Liu Kun, Zheng Li, Huang Qian-Yu, Li Hong-Ji, Li Cheng, Zhao Hui, Ye Ze-Bing, Wang Hao, Qi Xu-Feng, Wang Meng
Department of Cardiology, Zhongshan Torch Development Zone People's Hospital, Zhongshan, 528437, China.
Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Department of Developmental & Regenerative Biology, and Department of Cardiology, The Affiliated Guangdong Second Provincial General Hospital, Jinan University, Guangzhou, 510632, China.
Chin Med. 2025 Jun 18;20(1):90. doi: 10.1186/s13020-025-01141-x.
Ischemic heart diseases are the leading cause of death worldwide due to the inability of regeneration of adult cardiomyocytes (CMs). Natural products from medical herbs are an important source of innovative drugs for many diseases including cardiovascular diseases.
In this study, we set out to screen novel small-molecule therapies from natural products to protect heart against ischemic injury.
High-throughput screening was performed using a natural product library to identify the potential small molecules which can promote survival of CMs under ischemic and ischemic/reperfusion conditions. In addition, myocardial infarction (MI) and ischemia/reperfusion (I/R) mice models were used to evaluate the in vivo effects of the screened candidate. We also applied various analysis including cell viability, qPCR, Western blot, immunofluorescent staining, echocardiography, Masson's staining, TTC staining, and network pharmacology.
High-throughput screening showed that the small molecule compound Darutigenol (Dar), derived from the Chinese traditional herb Herba Siegesbeckiae, could significantly promote CM survival and proliferation under ischemic conditions. Moreover, I/R-induced CM apoptosis and ROS generation could be significantly reduced by Dar treatment. In addition, in vivo administration of Dar was able to attenuate MI- and I/R-induced cardiac injury in adult mice by decreasing fibrosis and apoptosis, thereby improving cardiac function. Network pharmacology analysis and molecule docking assay showed that Dar has the highest binding affinity with AKT1 protein. Western blotting assay further revealed that AKT1 activation was significantly enhanced by Dar administration in the infarcted hearts.
Our data revealed that the small molecule compound Dar, screened from the natural product library in this study, is capable of protecting heart against MI and I/R injury by activating AKT1 pathway. These findings enrich the natural product candidates for cardiovascular disease treatment and provide new insights into potential therapeutic agents for MI and I/R injury.
由于成体心肌细胞（CMs）无法再生，缺血性心脏病是全球范围内主要的死亡原因。草药中的天然产物是包括心血管疾病在内的许多疾病创新药物的重要来源。
在本研究中，我们着手从天然产物中筛选新型小分子疗法以保护心脏免受缺血性损伤。
使用天然产物库进行高通量筛选，以鉴定在缺血和缺血/再灌注条件下可促进CMs存活的潜在小分子。此外，采用心肌梗死（MI）和缺血/再灌注（I/R）小鼠模型评估筛选出的候选物的体内效应。我们还应用了各种分析方法，包括细胞活力分析、qPCR、蛋白质免疫印迹、免疫荧光染色、超声心动图、Masson染色、TTC染色和网络药理学。
高通量筛选表明，源自中国传统草药豨莶草的小分子化合物达芦替诺尔（Dar）在缺血条件下可显著促进CMs的存活和增殖。此外，Dar处理可显著减少I/R诱导的CM凋亡和活性氧生成。另外，在成年小鼠体内给予Dar能够通过减少纤维化和凋亡来减轻MI和I/R诱导的心脏损伤，从而改善心脏功能。网络药理学分析和分子对接试验表明，Dar与AKT1蛋白具有最高的结合亲和力。蛋白质免疫印迹分析进一步显示，在梗死心脏中，Dar给药可显著增强AKT1的激活。
我们的数据表明，本研究从天然产物库中筛选出的小分子化合物Dar能够通过激活AKT1途径保护心脏免受MI和I/R损伤。这些发现丰富了用于心血管疾病治疗的天然产物候选物，并为MI和I/R损伤的潜在治疗药物提供了新的见解。
