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杨淑然, 艾民, 吕淼淼, 杨毅敬, 肖莉, 徐剑, 彭清华.滋阴明目丸通过Nrf2/HO-1/GPX4通路抑制视网膜色素变性小鼠铁死亡的机制研究[J].湖南中医药大学学报,2026,46(2):259-267[点击复制] |
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| 滋阴明目丸通过Nrf2/HO-1/GPX4通路抑制视网膜色素变性小鼠铁死亡的机制研究 |
| 杨淑然,艾民,吕淼淼,杨毅敬,肖莉,徐剑,彭清华 |
| (湖南中医药大学中医学院, 湖南 长沙 410208;同济大学附属东方医院, 上海 200120;湖南中医药大学第一附属医院, 湖南 长沙 410007) |
| 摘要: |
| 目的 探讨滋阴明目丸对小鼠视网膜色素变性（RP）的改善作用及其可能机制。方法 选取12只C57BL/6J小鼠作为正常对照组，48只视网膜变性10型（rd10）小鼠随机分为模型组、乐盯组（0.13 g/kg）、滋阴明目丸低剂量组（5.20 g/kg）、滋阴明目丸高剂量组（10.40 g/kg），每组12只，每日灌胃1次，连续干预28 d。视网膜电图观测并记录A波与B波振幅；光学相干断层成像（OCT）观察小鼠眼底形态改变，以及观测眼底血流分布情况并检测视网膜的厚度；HE染色观察视网膜病理形态，测定外核层厚度；用Western blot检测小鼠视网膜组织核因子E2相关因子2（Nrf2）、血红素氧合酶1（HO-1）、谷胱甘肽过氧化酶4（GPX4）蛋白表达；ELISA检测视网膜组织中谷胱甘肽（GSH）、丙二醛（MDA）、超氧化物歧化酶（SOD）和亚铁离子（Fe2+）的水平。结果 与空白对照组比较，模型组小鼠视网膜电图的A波与B波振幅均降低（P＜0.01）；眼底血管明显变细、萎缩，视盘苍白；血流灌注显著减少；视网膜厚度降低（P＜0.01）；视网膜结构模糊，损伤明显，外核层厚度降低（P＜0.01）；视网膜组织中Nrf2、HO-1、GPX4蛋白表达水平下降（P＜0.05，P＜0.01）；视网膜组织中Fe2+、MDA水平升高（P＜0.01），SOD、GSH水平降低（P＜0.01）。与模型组相比，滋阴明目丸低、高剂量组和乐盯组小鼠视网膜电图的A波与B波振幅均升高（P＜0.01）；眼底血管较为清晰，血管充盈，眼底血流量增加；视网膜厚度增加（P＜0.01）；视网膜形态改善较明显；外核层厚度增加（P＜0.01）；视网膜组织中Nrf2、HO-1、GPX4蛋白表达水平升高（P＜0.01）；视网膜组织中Fe2+、MDA水平降低（P＜0.01），SOD、GSH水平升高（P＜0.01）。与滋阴明目丸低剂量组相比，滋阴明目丸高剂量组及乐盯组小鼠视网膜电图的A波与B波振幅均升高（P＜0.01）；眼底血管清晰，血流灌注增多；视网膜厚度增加（P＜0.01）；外核层厚度增加（P＜0.01）；滋阴明目丸高剂量组的Nrf2、HO-1、GPX4蛋白表达水平升高（P＜0.01），乐盯组的GPX4蛋白表达水平升高（P＜0.05）；滋阴明目丸高剂量组的Fe2+、MDA水平降低（P＜0.01），GSH水平升高（P＜0.05），乐盯组的Fe2+、MDA水平降低（P＜0.05），GSH、SOD水平升高（P＜0.01）。与滋阴明目丸高剂量组相比，乐盯组小鼠视网膜电图的A波与B波振幅均降低（P＜0.01）；眼底血管欠清晰，血流灌注减少；视网膜厚度降低（P＜0.01）；视网膜组织的Nrf2、HO-1、GPX4蛋白表达水平降低（P＜0.05，P＜0.01）；视网膜组织中Fe2+、MDA水平升高（P＜0.01），GSH、SOD水平降低（P＜0.01）。结论 滋阴明目丸可能通过Nrf2/HO-1/GPX4途径抑制RP小鼠铁死亡，改善视网膜结构和功能，延缓RP的进展。 |
| 关键词: 视网膜色素变性 滋阴明目丸 核因子E2相关因子2 血红素氧合酶1 谷胱甘肽过氧化酶4 铁死亡 |
| DOI：10.3969/j.issn.1674-070X.2026.02.006 |
| 投稿时间：2025-11-06 |
| 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;国家自然科学基金青年科学基金项目(82405487,82074196,82405179,82405490);国家中医药管理局中医眼科学重点学科建设项目(ZK1801YK015);湖南省教育厅科学研究项目(23A0278)。 |
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| Mechanism of Ziyin Mingmu Pill in inhibiting ferroptosis in retinitis pigmentosa mice via the Nrf2/HO-1/GPX4 pathway |
| YANG Shuran, AI Min, LYU Miaomiao, YANG Yijing, XIAO Li, XU Jian, PENG Qinghua |
| (School of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;The East Hospital Affiliated to Tongji University, Shanghai 200120, China;The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China) |
| Abstract: |
| Objective To investigate the ameliorative effects of Ziyin Mingmu Pill (ZYMMP) on retinitis pigmentosa (RP) in mice and the potential mechanisms. Methods Twelve C57BL/6J mice were selected as the normal control group, while forty-eight retinal degeneration 10 (rd10) mice were randomly allocated into four groups (12 mice per group):the model group, the low-dose Ziyin Mingmu Pills group (5.20 g/kg), the high-dose Ziyin Mingmu Pills group (10.40 g/kg), and the Leding group (0.13 g/kg). All groups received intragastric administration once daily for 28 consecutive days.Electroretinogram (ERG) was used to observe and record the amplitudes of the A-wave and B-wave; Optical coherence tomography (OCT) was used to observe morphological changes in the mouse fundus, assess the distribution of fundus blood flow, and measure the retinal thickness; Hematoxylin and eosin (HE) staining was used to observe retinal pathological morphology and measure the thickness of the outer nuclear layer (ONL); Western blot was used to detect the protein expression levels of Nrf2, HO-1, and GPX4 in mouse retinal tissue; Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and ferrous ion (Fe2+) in the retinal tissue. Results Compared with the blank control group, the amplitudes of both the A-wave and B-wave in the electroretinogram (ERG) were decreased in the model group (P<0.01); Markedly thinner and atrophic fundus vessels, a pale optic disc; Significantly decreased blood flow perfusion; A thinner average retinal thickness (P<0.01); Blurred retinal structure with obvious damage, a thinner ONL (P<0.01); Decreased protein expression levels of Nrf2, HO-1, and GPX4 in the retinal tissue (P<0.05, P<0.01), increased levels of Fe2+ and MDA in the retinal tissue (P<0.01), and decreased levels of SOD and GSH (P<0.01). Compared with the model group, the low-dose and high-dose Ziyin Mingmu Pills groups and the Leding group showed increased amplitudes of ERG A- and B-waves (P<0.01); Clearer and thicker fundus vessels, increased blood flow distribution; A increased full retinal thickness (P<0.01); Noticeably improved retinal morphology; A increased ONL thickness (P<0.01); Increased protein expression levels of Nrf2, HO-1, and GPX4 in the retinal tissue (P<0.01); Decreased levels of Fe2+ and MDA in the retinal tissue (P<0.01), and increased levels of SOD and GSH (P<0.01). Compared with the low-dose group of Ziyin Mingmu Pills, both the high-dose group of Ziyin Mingmu Pills and the Leding group showed increased amplitudes of the A-wave and B-waves in the mouse electroretinogram (ERG) (P<0.01); Clearer fundus vessels, increased blood flow perfusion; A increased retinal thickness (P<0.01); A increased ONL thickness (P<0.01); The high-dose Ziyin Mingmu Pills group showed increased protein expression levels of Nrf2, HO-1, and GPX4 (P<0.01), while the Leding group showed increased GPX4 protein expression (P<0.05); The high-dose Ziyin Mingmu Pills group showed decreased levels of Fe2+ and MDA (P<0.01) and increased GSH levels (P<0.05), the Leding group showed decreased levels of Fe2+ and MDA (P<0.05) and increased levels of GSH and SOD (P<0.01). Compared with the high-dose Ziyin Mingmu Pills group, the Leding group showed decreased amplitudes of ERG A- and B-waves (P<0.01); Less clear fundus vessels, decreased blood flow perfusion; A decreased retinal thickness (P<0.01); Decreased protein expression levels of Nrf2, HO-1, and GPX4 in the retinal tissue (P<0.05, P<0.01); The levels of Fe2+ and MDA in the retinal tissue were increased (P<0.01), and decreased levels of GSH and SOD (P<0.01). Conclusion Ziyin Mingmu Pills may inhibit ferroptosis and improve retinal structure and function in RP mice, potentially delaying the progression of RP, via the Nrf2/HO-1/GPX4 pathway. |
| Key words: retinitis pigmentosa Ziyin Mingmu Pill nuclear factor erythroid 2-related factor 2 heme oxygenase 1 glut-athione peroxidase 4 ferroptosis |
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