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艾民,李丹阳,周派,彭俊,杨毅敬,彭清华.滋阴明目方通过Akt/FoxO1/FasL通路抑制感光细胞凋亡治疗视网膜色素变性的机制研究[J].湖南中医药大学学报英文版,2024,44(2):206-212.[Click to copy
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| 滋阴明目方通过Akt/FoxO1/FasL通路抑制感光细胞凋亡治疗视网膜色素变性的机制研究 |
| 艾民,李丹阳,周派,彭俊,杨毅敬,彭清华 |
| (湖南中医药大学, 湖南 长沙 410208;湖南中医药大学, 湖南 长沙 410208;湖南中医药大学第一附属医院, 湖南 长沙 410007) |
| 摘要: |
| 目的 观察滋阴明目方对视网膜色素变性（retinitis pigmentosa，RP）小鼠视网膜组织中磷酸化蛋白激酶B（phosphorylated protein kinase B，p-Akt）、叉头框蛋白1（forkhead box transcription factor O1，FoxO1）以及凋亡相关因子配体（Fas ligand，FasL）表达的影响，探讨滋阴明目方抑制感光细胞凋亡的机制。方法 将60只rd10小鼠随机分为模型组、滋阴明目方低剂量组[10 g/（kg·d）]、滋阴明目方中剂量组[20 g/（kg·d）]、滋阴明目方高剂量组[40 g/（kg·d）]、维生素A组[5 g/（kg·d）]，每组12只；选取12只C57小鼠作为空白对照组（等量生理盐水），每组连续干预28 d。通过眼底照相观察小鼠眼底形态改变；进行视网膜电图检查并记录A波和B波振幅；HE染色观察病理形态学变化并测定外核层厚度；Western blot法检测小鼠视网膜组织pAkt、FoxO1、FasL、半胱氨酸天冬氨酸特异性蛋白（cysteine aspartate-specific protease，Caspase）-3和Caspase-8蛋白表达。结果 与空白对照组比较，模型组小鼠视盘苍白、变形，血管萎缩，视网膜电图的A波与B波振幅均降低（P<0.01），视网膜结构模糊，各层界限不清，感光细胞大量丧失，外核层明显变薄（P<0.01），视网膜组织中p-Akt蛋白表达水平明显降低（P<0.01），FoxO1、FasL、Caspase-3和Caspase-8蛋白表达水平明显升高（P<0.01）。与模型组比较，滋阴明目方中、高剂量组及维生素A组小鼠眼底血管较清晰，无视盘苍白表现；视网膜各层结构清晰，细胞排列相对整齐。与模型组、滋阴明目方低剂量组比较，滋阴明目方中、高剂量组的A波与B波振幅、视网膜外核层厚度均明显升高（P<0.01），维生素A组的B波振幅、视网膜外核层厚度明显升高（P<0.01）；与滋阴明目方中剂量组比较，滋阴明目方高剂量组的A波与B波振幅、视网膜外核层厚度均明显升高（P<0.01），维生素A组的A波与B波振幅均明显降低（P<0.01）；与滋阴明目方高剂量组比较，维生素A组的A波与B波振幅、视网膜外核层厚度均明显降低（P<0.01）。与模型组比较，滋阴明目方低、中、高剂量组和维生素A组p-Akt蛋白表达水平明显升高（P<0.01），FoxO1、FasL和Caspase-3蛋白表达水平降低（P<0.05，P<0.01），滋阴明目方中、高剂量组Caspase-8蛋白表达水平明显降低（P<0.01）。与滋阴明目方低剂量组比较，滋阴明目方高剂量组和维生素A组p-Akt蛋白表达水平明显升高（P<0.01），滋阴明目方中、高剂量组Fox O1、FasL、Caspase-3和Caspase-8蛋白表达水平明显降低（P<0.01）。与滋阴明目方中剂量组比较，滋阴明目方高剂量组和维生素A组p-Akt蛋白表达水平明显升高（P<0.01），滋阴明目方高剂量组FoxO1、Caspase-3和Caspase-8蛋白表达水平明显降低（P<0.01），维生素A组FoxO1、FasL、Caspase-3和Caspase-8蛋白表达水平明显升高（P<0.01）。与滋阴明目方高剂量组比较，维生素A组p-Akt蛋白表达水平明显降低（P<0.01），FoxO1、FasL、Caspase-3和Caspase-8蛋白表达水平明显升高（P<0.01）。结论 滋阴明目方可能通过调控Akt/FoxO1/FasL通路，增强p-Akt表达，抑制FoxO1及下游基因FasL、Caspase-3和Caspase-8的蛋白表达，从而减少rd10小鼠视网膜细胞的凋亡，保护视网膜结构和功能，延缓RP的进展。 |
| 关键词: 视网膜色素变性 滋阴明目方 磷酸化蛋白激酶B 叉头框蛋白1 凋亡相关因子配体 感光细胞 细胞凋亡 |
| DOI：10.3969/j.issn.1674-070X.2024.02.005 |
| Received:October 31, 2023 |
| 基金项目:国家中医药管理局国家中医药领军人才支持计划——“岐黄学者”计划项目；国家中医药管理局中医眼科学重点学科建设项目（ZK1801YK015）；国家自然科学基金面上项目（81574031）；“刘良院士工作站”指导项目（21YS002）；湖南省教育厅科研基金重点项目（21A0238）；湖南省研究生科研创新项目（2023CX84）。 |
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| Mechanism of Ziyin Mingmu Fomula in treating retinitis pigmentosa by inhibiting photoreceptor apoptosis through Akt/FoxO1/FasL pathway |
| AI Min,LI Danyang,ZHOU Pai,PENG Jun,YANG Yijing,PENG Qinghua |
| (Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China) |
| Abstract: |
| Objective To observe the effects of Ziyin Mingmu Fomula(ZYMMF) on the expressions of phosphorylated protein kinase B(p-Akt), forkhead box transcription factor O1(FoxO1), and Fas ligand(FasL) in the retinal tissue of mice with retinitis pigmentosa(RP), so as to explore the mechanism of ZYMMF in inhibiting photoreceptor apoptosis.Methods A total of 60 rd10mice were randomized into model group, low-, medium-, and high-dose ZYMMF groups [10 g/(kg·d), 20 g/(kg·d), and 40 g/(kg·d),respectively], and vitamin A group [5 g/(kg·d)], with 12 mice in each group. Additionally, twelve C57 mice were used as blank control group(equal amount of normal saline). Each group was continuously intervened for 28 d. Fundus photography was used to observe the morphological changes of the fundus of mice, and electroretinography was performed to record a-and b-wave amplitudes.HE staining was used to observe the pathological changes in the retinal tissue of mice and determine the thickness of the outer nuclear layer, and Western blot was used to check the protein expressions of p-Akt, FoxO1, FasL, cysteine aspartate-specific protease(Caspase)-3, and Caspase-8 in the retinal tissue.Results Compared with blank control group, the retina in model group showed pale and deformed optic disc, vascular atrophy, reduced amplitudes of both a-and b-waves in the electroretinogram(P<0.01), blurred retinal structure, unclear boundaries of each layer, massive loss of photoreceptor cells, significant thinning of the outer nuclear layer(P<0.01), significantly lower p-Akt protein expression level(P<0.01), and markedly higher protein expression levels of FoxO1, FasL, Caspase-3, and Caspase-8(P<0.01). Compared with model group, the fundus blood vessels in medium-and high-dose ZYMMF groups and vitamin A group were clearer, the optic disc showed no paleness, each layer of the retina was structured clearly, and the cells were arranged relatively neatly. Compared with model and low-dose ZYMMF groups, medium-and high-dose ZYMMF groups showed significantly increased a-and b-wave amplitudes and thicker outer nuclear layer of retina(P<0.01), and vitamin A group showed significantly increased b-wave amplitude and also obviously thicker outer nuclear layer of retina(P<0.01).Compared with medium-dose ZYMMF group, high-dose ZYMMF group showed significantly elevated a-and b-wave amplitudes and thicker outer nuclear layer of retina(P<0.01), while vitamin A group showed significantly decreased a-and b-wave amplitudes(P<0.01). Compared with high-dose ZYMMF group, vitamin A group showed obviously decreased a-and b-wave amplitudes and thinner outer nuclear layer of retina(P<0.01). Compared with model group, the protein expression level of p-Akt in low-, medium-,and high-dose ZYMMF groups and vitamin A group was significantly higher(P<0.01), while those of FoxO1, FasL, and Caspase-3were lower(P<0.05, P<0.01); the Caspase-8 protein expression level in medium-and high-dose ZYMMF groups was significantly reduced(P<0.01). Compared with low-dose ZYMMF group, the p-Akt protein expression level in high-dose ZYMMF and vitamin A groups was obviously elevated(P<0.01), and the protein expression levels of FoxO1, FasL, Caspase-3, and Caspase-8 in mediumand high-dose ZYMMF groups were significantly reduced(P<0.01). Compared with medium-dose ZYMMF group, the p-Akt protein expression level in high-dose ZYMMF and vitamin A groups was significantly higher(P <0.01), the protein expression levels of FoxO1, Caspase-3, and Caspase-8 in high-dose ZYMMF group were significantly lower(P <0.01), and those of FoxO1, FasL,Caspase-3, and Caspase-8 in vitamin A group were significantly higher(P<0.01). Compared with high-dose ZYMMF group, vitamin A group showed obviously lower p-Akt protein expression level(P<0.01) but significantly higher protein expression levels of FoxO1,FasL, Caspase-3, and Caspase-8(P<0.01).Conclusion ZYMMF may enhance p-Akt expression and inhibit protein expressions of FoxO1 and its downstream genes such as FasL, Caspase-3, and Caspase-8 by regulating Akt/FoxO1/FasL pathway, thereby reducing the retinal apoptosis in rd10 mice, protecting the retinal structure and function, and delaying the progression of RP. |
| Key words: retinitis pigmentosa Ziyin Mingmu Fomula phosphorylated protein kinase B forkhead box transcription factor O1 Fas ligand photoreceptor cell apoptosis |
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