基于中医“脾统血”理论探讨紫苏叶抗再生障碍性贫血的物质基础及作用机制

Aplastic anemia (AA) is a refractory blood disease. As a medical challenge, ideal medicine is lacked for AA. Our previous study found that Perilla frutescens leaves extract could significantly improve the hematopoietic function of AA mice model, implying its application prospects in AA treatment. However the basis of pharmacodynamic material for hematopoietic promotion is not yet clear, which becomes a major factor restricting its further research and development. So this project will focus on the interpretation of the material basis and pharmacological mechanism of Perilla frutescens leaves. High-resolution mass spectrometry and liquid preparative chromatography will be applied to obtain the composition of Perilla frutescens leaves in vivo after oral administration; tissue distribution experiment and balance dialysis technology will be used to understand their distribution in the target tissue, blood, spleen and bone marrow. Activity screening for regulators of immune disorders of aplastic anemia in the key aspects of dendritic cell activation, T lymphocyte migration and hematopoietic stem cell suppression in vitro and efficacy verification in vivo will be carried out under the guidance of Chinese medicine theory of the spleen controlling blood to obtained the main active ingredients of Perilla frutescens. A preliminary discussion of the mechanism will also be involved in the levels of animal and cell. This research will help to understand the immunological mechanism and material basis of Perilla frutescens leaves for the treatment of aplastic anemia, enrich the scientific content of the traditional Chinese medicine theory of the spleen controlling blood and provide pilot drugs and new ideas for anti-aplastic anemia innovative drug research and development.

再生障碍性贫血（AA）是一种难治性血液系统疾病，作为医学难题，目前仍缺乏理想治疗药物。本课题组前期研究发现，归脾经中药紫苏叶可显著改善AA小鼠的造血功能，其免疫调节作用有望克服免疫抑制疗法对免疫系统全面抑制所带来的诸多不良反应，具有应用前景。但其药效物质基础尚不明确，成为制约其进一步研发的主要因素。因此，本项目拟在中医“脾统血”理论的指导下，运用高分辨质谱与液相色谱制备技术获得紫苏叶口服入血成分；采用组织分布与平衡透析技术追踪其在血液、脾脏与骨髓的分布；利用细胞培养技术建立抗原提呈细胞激活、T淋巴细胞亚群偏移和造血干细胞抑制筛选模型，筛选获得紫苏叶“助脾统血”有效成分群；并对其中的关键成分进行药效评价与免疫调节机制研究。本课题将有助于发现紫苏叶治疗AA的药效物质基础，阐明脾、免疫、造血系统之间的内在联系以及药效物质对三者的综合调控方式，为抗AA理想药物的研制提供数据支持与理论依据。

本项目在“脾统血”理论的指导下进行紫苏抗再生障碍性贫血的物质基础及作用机制研究，为抗再障理想药物的研制奠定基础。通过综合运用药学各学科技术手段，本项目鉴定了部分紫苏提取物成分、研究了其在肠道的吸收与代谢转化过程，获得提取物大极性部位与黄酮和小分子酸类成分，经体外药效学筛选，发现具有促小肠隐窝上皮细胞增殖作用、毒性T淋巴细胞抑制作用和脾酪氨酸激酶活性抑制作用的紫苏提取物有效成分群，初步揭示了紫苏提取物通过促进胃肠黏膜损伤修复、改善脾胃运化功能，抑制毒性T淋巴过度激活、调节免疫系统功能紊乱，“助脾统血”治疗再障的部分潜在作用机制；并对其中的关键成分进行结构改造、活性筛选、药效评价、代谢研究与初步作用机制探讨，获得了具有较好抗再障药效活性的新结构化合物3个，为高效低毒抗再障药物的研究开发以及潜在新药物靶点的发现提供了良好的前期基础。

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