芪参益气滴丸对索拉非尼诱导大鼠心肌损伤的改善作用及其机制

doi:10.13481/j.1671-587X.20260202

Abstract

Abstract:

Objective To discuss the protective effect of Qishen Yiqi （QSYQ） dropping pill against sorafenib （SOR）-induced myocardium injury in the rats， and to clarify its possible mechanism. Methods Forty SD rats were randomly divided into control group， SOR group， SOR+QSYQ group， and SOR+ferroptosis inhibitor 1 （Fer-1） group， with 10 rats in each group. The rats in SOR group， SOR+QSYQ group， and SOR+Fer-1 group were intraperitoneally injected with SOR （50 mg·kg^-1） daily for 4 weeks； the rats in SOR+QSYQ group were intragastrically administered with QSYQ dropping pill （300 mg·kg^-1） daily； the rats in SOR+Fer-1 group were intraperitoneally injected with Fer-1 （2 mg·kg^-1） daily starting from 1 d before SOR administration. After the intervention， kits were used to detect the levels of creatine kinase isoenzyme-MB （CK-MB） in serum of the rats in various groups； echocardiography was used to evaluate the left ventricular ejection fraction （LVEF） and left ventricular fractional shortening （LVFS） of the rats in various groups； the heart mass and body mass of the rats were recorded， and the cardiac index was calculated. HE staining was used to observe the morphology of myocardium tissue of the rats in various groups； kits were used to detect the levels of iron ion， glutathione （GSH）， malondialdehyde （MDA）， and reactive oxygen species （ROS） in the myocardium tissue of the rats in various groups； Western blotting method was used to detect the expression levels of acyl-CoA synthetase long-chain family member 4 （ACSL4）， solute carrier family 7 member 11 （SLC7A11）， and glutathione peroxidase 4 （GPX4） proteins in the myocardium tissue of the rats in various groups. Additionally， H9c2 cardiomyocytes were divided into control group， SOR group， SOR+QSYQ group， and SOR+Fer-1 group. CCK-8 method was used to detect the survival rates of the cells in various groups； Western blotting method was used to detect the expression levels of ACSL4 and GPX4 proteins in the cells in various groups. Results Compared with control group， the level of CK-MB in serum of the rats in SOR group was significantly increased （P<0.05）， while the LVEF and LVFS were significantly decreased （P<0.05）； compared with SOR group， the levels of CK-MB in the serum of the rats in SOR+QSYQ group and SOR+Fer-1 group were significantly decreased （P<0.05）， while the LVEFs were significantly increased （P<0.05）. The HE staining results showed that compared with control group， the myocardial fibers of the rats in SOR group were disorderly arranged with enlarged intercellular spaces； compared with SOR group， the degrees of myocardial cell injury in SOR+QSYQ group and SOR+Fer-1 group were alleviated， and the myocardial fibers were arranged more neatly. The kit detection results showed that compared with control group， the levels of iron ion， MDA， and ROS in the myocardium tissue of the rats in SOR group were significantly increased （P<0.05）， while the level of GSH was significantly decreased （P<0.05）； compared with SOR group， the levels of iron ion and ROS in the myocardium tissue of the rats in SOR+QSYQ group and SOR+Fer-1 group were significantly decreased （P<0.05）， while the levels of GSH were significantly increased （P<0.05）. The Western blotting method results showed that compared with control group， the expression level of ACSL4 protein in the myocardium tissue of the rats in SOR group was significantly increased （P<0.05）， while the expression levels of SLC7A11 and GPX4 proteins were significantly decreased （P<0.05）； compared with SOR group， the expression levels of SLC7A11 and GPX4 proteins in the myocardium tissue of the rats in SOR+QSYQ group and SOR+Fer-1 group were significantly increased （P<0.05）， while the expression level of ACSL4 protein was significantly decreased （P<0.05）. The CCK-8 assay results showed that compared with 0 μmol·L^-1 SOR group， the survival rates of H9c2 cells treated with higher doses of SOR were significantly decreased （P<0.05）； compared with SOR group， the survival rates of the cells treated with different concentrations of QSYQ were significantly increased （P<0.05）， and the survival rate of the cells in 1 mg·L^-1 QSYQ intervention group was the highest. The Western blotting method results showed that compared with control group， the expression level of ACSL4 protein in the H9c2 cardiomyocytes in SOR group was significantly increased （P<0.05）， while the expression level of GPX4 protein was significantly decreased （P<0.05）； compared with SOR group， the expression levels of ACSL4 protein in the cells in SOR+QSYQ group and SOR+Fer-1 group were significantly decreased （P<0.05）， while the expression levels of GPX4 protein were significantly increased （P<0.05）. Conclusion ?QSYQ dropping pill can alleviate SOR-induced myocardial injury in the rats， and its mechanism may be related to the inhibition of ferroptosis in cardiomyocytes.

Key words: Qishen Yiqi dropping pill, Sorafenib, Ferroptosis, Myocardium injury, Oxidative stress

CLC Number:

R285.5

Zheng TANG,Wei LIU,Hongmin HU,Qi LAI,Yan SHI,Shengquan LIU,Jun YANG,Chun CHU. Improvement effect of Qishen Yiqi dropping pills on myocardium injury in rats induced by sorafenib and its mechanism[J].Journal of Jilin University(Medicine Edition), 2026, 52(2): 308-317.

Figures/Tables 9

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References 29

[1]	VIRANI S A， DENT S， BREZDEN-MASLEY C， et al. Canadian cardiovascular society guidelines for evaluation and management of cardiovascular complications of cancer therapy［J］. Can J Cardiol， 2016， 32（7）： 831-841.
[2]	KONG F H， YE Q F， MIAO X Y， et al. Current status of sorafenib nanoparticle delivery systems in the treatment of hepatocellular carcinoma［J］. Theranostics， 2021， 11（11）： 5464-5490.
[3]	BRIELER J， BREEDEN M A， TUCKER J. Cardiomyopathy： An overview［J］. Am Fam Physician， 2017， 96（10）： 640-646.
[4]	CHAAR M， KAMTA J， AIT-OUDHIA S. Mechanisms， monitoring， and management of tyrosine kinase inhibitors-associated cardiovascular toxicities［J］. Onco Targets Ther， 2018， 11： 6227-6237.
[5]	SCHLITT A， JORDAN K， VORDERMARK D， et al. Cardiotoxicity and oncological treatments［J］. Dtsch Arztebl Int， 2014， 111（10）： 161-168.
[6]	ABDEL-RAHMAN O， FOUAD M. Risk of cardiovascular toxicities in patients with solid tumors treated with sorafenib： an updated systematic review and meta-analysis［J］. Future Oncol， 2014， 10（12）： 1981-1992.
[7]	DIXON S J， LEMBERG K M， LAMPRECHT M R， et al. Ferroptosis： an iron-dependent form of nonapoptotic cell death［J］. Cell， 2012， 149（5）： 1060-1072.
[8]	GUO L L， HU C T， YAO M W， et al. Mechanism of sorafenib resistance associated with ferroptosis in HCC［J］. Front Pharmacol， 2023， 14： 1207496.
[9]	刘洋，贾孟晓，赵婷，等. 基于UPLC-Q-Exactive Orbitrap-MS和网络药理学的芪参益气滴丸治疗心肌缺血的配伍机制研究［J］. 中国中药杂志， 2024， 49（14）： 3769-3783.
[10]	CHEN J R， WEI J， WANG L Y， et al. Cardioprotection against ischemia/reperfusion injury by QiShenYiQi Pill^® via ameliorate of multiple mitochondrial dysfunctions［J］. Drug Des Devel Ther， 2015， 9： 3051-3066.
[11]	WU L L， FAN Z Y， GU L F， et al. QiShenYiQi dripping pill alleviates myocardial ischemia-induced ferroptosis via improving mitochondrial dynamical homeostasis and biogenesis［J］. J Ethnopharmacol， 2023， 308： 116282.
[12]	詹玲君，秦伟彬，何贵新，等. 基于mitoKATP/PI3K/mTOR探讨芪参益气滴丸影响H9C2心肌细胞损伤后钙稳态及炎性环境的机制［J］. 时珍国医国药， 2023， 34（9）： 2087-2090.
[13]	BALACHANDRAN L， HAW T J， LEONG A J W， et al. Cancer therapies and cardiomyocyte viability： Which drugs are directly cardiotoxic？［J］. Heart Lung Circ， 2024， 33（5）： 747-752.
[14]	TANG W W， CHEN Z Y， ZHANG W L， et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma： theoretical basis and therapeutic aspects［J］. Signal Transduct Target Ther， 2020， 5（1）： 87.
[15]	LI Z X， YU Y J， BU Y， et al. QiShenYiQi pills preserve endothelial barrier integrity to mitigate sepsis-induced acute lung injury by inhibiting ferroptosis［J］. J Ethnopharmacol， 2024， 322： 117610.
[16]	HUANG Y T， ZHANG K， LIU M， et al. An herbal preparation ameliorates heart failure with preserved ejection fraction by alleviating microvascular endothelial inflammation and activating NO-cGMP-PKG pathway［J］. Phytomedicine， 2021， 91： 153633.
[17]	胡越，阮益莉，龚子莹，等. 基于网络药理学和实验验证探讨芪参益气滴丸预防心肌缺血再灌注损伤的机制［J］. 中药药理与临床， 2025， 41（4）： 61-67.
[18]	ZHANG S Y， WANG H， LI L X， et al. Qishen Yiqi Drop Pill， a novel compound Chinese traditional medicine protects against high glucose-induced injury in cardiomyocytes［J］. J Cell Mol Med， 2019， 23（9）： 6393-6402.
[19]	刘耀武. 四逆汤联合溶栓治疗急性心肌梗死缺血再灌注损伤及对患者动态心电图和SOD、CK-MB、LDH的影响［J］. 陕西中医， 2019， 40（7）： 858-860.
[20]	刘满义. 心脏彩超联合血清心肌损伤标志物诊断急性心肌梗死的价值分析［J］. 临床研究， 2020， 28（10）： 146-148.
[21]	JIANG X J， STOCKWELL B R， CONRAD M. Ferroptosis： mechanisms， biology and role in disease［J］. Nat Rev Mol Cell Biol， 2021， 22（4）： 266-282.
[22]	WU X G， LI Y， ZHANG S C， et al. Ferroptosis as a novel therapeutic target for cardiovascular disease［J］. Theranostics， 2021， 11（7）： 3052-3059.
[23]	WANG B Q， WANG Y， ZHANG J， et al. ROS-induced lipid peroxidation modulates cell death outcome： mechanisms behind apoptosis， autophagy， and ferroptosis［J］. Arch Toxicol， 2023， 97（6）： 1439-1451.
[24]	MA W Z， LIU M， LIANG F F， et al. Cardiotoxicity of sorafenib is mediated through elevation of ROS level and CaMKII activity and dysregulation of calcium homoeostasis［J］. Basic Clin Pharmacol Toxicol， 2020， 126（2）： 166-180.
[25]	WANG C， ZENG J， LI L J， et al. Cdc25A inhibits autophagy-mediated ferroptosis by upregulating ErbB2 through PKM2 dephosphorylation in cervical cancer cells［J］. Cell Death Dis， 2021， 12（11）： 1055.
[26]	JIANG H， WANG C， ZHANG A， et al. ATF4 protects against sorafenib-induced cardiotoxicity by suppressing ferroptosis［J］. Biomed Pharmacother， 2022， 153： 113280.
[27]	王新羽，张霖柯，符艾青，等. 铁死亡在心血管疾病中的研究进展［J］. 中国现代医学杂志， 2022， 32（17）： 61-66.
[28]	TANG D L， CHEN X， KANG R， et al. Ferroptosis： molecular mechanisms and health implications［J］. Cell Res， 2021， 31（2）： 107-125.
[29]	STOCKWELL B R， FRIEDMANN ANGELI J P， BAYIR H， et al. Ferroptosis： a regulated cell death nexus linking metabolism， redox biology， and disease［J］. Cell， 2017， 171（2）： 273-285.

Group	n	CK-MB
Control	10	505.28±119.20
SOR	7	1 930.00±467.90^*
SOR+QSYQ	8	1 072.72±272.60^△
SOR+Fer-1	9	789.97±184.50^△

Group	LVEF（η/%）	LVFS（η/%）	Cardiac index [ω_B/（mg·g^-1）]
Control	85.40±3.58	49.80±4.66	2.65±0.18
SOR	74.00±4.85^*	38.00±4.30^*	3.04±0.50
SOR+QSYQ	82.80±5.93^△	46.80±7.29	2.90±0.14
SOR+Fer-1	84.40±4.51^△	47.00±6.36	2.86±0.60

Group	Fe²⁺ [m_B/（μmol·g^-1）]	MDA [m_B/（μmol·g^-1）]	GSH [m_B/（μmol·g^-1）]	ROS
Control	16.38±8.05	3.40±1.05	13.31±4.24	30.26±2.32
SOR	33.51±4.67^*	6.76±1.80^*	3.00±2.55^*	53.07±8.14^*
SOR+QSYQ	17.09±6.40^△	5.24±1.16	11.53±5.00^△	34.05±4.45^△
SOR+Fer-1	23.11±4.61^△	5.16±1.41	11.34±3.88^△	43.63±7.05^△

Improvement effect of Qishen Yiqi dropping pills on myocardium injury in rats induced by sorafenib and its mechanism

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