Abstract
Ischemic stroke presents a leading cause of mortality and morbidity worldwide. Theaflavic acid (TFA) is a theaflavin isolated from black tea that exerts a potentially neuro-protective effect. However, the dynamic properties of TFA-mediated protection remain largely unknown. In the current study, we evaluated the function of TFA in the mitochondria apoptotic pathway using mathematical modeling. We found that TFA-enhanced B-cell lymphoma 2 (Bcl-2) overexpression can theoretically give rise to bistability. The bistability is highly robust against parametric stochasticity while also conferring considerable variability in survival threshold. Stochastic simulations faithfully match the TFA dose response pattern seen in experimental studies. In addition, we identified a dose- and time-dependent synergy between TFA and nimodipine, a clinically used neuro-protective drug. This synergistic effect was enhanced by bistability independent of temporal factors. Precise application of pulsed doses of TFA can also promote survival compared with sustained TFA treatment. These data collectively demonstrate that TFA treatment can give rise to bistability and that synergy between TFA and nimodipine may offer a promising strategy for developing therapeutic neuro-protection against ischemic stroke.
概要
目的
利用数学建模方法来研究茶黄素酸和尼莫地平在线粒体凋亡途径中的协同神经保护作用.
创新点
茶黄素酸诱导的 Bcl-2 表达在理论上可以引起系统性的双稳态. 此双稳态对模型参数变化具有很强的鲁棒性, 但同时又对生存状态阈值的变化具有相当的敏感性. 通过随机模拟, 我们可以很好地拟合实验中测定的茶黄素酸剂量反应. 此外, 我们确定了茶黄素酸和尼莫地平 (一种临床应用的神经保护药物) 之间的剂量和时间依赖性协同作用, 这种协同效应通过双稳态得到增强.
方法
采用微分方程描述分子间相互作用; 运用局部敏感性分析探讨系统参数敏感性; 运用 Bliss 和 Loewe 联合指数计算茶黄素酸和尼莫地平的协同性; 使用 MATCONT 工具箱揭示系统的分岔性质.
结论
与持续的茶黄素酸处理相比, 对细胞给予脉冲样茶黄素酸处理可以显著提高细胞生存率. 这些数据表明, 茶黄素酸可以诱导系统产生双稳态, 同时茶黄素酸与尼莫地平的协同作用可能为缺血性中风的治疗提供了一种有效的方式.
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Acknowledgments
This research was supported by the National Natural Science Foundation of China (Nos. 31971185 and 31800316), the Key Projects of Support Program for Outstanding Young Talents in Colleges and Universities of Anhui Province (Nos. gxyqZD2020031 and gxyq2018034), and the Key Project of the Education Department of Anhui Province, China (No. KJ2017A359).
We thank Dr. Liangliang ZHU (School of Life Sciences, the Province Key Laboratory of the Biodiversity Study and Ecology Conservation in Southwest Anhui, Anqing Normal University, Anhui, China) for critical reading of the manuscript.
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Dan MU and Tingzhe SUN conceptualized the study, performed project administration, and acquired the funding; Dan MU, Huaguang QIN, and Tingzhe SUN developed the methodology and wrote the manuscript; Dan MU, Huaguang QIN, Mengjie JIAO, Shaogui HUA, and Tingzhe SUN validated the study, performed the data analysis and curation, and reviewed the draft; Tingzhe SUN supervised the study. All authors have read and agreed to the published version of the manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
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Dan MU, Huaguang QIN, Mengjie JIAO, Shaogui HUA, and Tingzhe SUN declare that they have no conflict of interest.
This article does not contain any studies with human or animal subjects performed by any of the authors.
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Mu, D., Qin, H., Jiao, M. et al. Modeling the neuro-protection of theaflavic acid from black tea and its synergy with nimodipine via mitochondria apoptotic pathway. J. Zhejiang Univ. Sci. B 22, 123–135 (2021). https://doi.org/10.1631/jzus.B2000540
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DOI: https://doi.org/10.1631/jzus.B2000540