Metabolic switch induced by Cimicifuga racemosa extract prevents mitochondrial damage and oxidative cell death
Metabolic switch induced by Cimicifuga racemosa extract prevents mitochondrial damage and oxidative cell death
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DOI：
10.1016/j.phymed.2018.09.177
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发表时间：
2019-01-01
期刊：
影响因子：
7.9
通讯作者：
Culmsee, Carsten
中科院分区：
文献类型：
--
作者：
Rabenau, Malena;Unger, Matthias;Culmsee, Carsten
背景：总状升麻提取物是治疗更年期症状的成熟疗法。升麻提取物的多种治疗作用的机制，例如减少潮热和大量出汗的作用尚无明确定义。最近的研究表明，Ze 450（一种通过标准化程序生产的总状升麻提取物）通过在体外激活 AMP 激活的蛋白激酶对能量代谢产生显着影响，并在体内发挥有益的抗糖尿病作用。 目的：本研究的目的是研究 Ze 450 对能量代谢的影响。由于线粒体是细胞能量稳态的关键调节因子，我们想要阐明 Ze 450 是否会影响线粒体弹性，并能提供针对神经元和肝细胞氧化损伤的保护。 方法/研究设计：在本研究中，我们研究了 Ze 450 (1-200 mu g/ml) 对线粒体完整性和功能以及氧化模型中细胞活力的影响 erastin 和 RSL-3 在神经元和肝细胞中诱导的应激。使用 FACS 分析 Ze 450 在对照条件下和诱导氧化应激后的影响，以检测脂质过氧化 (BODIPY)、线粒体 ROS 形成 (MitoSOX)、线粒体膜电位 (TMRE) 和细胞死亡（AnnexinV/PI 染色）。此外，我们还测定了代谢活性（MTT 测定）、ATP 水平以及线粒体呼吸和糖酵解（耗氧率、细胞外酸化率；Seahorse）。结果：Ze 450 保留了线粒体完整性和 ATP 水平，并防止线粒体 ROS 形成、线粒体膜电位损失和细胞死亡。值得注意的是，单独的升麻提取物不会改变线粒体 ROS 水平，并且在提取提取物后，对细胞增殖的微妙抑制作用被逆转。此外，Ze 450 不会对肝细胞产生毒性作用，而是保护它们免受氧化挑战。对线粒体耗氧率和细胞外酸化率的进一步分析表明，Ze 450介导了从线粒体呼吸到糖酵解的转变，而这种代谢转变是对抗氧化损伤的保护作用的先决条件。结论：综上所述，Ze 450诱导的生物能转变对不同细胞类型产生了保护作用，并提供了有前景的治疗作用。 涉及氧化应激和线粒体损伤的年龄相关疾病的潜力。
Background: Cimicifuga racemosa extract is a well-established therapy for menopausal symptoms. The mechanisms underlying the multiple therapeutic effects of Cimicifuga extract, e.g. reducing hot flushes and profuse sweating are not well defined. Recent studies revealed pronounced effects of Ze 450, a Cimicifuga racemosa extract that was produced by a standardized procedure, on energy metabolism through activation of AMP-activated protein kinase in vitro and beneficial anti-diabetic effects in vivo.Purpose: The aim of the study was to investigate the effects of Ze 450 on energy metabolism. Since mitochondria are the key regulators of cellular energy homeostasis, we wanted to elucidate whether Ze 450 affects mitochondrial resilience and can provide protection against oxidative damage in neuronal and liver cells.Methods/study design: In this study, we investigated the effects of Ze 450 (1-200 mu g/ml) on mitochondrial integrity and function, and cell viability in models of oxidative stress induced by erastin and RSL-3 in neuronal and liver cells. The effects of Ze 450 in control conditions and after induction of oxidative stress were analyzed using FACS for detecting lipid peroxidation (BODIPY), mitochondrial ROS formation (MitoSOX), mitochondrial membrane potential (TMRE) and cell death (AnnexinV/PI staining). Furthermore, we determined metabolic activity (MTT assay), ATP levels and mitochondrial respiration and glycolysis (oxygen consumption rates, extracellular acidification rates; Seahorse).Results: Ze 450 preserved mitochondrial integrity and ATP levels, and prevented mitochondrial ROS formation, loss of mitochondrial membrane potential and cell death. Notably, Cimicifuga racemosa extract alone did not alter mitochondrial ROS levels, and subtle inhibitory effects on cell proliferation were reversed after withdrawal of the extract. In addition, Ze 450 did not exert toxic effects to liver cells, but rather protected these from the oxidative challenge. Further analysis of the mitochondrial oxygen consumption rate and the extracellular acidification rate revealed that Ze 450 mediated a switch from mitochondrial respiration to glycolysis, and this metabolic shift was a prerequisite for the protective effects against oxidative damage.Conclusion: In conclusion, the bioenergetic shift induced by Ze 450 exerted protective effects in different cell types, and offers promising therapeutic potential in age related diseases involving oxidative stress and mitochondrial damage.