Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Dongcheng District, Beijing 100700, China.
Department of Neurological Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224, USA.
Pharmacol Res. 2021 Jul;169:105617. doi: 10.1016/j.phrs.2021.105617. Epub 2021 Apr 17.
Traditional Chinese multi-herb-combined prescriptions usually show better performance than a single agent since a group of effective compounds interfere multiple disease-relevant targets simultaneously. Huang-Lian-Jie-Du decoction is a remedy made of four herbs that are widely used to treat oral ulcers, gingivitis, and periodontitis. However, the active ingredients and underlying mechanisms are not clear. To address these questions, we prepared a water extract solution of Huang-Lian-Jie-Du decoction (HLJDD), called it as WEH (Water Extract Solution of HLJDD), and used it to treat LPS-induced systemic inflammation in mice. We observed that WEH attenuated inflammatory responses including reducing production of cytokines, chemokines and interferons (IFNs), further attenuating emergency myelopoiesis, and preventing mice septic lethality. Upon LPS stimulation, mice pretreated with WEH increased circulating Ly6C patrolling and splenic Ly6C inflammatory monocytes. The acute myelopoiesis related transcriptional factor profile was rearranged by WEH. Mechanistically we confirmed that WEH interrupted LPS/TLR4/CD14 signaling-mediated downstream signaling pathways through its nine principal ingredients, which blocked LPS stimulated divergent signaling cascades, such as activation of NF-κB, p38 MAPK, and ERK1/2. We conclude that the old remedy blunts LPS-induced "danger" signal recognition and transduction process at multiple sites. To translate our findings into clinical applications, we refined the crude extract into a pure multicomponent drug by directly mixing these nine chemical entities, which completely reproduced the effect of protecting mice from lethal septic shock. Finally, we reduced a large number of compounds within a multi-herb water extract to seven-chemical combination that exhibited superior therapeutic efficacy compared with WEH.
传统的中草药复方通常比单一药物表现更好，因为一组有效的化合物可以同时干扰多个与疾病相关的靶点。黄连解毒汤是一种由四种草药组成的方剂，广泛用于治疗口腔溃疡、牙龈炎和牙周炎。然而，其活性成分和作用机制尚不清楚。为了解决这些问题，我们制备了黄连解毒汤的水提取物溶液（HLJDD），称为 WEH（黄连解毒汤的水提取物溶液），并用于治疗 LPS 诱导的小鼠全身炎症。我们观察到 WEH 减轻了炎症反应，包括减少细胞因子、趋化因子和干扰素（IFNs）的产生，进一步减弱了紧急髓样细胞生成，并防止了小鼠脓毒性致死。在 LPS 刺激下，用 WEH 预处理的小鼠增加了循环 Ly6C 巡逻和脾脏 Ly6C 炎性单核细胞。WEH 重新排列了急性髓样细胞生成相关转录因子谱。从机制上讲，我们证实 WEH 通过其九个主要成分干扰了 LPS/TLR4/CD14 信号转导介导的下游信号通路，阻断了 LPS 刺激的不同信号级联，如 NF-κB、p38 MAPK 和 ERK1/2 的激活。我们得出结论，旧疗法在多个部位阻断了 LPS 诱导的“危险”信号识别和转导过程。为了将我们的发现转化为临床应用，我们通过直接混合这九个化学实体，将粗提取物精制为纯多组分药物，完全复制了保护小鼠免受致命性脓毒症休克的作用。最后，我们将大量化合物在一种多草药水提取物中减少到七种化学组合，与 WEH 相比，该组合表现出更好的治疗效果。
