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廉艺童,刘志敏,聂辅娇,胡卓瑜,付美林,胡齐,江婕妤,陈向东.益肝明目汤对糖尿病视网膜水肿模型大鼠NLRP3/Caspase-1信号通路的影响[J].湖南中医药大学学报英文版,2023,43(3):421-429.[Click to copy
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| 益肝明目汤对糖尿病视网膜水肿模型大鼠NLRP3/Caspase-1信号通路的影响 |
| 廉艺童,刘志敏,聂辅娇,胡卓瑜,付美林,胡齐,江婕妤,陈向东 |
| (湖南中医药大学第一附属医院, 湖南 长沙 410007;湖南中医药大学, 湖南 长沙 410208) |
| 摘要: |
| 目的 观察益肝明目汤对糖尿病视网膜水肿模型大鼠NOD样受体热蛋白结构域相关蛋白3（NOD-like receptor thermal protein domain associated protein 3, NLRP3）/半胱氨酸天冬氨酸特异性蛋白酶-1（cysteine aspartate-specific proteinase-1, Caspase-1）信号通路的影响，从细胞焦亡的角度探讨其治疗糖尿病视网膜水肿的作用机制。方法 将36只SD大鼠随机分为空白组（6只）和造模组（30只）。采用一次性腹腔注射40 mg/kg链脲佐菌素（streptozocin, STZ）溶液联合高糖高脂饲料喂养建立糖尿病视网膜水肿大鼠模型。将成模大鼠随机分为模型组，安多明组，低、中、高剂量组，每组6只，分别予以蒸馏水、羟苯磺酸钙胶囊（0.09 g/kg）、益肝明目汤（2.8、5.6、11.2 g/kg）进行灌胃，每日2次，连续4周。观察大鼠一般生物学特征，监测不同时期血糖、体质量变化；采用眼底荧光血管造影（fundus fluorescence angiography, FFA）和光学相关断层扫描技术（optical correlation tomography, OCT）观测各阶段视网膜血管渗漏及视网膜厚度的变化；HE染色检测视网膜组织病理变化；免疫组化法检测视网膜组织NLRP3与衔接蛋白（apoptosis-associated speck-like protein, ASC）表达水平；Western blot检测视网膜组织Caspase-1与NLRP3表达水平；ELISA检测血清炎症因子白细胞介素-1β（interleukin-1β, IL-1β）和白细胞介素-18（interleukin-18, IL-18）含量。结果 与空白组比较，模型组大鼠一般生物学特征出现较明显的改变；血糖显著升高（P＜0.01）；体质量显著降低（P＜0.01）；视网膜厚度增加（P＜0.01）；FFA可见视网膜血管走行迂曲，散在微血管瘤及少许点状强荧光；病理形态见各层细胞排列紊乱、稀疏，内丛状层、内外核层松散，结构紊乱，视网膜厚度增加；视网膜组织中NLRP3、ASC、Caspase-1蛋白表达及炎症因子IL-1β、IL-18含量显著升高（P＜0.01）。与模型组比较，中剂量组、高剂量组大鼠血糖均降低（P＜0.05）；安多明组、低剂量组、中剂量组、高剂量组大鼠体质量均升高（P＜0.01）；各给药组大鼠视网膜厚度呈不同程度减少（P＜0.01）；FFA见微血管瘤及点状强荧光减少；病理形态见视网膜各层结构基本完整，排列规整，厚度减少；视网膜组织中NLRP3、ASC、Caspase-1蛋白表达及炎症因子IL-1β、IL-18含量显著降低（P＜0.01，P＜0.05）。结论 以疏肝健脾、活血利水为治法的益肝明目汤可能通过干预NLRP3/Caspase-1介导的细胞焦亡，进而减轻炎症因子的释放，减轻视网膜水肿，从而改善视网膜功能。 |
| 关键词: 益肝明目汤 糖尿病视网膜病变 视网膜水肿 细胞焦亡 NLRP3/Caspase-1信号通路 |
| DOI：10.3969/j.issn.1674-070X.2023.03.009 |
| Received:November 15, 2022 |
| 基金项目:湖南省中医药科研计划课题项目（201917）；湖南省中医药科研计划项目（C2022003，E2022044）；湖南省自然科学基金面上项目（2021JJ30520）；长沙市自然科学基金项目（kq2014226）；湖南省教育厅科学研究项目（19A362）；湖南中医药大学中医学一流学科开放基金项目（2018ZYX60）；湖南中医药大学研究生创新课题项目（2021CX76）。 |
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| Effects of Yigan Mingmu Decoction on the NLRP3/Caspase-1 signaling pathway in rats model with diabetic retinal edema |
| LIAN Yitong,LIU Zhimin,NIE Fujiao,HU Zhuoyu,FU Meilin,HU Qi,JIANG Jieyu,CHEN Xiangdong |
| (The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China;Hunan University of Chinese Medicine, Changsha, Hunan 410208, China) |
| Abstract: |
| Objective To investigate the effects of Yigan Mingmu Decoction on the NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/cysteine aspartate-specific proteinase-1 (Caspase-1) signaling pathway in rats with diabetic retinal edema, and to explore the mechanism of action in the treatment of diabetic retinal edema from the perspective of pyroptosis. Methods A total of 36 SD rats were randomly divided into blank group (n=6) and model group (n=30). The one-time intraperitoneal injection of 40 mg/kg streptozocin (STZ) solution combined with high-sugar and high-fat feed was applied to establish the rat model of diabetic retinal edema. Then the above models were divided into model groups, andomine group, low-dose, medium-dose and high-dose Yigan Mingmu Decoction groups, with 6 rats in each group. All the rats were treated with distilled water, calcium hydroxybenzenesulfonate granules (0.09 g/kg), and Yigan Mingmu Decoction (2.8, 5.6, 11.2 g/kg) respectively, twice a day in 4 consecutive weeks. The general biological characteristics of rats were observed; the changes in blood sugar and body weight in different periods were monitored; the retinal vascular leakage and retinal thickness changes at various stages were found using fundus fluorescence angiography (FFA) and optical correlation tomography (OCT); the renal tissue pathological morphology was detected by HE staining; the expression of NLRP3 and apoptosis-associated speck-like protein (ASC) in retinal tissue was detected by immunohistochemistry; the expression of Caspase-1 and NLRP3 in retinal tissues was detected by Western blot; the content of serum inflammatory factors interleukin-1β (IL-1β) and interleukin-18 (IL-18) was detected by ELISA. Results Compared with blank group, the general biological characteristics of rats in model group were significantly changed, blood glucose increased significantly (P<0.01), body weight decreased significantly (P<0.01), and retinal thickness increased (P<0.01). FFA showed that the retinal blood vessels were tortuous, scattered with microangiomas and a few punctate strong fluorescence points. Pathological morphology showed disordered and sparse arrangement of cells in each layer, loose inner plexiform layer, inner and outer nuclear layers, disordered structure, and increased retinal thickness. The protein expression of NLRP3, ASC, Caspase-1 and the inflammatory factors of IL-1β, IL-18 significantly increased (P<0.01). Compared with model group, blood glucose in medium-dose group and high-dose group decreased (P<0.05). The body weight of andomine group, low-dose group, medium-dose group and high-dose group was higher than that of model group; the retinal thickness of the rats in each administration group was reduced to varying degrees, and FFA showed that the microvascular tumors and punctate strong fluorescence were reduced. Pathological morphology showed that the structure of each layer of retina was basically intact, regular arranged, and the thickness was reduced. The protein expression of NrLRP3, ASC, and Caspase-1 and the inflammatory factors of IL-1β, IL-18 in retinal tissue were significantly lower (P<0.01, P<0.05). Conclusion Yigan Mingmu Decoction soothes the liver and fortifies the spleen, activate blood and drain water retention. It may intervene the NLRP3/Caspase-1 mediated pyroptosis, release less inflammatory factors, and relieve the retinal edema and thus improve retinal function. |
| Key words: Yigan Mingmu Decoction diabetic retinopathy retinal edema pyrolysis NLRP3/Caspase-1 signaling pathway |
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