目的 探讨补肾活血方对肾虚血瘀型畸形精子症模型大鼠的治疗作用及其基于AKT1/STAT3/FOXO1信号通路的分子机制。 方法 采用精索静脉曲张（Varicocele, VC）手术法建立肾虚血瘀型畸形精子症大鼠模型，随机分为VC模型组、补肾活血方低、中、高剂量组及假手术阴性对照组。干预后，综合评价模型证候（睾丸指数、精索静脉直径）、精子质量（活力、形态）、睾丸组织病理与氧化应激水平（ROS、MDA、SOD），并检测睾丸组织中AKT1/STAT3/FOXO1通路关键蛋白的表达变化。 结果 与VC模型组相比，补肾活血方中、高剂量组能显著改善VC模型大鼠的“肾虚血瘀”证候表征，包括提高睾丸指数、缩小精索静脉直径；并有效提升精子活力与正常形态率，减轻睾丸组织氧化损伤。分子机制显示，补肾活血方可双向调控失衡的AKT1/STAT3/FOXO1信号网络，表现为下调VC模型组中异常升高的p-AKT1及STAT3蛋白表达，同时上调被抑制的FOXO1蛋白并降低其磷酸化水平。 结论 补肾活血方对肾虚血瘀型畸形精子症具有明确的改善作用，其机制可能与纠正AKT1/STAT3信号过度活化、激活FOXO1介导的抗氧化防御有关，为从“补肾活血”法论治该病症提供了药理学依据。
Abstract
Objective To investigate the therapeutic effect of kidney-tonifying and blood-activating compound (KBAC) on a rat model of teratozoospermia with the pattern of "kidney deficiency and blood stasis" and its underlying molecular mechanism focusing on the AKT1/STAT3/FOXO1 signaling pathway. Methods The rat model, mimicking the aforementioned pattern, was established by inducing experimental varicocele. Rats were randomly assigned to VC model, low, medium, and high-dose KBAC, and sham-operated control groups. After intervention, comprehensive evaluations were conducted, including syndrome manifestations (testicular index, spermatic vein diameter), sperm quality (motility, morphology), testicular histopathology, oxidative stress markers (ROS, MDA, SOD). The expression of key proteins in the AKT1/STAT3/FOXO1 pathway in testicular tissue was detected. Results Compared with the model group, medium and high-dose KBAC significantly ameliorated the syndrome manifestations, including increasing the testicular index and reducing the diameter of the spermatic vein, improved sperm motility and normal morphology rate, and alleviated testicular oxidative damage. Mechanistically, KBAC directionally modulated the dysregulated AKT1/STAT3/FOXO1 signaling network: it downregulated the abnormally elevated expressions of p-AKT1 and STAT3 proteins while upregulating the suppressed FOXO1 expression and reducing its phosphorylation level observed in the model group. Conclusions KBAC exerts a therapeutic effect on teratozoospermia with the "kidney deficiency and blood stasis" pattern. The mechanism may involve correcting the overactivation of the AKT1/STAT3 signaling and activating the FOXO1-mediated antioxidant defense, providing a pharmacological basis for treating this condition with the “Tonifying Kidney and Activating Blood” principle in traditional Chinese medicine.
关键词
补肾活血方 /
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肾虚血淤 /
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畸形精子症 /
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AKT1/STAT3/FOXO1信号通路 /
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氧化应激
Key words
Kidney-tonifying and blood-activating compound /
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Kidney deficiency and blood stasis /
Teratozoospermia /
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AKT1/STAT3/FOXO1 signaling pathway /
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Oxidative Stress
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基金
广东省中医药局科研项目（20241103, 20242036）；国家中医药传承创新中心科研专项青年项目（2023QN02）；广东省医学科研基金项目（A2023401）
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