text]m), and reactive oxygen species (ROS), cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) levels. The binding of HSF1 to NRF1 promoter was evaluated. HSF1 and NRF1 expression was examined. Lastly, PD mouse models were established, followed by observation of the behavioral features of mice. Apoptosis; cleaved-Caspase 3, cleaved-Caspase 8, repulsive guidance molecule A (RGMa), GAP-43, and brain-derived neurotrophic factor (BDNF) expression; and superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), catalase (CAT), tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-6, and IL-10 levels were determined in mice and cells. HSF1 and NRF1 were downregulated, and HSF1 promoted NRF1 transcription and PF dose-dependently augmented HSF1 and NRF1 expression. PF dose-dependently reduced RGMa expression, ROS, MDA, TNF-α, IL-2, and IL-6 levels; mitigated apoptosis; and lowered cleaved-Caspase 3, cleaved-Caspase 8, COX-2, and iNOS expression while improving cell viability; increasing [Formula: see text]m, GAP-43, and BDNF expression; and raising SOD, GSH-Px, CAT, and IL-10 levels in PFF-induced SH-SY5Y cells. These effects were neutralized by HSF1 knockdown. In conclusion, PF dose-dependently activated the HSF1-NRF1 axis and alleviated OS and inflammation in PFF-treated mice, thereby impeding PD progression in mice.
本研究旨在通过热休克因子1（HSF1）-核呼吸因子1（NRF1）轴探讨芍药苷（PF）对帕金森病（PD）氧化应激（OS）和炎症的影响。用PF预处理SH-SY5Y细胞，并用α-突触核蛋白原纤维（PFF）诱导，随后进行功能获得和功能缺失实验。之后，检测细胞活力、线粒体膜电位（ΔΨm）、活性氧（ROS）、环氧化酶（COX）-2和诱导型一氧化氮合酶（iNOS）水平。评估HSF1与NRF1启动子的结合情况。检测HSF1和NRF1的表达。最后，建立PD小鼠模型，观察小鼠的行为特征。测定小鼠和细胞中的凋亡情况；裂解的半胱天冬酶3、裂解的半胱天冬酶8、排斥导向分子A（RGMa）、生长相关蛋白43（GAP-43）和脑源性神经营养因子（BDNF）的表达；以及超氧化物歧化酶（SOD）、丙二醛（MDA）、谷胱甘肽过氧化物酶（GSH-Px）、过氧化氢酶（CAT）、肿瘤坏死因子（TNF）-α、白细胞介素（IL）-2、IL-6和IL-10水平。HSF1和NRF1表达下调，HSF1促进NRF1转录，PF剂量依赖性地增加HSF1和NRF1的表达。PF剂量依赖性地降低RGMa表达、ROS、MDA、TNF-α、IL-2和IL-6水平；减轻凋亡；降低裂解的半胱天冬酶3、裂解的半胱天冬酶8、COX-2和iNOS的表达，同时提高细胞活力；增加ΔΨm、GAP-43和BDNF的表达；提高PFF诱导的SH-SY5Y细胞中SOD、GSH-Px、CAT和IL-10水平。这些作用被HSF1基因敲低所中和。总之，PF剂量依赖性地激活HSF1-NRF1轴，减轻PFF处理小鼠的OS和炎症，从而阻碍小鼠PD的进展。
