Mechanism of Panax notoginseng saponins modulation of miR-214-3p/NR1I3 affecting the pharmacodynamics and pharmacokinetics of warfarin

IF 6.8 2区 医学 Q1 CHEMISTRY, MEDICINAL
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Abstract

Background

With the prevalence of dietary supplements, the use of combinations of herbs and drugs is gradually increasing, together with the risk of drug interactions. In our clinical work, we unexpectedly found that the combination of Panax notoginseng and warfarin, which are herbs that activate blood circulation and remove blood stasis, showed antagonistic effects instead. The purpose of this study was to evaluate the drug interaction between Panax notoginseng saponins (PNS) and warfarin, the main active ingredient of Panax notoginseng, and to explore the interaction mechanism.

Methods

The effects and mechanisms of PNS on the pharmacodynamics and pharmacokinetics of warfarin were explored mainly in Sprague–Dawley rats and HepG2 cells. Elisa was used to detect the concentrations of coagulation factors, HPLC-MS to detect the blood concentrations of warfarin in rats, immunoblotting was employed to examine protein levels, qRT-PCR to detect mRNA levels, cellular immunofluorescence to detect the localization of NR1I3, and dual luciferase to verify the binding of miR-214-3p and NR1I3.

Results

PNS significantly accelerated warfarin metabolism and reduced its efficacy, accompanied by increased expression of NR1I3 and CYP2C9. Interference with NR1I3 rescued the accelerated metabolism of warfarin induce by PNS co-administration. In addition, we demonstrated that PNS significantly reduced miR-214-3p expression, whereas miR-214-3p overexpression reduced NR1I3 and CYP2C9 expression, resulting in a weakened antagonistic effect of PNS on warfarin. Additionally, we found that miR-214-3p bound directly to NR1I3 3′-UTR and significantly downregulated NR1I3 expression.

Conclusion

Our study demonstrated that PNS accelerates warfarin metabolism and reduces its pharmacodynamics by downregulating miR-214-3p, leading to increased expression of its target gene NR1I3, these findings provide new insights for clinical drug applications to avoid adverse effects.

Abstract Image

Abstract Image

三七皂苷调节 miR-214-3p/NR1I3 影响华法林药效学和药代动力学的机制
背景随着膳食补充剂的盛行,中草药与药物的联合使用逐渐增多,同时也带来了药物相互作用的风险。在临床工作中,我们意外地发现三七和华法林这两种活血化瘀的中药联合使用,反而出现了拮抗作用。本研究的目的是评估三七皂苷(PNS)与三七的主要有效成分华法林之间的药物相互作用,并探讨其相互作用机制。采用Elisa检测凝血因子的浓度,HPLC-MS检测大鼠血液中华法林的浓度,免疫印迹检测蛋白质水平,qRT-PCR检测mRNA水平,细胞免疫荧光检测NR1I3的定位,双荧光素酶验证miR-214-3p与NR1I3的结合。结果PNS明显加速了华法林的代谢并降低了其疗效,同时增加了NR1I3和CYP2C9的表达。对 NR1I3 的干扰可缓解同时服用 PNS 引起的华法林代谢加速。此外,我们还发现 PNS 能显著降低 miR-214-3p 的表达,而 miR-214-3p 过表达则会降低 NR1I3 和 CYP2C9 的表达,从而削弱 PNS 对华法林的拮抗作用。结论我们的研究表明,PNS 通过下调 miR-214-3p 导致其靶基因 NR1I3 的表达增加,从而加速华法林的代谢并降低其药效学,这些发现为临床药物应用提供了新的见解,以避免不良反应。
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来源期刊
Journal of Ginseng Research
Journal of Ginseng Research CHEMISTRY, MEDICINAL-INTEGRATIVE & COMPLEMENTARY MEDICINE
CiteScore
11.40
自引率
9.50%
发文量
111
审稿时长
6-12 weeks
期刊介绍: Journal of Ginseng Research (JGR) is an official, open access journal of the Korean Society of Ginseng and is the only international journal publishing scholarly reports on ginseng research in the world. The journal is a bimonthly peer-reviewed publication featuring high-quality studies related to basic, pre-clinical, and clinical researches on ginseng to reflect recent progresses in ginseng research. JGR publishes papers, either experimental or theoretical, that advance our understanding of ginseng science, including plant sciences, biology, chemistry, pharmacology, toxicology, pharmacokinetics, veterinary medicine, biochemistry, manufacture, and clinical study of ginseng since 1976. It also includes the new paradigm of integrative research, covering alternative medicinal approaches. Article types considered for publication include review articles, original research articles, and brief reports. JGR helps researchers to understand mechanisms for traditional efficacy of ginseng and to put their clinical evidence together. It provides balanced information on basic science and clinical applications to researchers, manufacturers, practitioners, teachers, scholars, and medical doctors.
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