Zhou Jun, Ma Xiaoqiong, Shi Min, Chen Cuiwei, Sun Yue, Li Jingjing, Xiong Youxiang, Chen Junjie, Li Fanzhu
College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, PR China; School of Basic Medical Science, Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.
National Clinical Research Base of Traditional Chinese Medicine, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, PR China.
Phytomedicine. 2017 Jul 15;31:18-31. doi: 10.1016/j.phymed.2017.01.009. Epub 2017 Jan 24.
Sini decoction (SND) is used for cardiovascular disease over thousands of years in China. However, it is still lacking of dose-response relationship of SND in cardiovascular disease at the metabolic level.
The present study is designed to explore the cardioprotective effects of different dosages of SND pretreatment on the isoproterenol (ISO)-induced myocardial injury and elucidate the mechanism underlying this protective effect.
The cardioprotective effects of different dosages of SND pretreatment on the isoproterenol-induced myocardial injury were compared through a serum metabolomics approach based on ultraperformance liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS). In addition, the cardioprotective effects were evaluated by serum biochemical analysis and histopathological examination of myocardial tissue. Finally, in view of the fact that these perturbed bile acid and phospholipid metabolisms are connected with NF-κB signaling pathway, nuclear expression of NF-κB p65 and the activation of NF-κB were analyzed by immunohistochemistry, immunoblotting and electrophoretic mobility shift assay (EMSA), respectively.
The cardioprotective effect was observed in SND pretreatment groups, especially in low dosage SND group. The results of serum enzyme activities and histopathology were consistent with the above effect. Meanwhile, fifteen latent biomarker candidates were identified involving glucose, phospholipid, bile acid and amino acid metabolisms. Among them, five bile acids including ursodeoxycholic acid, murideoxycholic acid, muricholic acid, hyodeoxycholic acid and cholic acid, were for the first time identified as latent pathological biomarkers related to ISO-induced myocardial injury. Further, different dose SND groups exerted different of inhibition degrees to the activation of NF-κB, which was obvious in the SND-L group.
The results revealed that Sini decoction protreatment protects myocardium better at a low dose level and one of possible cardioprotective mechanisms is modulating NF-κB signaling pathway against isoproterenol-induced myocardial injury through regulating phospholipid and bile acid metabolisms.
在中国，四逆汤（SND）用于治疗心血管疾病已有数千年历史。然而，在代谢水平上，四逆汤在心血管疾病中的剂量-反应关系仍不明确。
本研究旨在探讨不同剂量四逆汤预处理对异丙肾上腺素（ISO）诱导的心肌损伤的心脏保护作用，并阐明这种保护作用的潜在机制。
基于超高效液相色谱-四极杆-飞行时间质谱联用（UPLC-Q-TOF-MS）的血清代谢组学方法，比较不同剂量四逆汤预处理对异丙肾上腺素诱导的心肌损伤的心脏保护作用。此外，通过血清生化分析和心肌组织病理检查评估心脏保护作用。最后，鉴于这些受干扰的胆汁酸和磷脂代谢与NF-κB信号通路相关，分别通过免疫组织化学、免疫印迹和电泳迁移率变动分析（EMSA）分析NF-κB p65的核表达和NF-κB的激活情况。
在四逆汤预处理组中观察到心脏保护作用，尤其是低剂量四逆汤组。血清酶活性和组织病理学结果与上述作用一致。同时，鉴定出15种潜在生物标志物候选物，涉及葡萄糖、磷脂、胆汁酸和氨基酸代谢。其中，包括熊去氧胆酸、鼠脱氧胆酸、鼠胆酸、猪去氧胆酸和胆酸在内的5种胆汁酸首次被鉴定为与ISO诱导的心肌损伤相关的潜在病理生物标志物。此外，不同剂量四逆汤组对NF-κB激活的抑制程度不同，在SND-L组中尤为明显。
结果表明，四逆汤预处理在低剂量水平下对心肌的保护作用更好，其可能的心脏保护机制之一是通过调节磷脂和胆汁酸代谢来调节NF-κB信号通路，对抗异丙肾上腺素诱导的心肌损伤。
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