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On-line Access: 2021-02-07

Received: 2020-09-11

Revision Accepted: 2020-11-08

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Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Tingzhe SUN

https://orcid.org/0000-0002-9575-4993

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Journal of Zhejiang University SCIENCE B 2021 Vol.22 No.2 P.123-135

http://doi.org/10.1631/jzus.B2000540


Modeling the neuro-protection of theaflavic acid from black tea and its synergy with nimodipine via mitochondria apoptotic pathway


Author(s):  Dan MU, Huaguang QIN, Mengjie JIAO, Shaogui HUA, Tingzhe SUN

Affiliation(s):  School of Life Sciences, the Province Key Laboratory of the Biodiversity Study and Ecology Conservation in Southwest Anhui, Anqing Normal University, Anqing 246133, China

Corresponding email(s):   confucian007@126.com

Key Words:  Theaflavic acid (TFA), Nimodipine, Ischemic stroke, Apoptosis, Synergy


Dan MU, Huaguang QIN, Mengjie JIAO, Shaogui HUA, Tingzhe SUN. Modeling the neuro-protection of theaflavic acid from black tea and its synergy with nimodipine via mitochondria apoptotic pathway[J]. Journal of Zhejiang University Science B, 2021, 22(2): 123-135.

@article{title="Modeling the neuro-protection of theaflavic acid from black tea and its synergy with nimodipine via mitochondria apoptotic pathway",
author="Dan MU, Huaguang QIN, Mengjie JIAO, Shaogui HUA, Tingzhe SUN",
journal="Journal of Zhejiang University Science B",
volume="22",
number="2",
pages="123-135",
year="2021",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2000540"
}

%0 Journal Article
%T Modeling the neuro-protection of theaflavic acid from black tea and its synergy with nimodipine via mitochondria apoptotic pathway
%A Dan MU
%A Huaguang QIN
%A Mengjie JIAO
%A Shaogui HUA
%A Tingzhe SUN
%J Journal of Zhejiang University SCIENCE B
%V 22
%N 2
%P 123-135
%@ 1673-1581
%D 2021
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2000540

TY - JOUR
T1 - Modeling the neuro-protection of theaflavic acid from black tea and its synergy with nimodipine via mitochondria apoptotic pathway
A1 - Dan MU
A1 - Huaguang QIN
A1 - Mengjie JIAO
A1 - Shaogui HUA
A1 - Tingzhe SUN
J0 - Journal of Zhejiang University Science B
VL - 22
IS - 2
SP - 123
EP - 135
%@ 1673-1581
Y1 - 2021
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2000540


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.

红茶提取物茶黄素酸和尼莫地平通过线粒体途径凋亡介导的协同神经保护作用模型的研究

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。

关键词:茶黄素酸;尼莫地平;缺血性中风;凋亡;协同性

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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